Clinical Anesthesia

Editors: Barash, Paul G.; Cullen, Bruce F.; Stoelting, Robert K.
Title: Cl i ni cal Anest hesi a, 5t h Edi t i on

Copyri ght 2006 Li ppi ncott Wil l iams & Wil ki ns
> Front of Book > Dedi cati on
Dedication
THIS EDITION OF CLINICAL ANESTHESIA IS DEDICATED TO THE MEMORY AND SPIRIT OF
DANIEL BERNARD BARASH
> Front of Book > Edi tors
Edited By
Paul G. Barash MD
Professor
Department of Anesthesi ol ogy, Yal e University School of Medi cine, Attendi ng Anesthesi ol ogi st,
Yal eNew Haven Hospital, New Haven, Connecticut
Bruce F. Cullen MD
Professor
Department of Anesthesi ol ogy, Uni versi ty of Washi ngton School of Medici ne, Attending
Anesthesi ol ogi st, Harborvi ew Medi cal Center, Seattl e, Washi ngton
Robert K. Stoelting MD
Emeritus Professor and Chai r
Department of Anesthesi a, Indiana Uni versi ty School of Medici ne, Indi anapoli s, Indi ana
Secondary Editors
Brian Brown
Acquisi ti ons Edi tor
Grace Caputo
Developmental Edi tor
Dovetail Content Solutions
Dave Murphy
Producti on Editor
Ben Rivera
Manufacturi ng Manager
Doug Smock
Creati ve Di rector
Joseph DePinho
Cover Desi gner
Compositor: TechBooks
Printer: Courier-Westford
Contributing Authors
Stephen E. Abram MD
Professor
Department of Anesthesi ol ogy, Medi cal Col l ege of Wi sconsi n, Staff Anesthesi ologist, Froedtert
Memori al Hospital, Mil waukee, Wi sconsin
J. Jeffrey Andrews MD
Professor and Vice-Chai r for Education
Department of Anesthesi ol ogy, Uni versi ty of Al abama School of Medici ne, Birmi ngham, Al abama
Douglas R. Bacon MD, MA
Professor of Anesthesi ol ogy and Medi cal Hi story
Mayo Cl i ni c Coll ege of Medici ne, Consultant Anesthesiologist, Mayo Cl ini c, Rochester, Mi nnesota
Robert L. Barkin MBA, PharmD, FCP
Rush Uni versi ty Medi cal Col lege, Cli ni cal Pharmacol ogi st, Rush Pai n Center, Chi cago, Ill i noi s,
Cli nical Pharmacol ogi st, The Rush North Shore Pai n Center, Skoki e, Il li noi s
Audre A. Bendo MD
Professor and Vice Chair for Educati on
Department of Anesthesi ol ogy, State Uni versi ty of New York, Downstate Medi cal Center, Brookl yn,
New York
Christopher M. Bernards MD
Vi rgi nia Mason Medi cal Center, Cli ni cal Professor, Department of Anesthesi ology, Uni versity of
Washi ngton, Staff Anesthesi ol ogi st, Seattl e, Washi ngton
Arnold J. Berry MD, MPH
Professor
Department of Anesthesi ol ogy, Emory University, Staff Anesthesi ologist, Emory Uni versi ty
Hospi tal , Atl anta, Georgi a
Frederic A. Berry MD
Professor Emeritus of Pedi atrics and Anesthesi ol ogy
Department of Anesthesi ol ogy, The Uni versi ty of Virginia, Charlottesvi ll e, Vi rgi ni a
David R. Bevan MB
Professor and Chai r
Department of Anesthesi a, Uni versi ty of Toronto, Anesthesi ologist-i n-Chi ef, Uni versi ty Heal th
Network, Toronto, Ontari o, Canada
Barbara W. Brandom MD
Professor
Department of Anesthesi ol ogy, Uni versi ty of Pi ttsburgh, Attending Physi ci an, Department of
Anesthesi ol ogy, Chil dren' s Hospi tal of Pi ttsburgh, Pi ttsburgh, Pennsyl vani a
Ferne R. Braverman MD
Professor
Department of Anesthesi ol ogy, Di rector, Secti on of Obstetri c Anesthesi ology, Yal e Uni versi ty
School of Medici ne, New Haven, Connecticut
Russell C. Brockwell MD
Associ ate Professor
Uni versi ty of Al abama School of Medi cine, Chief of Anesthesi ology Bi rmi ngham Veterans Affai rs
Medi cal Center, Birmi ngham, Alabama
Levon M. Capan MD
Professor of Anesthesi ol ogy
Department of Anesthesi ol ogy, New York Uni versi ty School of Medici ne, Associate Di rector,
Department of Anesthesi ol ogy, Bel levue Hospi tal Center, New York, New York
Barbara A. Castro MD
Associ ate Professor of Anesthesi ol ogy and Pedi atri cs
Uni versi ty of Vi rgi ni a School of Medici ne, Uni versi ty of Vi rgi ni a Heal th System, Charlottesvi ll e,
Vi rgi nia
Frederick W. Cheney Jr. MD
Department of Anesthesi ol ogy, Uni versi ty of Washi ngton School of Medici ne, Attending
Anesthesi ol ogi st, Uni versi ty of Washi ngton Medical Center, Seattle, Washi ngton
Barbara A. Coda MD
Cli nical Associ ate Professor
Department of Anesthesi ol ogy, Uni versi ty of Washi ngton School of Medici ne, Seattl e, Washington,
Staff Anesthesi ol ogi st, McKenzi e Anesthesi a Group, McKenzi e-Wil l amette Hospi tal , Spri ngfi eld,
Oregon
Edmond Cohen MD
The Mount Si nai School of Medi cine, Di rector of Thoraci c Anesthesi a, The Mount Si nai Medi cal
Center, New York, New York
James E. Cottrell MD
Professor and Chai rman
Department of Anesthesi ol ogy, State Uni versi ty of New York, Downstate Medi cal Center, Brookl yn,
New York
Joseph P. Cravero MD
Associ ate Professor of Anesthesi ol ogy
Dartmouth Hitchcock Medical Center, Lebanon, New Hampshi re
C. Michael Crowder MD, PhD
Associ ate Professor of Anesthesi ol ogy and Molecul ar Bi ol ogy/Pharmacol ogy
Washi ngton Uni versity School of Medici ne, Attendi ng Anesthesi ologist, Di vi si on of
Neuroanesthesi a, Barnes-Jewi sh Hospi tal , St. Louis, Mi ssouri
Marie Csete MD, PhD
Associ ate Professor and John E. Steinhaus Professor of Anesthesi ology
Emory University, Director, Liver Transpl ant Anesthesiology, Department of Anesthesi ol ogy, Emory
Uni versi ty Hospi tal , Atl anta, Georgi a
Anthony J. Cunningham MD
Professor/Cl i ni cal Vi ce Dean
Department of Anaesthesi a, Royal Col l ege of Surgeons i n Irel and, Consul tant and Professor,
Department of Anaesthesi a, Beaumont Hospi tal , Dubl in, Irel and
Jacek B. Cywinski MD
Department of General Anesthesi ol ogy, The Clevel and Cl i ni c Foundation, Cl evel and, Ohi o
Steven Deem MD
Associ ate Professor of Anesthesi ol ogy and Medi ci ne (Adjunct, Pul monary and Cri ti cal Care)
Uni versi ty of Washington, Harborvi ew Medi cal Center, Seattl e, Washi ngton
Stephen F. Dierdorf MD
Professor
Department of Anesthesi a, Medi cal Uni versi ty of South Carol ina, Charleston, South Carol i na
Franois Donati PhD, MD, FRCPC
Professor
Department of Anesthesi ol ogy, Uni versi ty of Montreal, Staff Anesthesi ologist, Hospi tal
Mai sonneuve-Rosemont, Montreal, Quebec, Canada
John C. Drummond MD, FRCPC
Uni versi ty of Cal i forni a, San Di ego, Staff Anesthesi ologist, VA Medical Center, San Di ego, La Joll a,
Cal i fornia
Thomas J. Ebert MD, PhD
Professor
Department of Anesthesi ol ogy, Medi cal Col l ege of Wi sconsi n, Staff Anesthesi ologist, VA Medical
Center, Mi l waukee, Wi sconsin
Jan Ehrenwerth MD
Professor
Department of Anesthesi ol ogy, Yal e University School of Medi cine, Attendi ng Anesthesi ol ogi st,
John H. Eichhorn MD
Professor
Department of Anesthesi ol ogy, Uni versi ty of Kentucky Col l ege of Medici ne, Department of
Anesthesi ol ogy, UK Chandler Medical Center, Lexi ngton, Kentucky
James B. Eisenkraft MD
Mount Si nai School of Medici ne, Attendi ng Anesthesiol ogi st, The Mount Si nai Hospi tal , New York,
New York
John E. Ellis MD
Professor
Department of Anesthesi a and Criti cal Care, Pri tzker School of Medici ne, The University of
Chi cago, Secti on Chi ef, Anesthesi a for Vascul ar, Thoracic, and General Surgery, Uni versi ty of
Chi cago Hospi tal s, Chicago, Il l inoi s
Alex S. Evers MD
Henry E. Mal l i nckrodt Professor and Chai rman
Department of Anesthesi ol ogy, Washi ngton Uni versi ty School of Medici ne, Anesthesi ol ogi st-in-
Chi ef, Barnes-Jewi sh Hospi tal , St. Loui s, Missouri
Lynne R. Ferrari MD
Associ ate Professor of Anesthesi ol ogy
Harvard Medi cal School , Medi cal Director, Peri operative Servi ces, Department of Anesthesi a,
Peri operative and Pain Medi ci ne, Chi l dren' s Hospital, Boston, Massachusetts
Mieczyslaw Finster MD
Professor of Anesthesi ol ogy and Obstetri cs and Gynecol ogy
Col umbi a Uni versi ty Coll ege of Physi cians and Surgeons, New York Presbyteri an Hospi tal , New
York, New York
Jeffrey E. Fletcher PhD
Cl i ni cal Publ i cati ons Lead
Medi cal Communi cations, AstraZeneca, Wil mington, Del eware
J. Sean Funston MD
Assi stant Professor
Department of Anesthesi ol ogy, Uni versi ty of Texas Medical Branch, Gal veston, Texas
Steven I. Gayer MD, MBA
Departments of Anesthesiology and Ophthal mol ogy, Uni versi ty of Miami Mi l ler School of Medi cine,
Di rector of Anesthesi a Servi ces, Bascom Pal mer Eye Insti tute, Mi ami , Fl orida
Kathryn Glas MD
Department of Anesthesi ol ogy, Associ ate Director, Cardiothoracic Anesthesi ology, Di rector, Intra-
Operative Echo Service, Emory Uni versi ty School of Medici ne, Atl anta, Georgi a
Alexander W. Gotta MD
Emeritus Professor of Anesthesi ol ogy
State Uni versi ty of New York, Downstate Medi cal Center, Brooklyn, New York
John Hartung PhD
Associ ate Editor
Journal of Neurosurgi cal Anesthesi ol ogy, State University of New York, Brookl yn, New York
Tara M. Hata MD
Department of Anesthesi a, Uni versi ty of Iowa, Roy J. and Luci l l e A. Carver Col l ege of Medi ci ne,
Uni versi ty of Iowa Hospi tals and Clinics, Iowa City, Iowa
Laurence M. Hausman MD
Department of Anesthesi ol ogy, Mount Si nai School of Medici ne, Vi ce Chai r, Academi c Affi l iations,
Department of Anesthesi ol ogy, Mount Si nai Hospi tal , New York, New York
Thomas K. Henthorn MD
Department of Anesthesi ol ogy, Uni versi ty of Col orado Heal th Sci ences Center, Denver, Col orado
Simon C. Hillier MB, ChB
Department of Anesthesi a, Indiana Uni versi ty School of Medici ne, Staff Anesthesi ologist, Ri ley
Hospi tal for Chi l dren, Indi anapoli s, Indi ana
Terese T. Horlocker MD
Professor
Departments of Anesthesiology and Orthopedi cs, Mayo Cl i ni c Coll ege of Medici ne, Rochester,
Mi nnesota
Robert J. Hudson MD, FRCPC
Cl i ni cal Professor
Department of Anesthesi ol ogy and Pai n Medi ci ne, Uni versity of Alberta, Attendi ng
Anesthesi ol ogi st, Uni versi ty of Al berta Hospi tal s, Edmonton, Alberta, Canada
Anthony D. Ivankovitch MD
Department of Anesthesi ol ogy, Rush Uni versi ty Medi cal Center, Chi cago, Ill i noi s
Joel O. Johnson MD, PhD
Department of Anesthesi ol ogy, Uni versi ty of Mi ssouri -Col umbi a Hospi tal s and Cl i ni cs, Col umbi a,
Mi ssouri
Raymond S. Joseph Jr. MD
Staff Anesthesi ol ogi st
Vi rgi ni a Mason Medi cal Center, Seattl e, Washi ngton
Zeev N. Kain MD, MBA
Professor and Executi ve Vi ce-Chai rman
Department of Anesthesi ol ogy, Yal e University School of Medi cine, Anesthesi ol ogi st-i n-Chi ef, Yal e
New Haven Chi ldren' s Hospi tal , New Haven, Connecticut
Ira S. Kass MD
Professor
Departments of Anesthesiology, Physiology, and Pharmacology, Downstate Medi cal Center,
Brookl yn, New York
Jonathan D. Katz MD
Cli nical Professor of Anesthesi ol ogy
Yal e Universi ty School of Medi cine, New Haven, Connecticut
Brian S. Kaufman MD
Departments of Anesthesiology, Medi ci ne, and Neurosurgery, New York Universi ty School of
Medi ci ne, Co-Di rector, Criti cal Care, Ti sch Hospital, New York, New York
Charbel A. Kenaan MD
Chi ef Resi dent i n Anesthesi ol ogy
Department of Anesthesi ol ogy, Peri operati ve Medi ci ne, and Pai n Management, Jackson Memorial
Hospi tal , University of Mi ami Mi ll er School of Medici ne, Mi ami , Florida
Donald A. Kroll MD, PhD
Staff Anesthesi ol ogi st
Veterans Affai rs Medi cal Center, Bil oxi , Mississippi
Carol L. Lake MD, MBA, MPH
CEO
Verefi Technol ogi es, Inc., El izabethtown, Pennsyl vani a
Noel W. Lawson MD
Professor
Department of Anesthesi ol ogy, Uni versi ty of Mi ssouri -Col umbi a, Staff Anesthesi ologist, University
of Missouri -Col umbi a Hospi tal s and Cl ini cs, Columbi a, Missouri
Wilton C. Levine MD
Instructor in Anesthesia
Harvard Medi cal School , Department of Anesthesi a and Cri ti cal Care, Massachusetts General
Hospi tal , Boston, Massachusetts
Jerrold H. Levy MD
Professor and Deputy Chair of Research
Department of Anesthesi ol ogy, Emory University School of Medici ne, Di rector of Cardi othoraci c
Anesthesi ol ogy Emory Heal thcare, Atl anta, Georgi a
Adam D. Lichtman MD
Assi stant Professor of Anesthesiology
Department of Anesthesi ol ogy, Weil l Cornell Medi cal Center, New York Presbyterian Hospi tal , New
York, New York
J. Lance Lichtor MD
Professor
Department of Anesthesi a, Uni versity of Iowa, Iowa City, Iowa
Spencer S. Liu MD
Cli nical Professor of Anesthesi ol ogy
Department of Anesthesi ol ogy, Uni versi ty of Washi ngton, Staff Anesthesi ologist, Department of
Anesthesi ol ogy, Virgini a Mason Medical Center, Seattle, Washi ngton
Richard L. Lock MD
Department of Anesthesi ol ogy, Uni versi ty of Kentucky Col l ege of Medici ne, Uni versi ty of Kentucky
Chandl er Medi cal Center, Lexington, Kentucky
David A. Lubarsky MD, MBA
Emanuel M. Papper Professor and Chai r
Department of Anesthesi ol ogy, Peri operati ve Medici ne, and Pai n Management, University of Mi ami
Mi l l er School of Medi cine, Chief of Service, Department of Anesthesi ol ogy, Jackson Memorial
Hospi tal , Mi ami, Fl ori da
Timothy R. Lubenow MD
Rush Medi cal Coll ege, Di rector, Secti on of Pai n Medi cine, Department of Anesthesi ol ogy, Rush
Uni versi ty Medical Center, Chi cago, Il l inoi s
Srinivas Mantha MD
Department of Anesthesi ol ogy and Intensive Care, Sub-Dean, Ni zam' s Insti tute of Medical
Sci ences, Hyberabad, Indi a
Joseph P. Mathew MD
Department of Anesthesi ol ogy, Chi ef, Di visi on of Cardi othoraci c Anesthesi a, Duke Uni versi ty
Medi cal Center, Durham, North Caroli na
Michael S. Mazurek MD
Assi stant Professor of Cl ini cal Anesthesia
Department of Anesthesi a, Indiana Uni versi ty School of Medici ne, Staff Anesthesi ologist, Ri ley
Hospi tal for Chi l dren, Indi anapoli s, Indi ana
Kathryn E. McGoldrick MD
Department of Anesthesi ol ogy, New York Medi cal Col lege, Director, Department of Anesthesi ol ogy,
Westchester Medical Center, Val hall a, New York
Roger S. Mecca MD
Chai rman
Department of Anesthesi ol ogy, Danbury Hospi tal, Danbury, Connecticut, Cli nical Associ ate
Professor of Anesthesi ol ogy, New York Medical Coll ege, New York, New York
Sanford M. Miller MD
Cli nical Associ ate Professor
New York University School of Medi ci ne, Assi stant Di rector of Anesthesi ology, Bel l evue Hospital
Center, New York, New York
Terri G. Monk MD, MS
Professor
Department of Anesthesi ol ogy, Duke Uni versi ty Medi cal Center, Facul ty, Department of
Anesthesi a, VA Hospi tal , Durham, North Caroli na
John R. Moyers MD
Professor
Department of Anesthesi a, Uni versi ty of Iowa, Roy J. and Luci l l e A. Carver Col l ege of Medi ci ne,
Uni versi ty of Iowa Hospi tals and Clinics, Iowa City, Iowa
Michael F. Mulroy MD
Cl i ni cal Professor
Department of Anesthesi ol ogy, Uni versi ty of Washi ngton School of Medici ne, Staff
Anesthesi ol ogi st, Department of Anesthesi ol ogy, Virginia Mason Medical Center, Seattl e,
Washi ngton
Stanley Muravchick MD, PhD
Professor
Department of Anesthesi a, Uni versi ty of Pennsylvania School of Medici ne, Vi ce Chai r for Cl i ni cal
Operations, Department of Anesthesia, Hospi tal of the Uni versity of Pennsyl vani a, Phi ladel phi a,
Pennsyl vani a
Glenn S. Murphy MD
Department of Anesthesi ol ogy, Fei nberg School of Medi ci ne, Northwestern Uni versi ty, Di rector,
Cardi ac Anesthesia, Department of Anesthesi ology, Evanston Northwestern Heal thcare, Evanston,
Il l inoi s
Michael J. Murray MD, PhD
Department of Anesthesi ol ogy, Mayo Cl i ni c Coll ege of Medici ne, Jacksonvi l le, Fl ori da
Steven M. Neustein MD
Department of Anesthesi ol ogy, Mount Si nai School of Medici ne, Attendi ng Anesthesi ol ogi st, Mount
Si nai Hospi tal , New York, New York
Cathal Nolan MB
Lecturer i n Anaesthesi a
Department of Anaesthesi a, Beaumont Hospi tal , Royal Col l ege of Surgeons i n Irel and, Dubli n,
Ireland
Babatunde O. Ogunnaike MD
Di rector of Anesthesi a Surgical Servi ces, Parkl and Memorial Hospi tal , Department of
Anesthesi ol ogy and Pain Management, Southwestern Medical School , Dal las, Texas
Jerome F. O'Hara Jr. MD
Associ ate Professor Head
Section of Urol ogi cal Anesthesiol ogy, Department of General Anesthesi ology, Cl evel and Cl i ni c
Foundati on, Cl eveland, Ohi o
Charles W. Otto MD, FCCM
Associ ate Professor of Medi ci ne, Uni versi ty of Arizona Col l ege of Medici ne, Director of Cri tical Care
Medi cine, Department of Anesthesi ology, Ari zona Heal th Sciences Center, Tucson, Arizona
Nathan Leon Pace MD, MStat
Professor
Department of Anesthesi ol ogy, Uni versi ty of Utah, Staff Anesthesi ologist, University of Utah
Heal th Sci ences Center, Sal t Lake Ci ty, Utah
Charise T. Petrovitch MD
George Washi ngton Universi ty, Washi ngton, DC
Mihai V. Podgoreanu MD
Department of Anesthesi ol ogy, Duke Uni versi ty Medi cal Center, Durham VA Hospi tal , Durham,
North Caroli na
Karen L. Posner PhD
Research Associ ate Professor
Department of Anesthesi ol ogy, Uni versi ty of Washi ngton, Seattle, Washington
Donald S. Prough MD
J. David Roccaforte MD
Department of Anesthesi ol ogy, New York Uni versi ty, Co-Director, SICU, Bell evue Hospi tal Center,
New York, New York
Michael F. Roizen MD
Professor and Chai rman
Di visi on of Anesthesiol ogy, Cri tical Care Medici ne, and Comprehensi ve Pai n Management,
Clevel and Cli ni cal Foundation, Cl eveland, Ohio
Gladys Romero MD
Visi ti ng Assi stant Professor
Department of Anesthesi ol ogy and Pai n Management, University of Texas Southwestern Medi cal
Center, Dal l as, Texas
Stanley H. Rosenbaum MD
Internal Medi ci ne, and Surgery, Vi ce Chai rman for Academic Affai rs, Department of
Anesthesi ol ogy, Yal e Uni versity School of Medici ne, Director of Peri operati ve and Adult Anesthesia,
Henry Rosenberg MD
Mount Si nai School of Medici ne, New York, New York, Director, Department of Medi cal Educati on
and Cl ini cal Research, Sai nt Barnabas Medi cal Coll ege, Li vingston, New Jersey
Meg A. Rosenblatt MD
Department of Anesthesi ol ogy, Di rector of Orthopedi c and Regi onal Anesthesi a, Mount Si nai School
of Medi ci ne, New York, New York
William H. Rosenblatt MD
Professor of Anesthesi a and Surgery
Yal e Universi ty School of Medi cine, Attending Physi ci an, Department of Anesthesi ology, YaleNew
Haven Hospital , New Haven, Connecticut
Carl E. Rosow MD, PhD
Professor
Department of Anaesthesi a, Harvard Medi cal School , Anesthetist, Department of Anesthesi a and
Cri tical Care, Massachusetts General Hospital, Boston, Massachusetts
Nyamkhishig Sambuughin PhD
Seni or Bi ologist
Cli nical Neurogeneti cs Uni t, Nati onal Institute of Neurol ogi cal Di sorders and Stroke, National
Insti tute of Heal th, Bethesda, Maryl and
Alan C. Santos MD, MPH
Chai rman of Anesthesiology
Ochsner Cl i ni c Foundati on, New Orl eans, Loui si ana
Jeffrey J. Schwartz MD
Department of Anesthesi ol ogy, Yal e University School of Medi cine, Attendi ng Physici an, YaleNew
Haven Hospital , New Haven, Connecticut
Margaret L. Schwarze
Cli nical Associ ates
Vascul ar Surgery, Uni versi ty of Chi cago, Chi cago, Il l inoi s
Harry A. Seifert MD, MSCE
Adjunct Assistant Professor of Cli nical Anesthesi ol ogy
Department of Anesthesi ol ogy and Criti cal Care, Chi l dren' s Hospital of Phi l adel phi a, Adjunct
Assistant Professor of Epi demi ol ogy, Department of Bi ostati sti cs and Epi demi ol ogy, Uni versi ty of
Pennsyl vani a School of Medici ne, Phi l adel phi a, Pennsyl vani a
Aarti Sharma MD
Department of Anesthesi ol ogy, Assi stant Di rector of Pedi atri c Anesthesi a, Wei ll Cornel l Medi cal
Center, New York Presbyterian Hospi tal , New York, New York
Nikolaos Skubas MD
Department of Anesthesi ol ogy, Weil l Cornell Medi cal Center, New York Presbyterian Hospi tal , New
York, New York
Hugh M. Smith MD, PhD
Resi dent
Department of Anesthesi ol ogy, Mayo Cl i ni c Coll ege of Medi ci ne, Mayo Cl i ni c, Rochester, Mi nnesota
Karen J. Souter MBBS, MSc, FRCA
Department of Anesthesi a, Uni versi ty of Washington Medi cal Center, Seattle, Washi ngton
M. Christine Stock MD, FCCM, FACP
James E. Eckenhoff Professor and Chair
Department of Anesthesi ol ogy, Fei nberg School of Medi ci ne, Northwestern Uni versi ty, Chi cago,
Il l inoi s
Christer H. Svensn MD, PhD, DEAA, MBA
Stephen J. Thomas MD
Topki n-Van Poznak Professor and Vice-Chai r
Department of Anesthesi ol ogy, Weil l Medical Col l ege of Cornel l Universi ty, New York Presbyteri an
Hospi tal , New York, New York
Miriam M. Treggiari MD, MPH
Department of Anesthesi ol ogy, Uni versi ty of Washi ngton School of Medici ne, Harborvi ew Medi cal
Center, Seattl e, Washi ngton
Jeffery S. Vender MD, FCCM, FCCP
Professor
Department of Anesthesi ol ogy, Fei nberg School of Medi ci ne, Northwestern Uni versi ty, Chai rman,
Department of Anesthesi ol ogy, Evanston Northwestern Heal thcare, Evanston, Ill i nois
J. Scott Walton MD
Department of Anesthesi a, Medi cal Uni versi ty of South Carol ina, Charleston, South Carol i na
Mark A. Warner MD
Department of Anesthesi ol ogy, Mayo Cl i ni c Coll ege of Medici ne, Rochester, Mi nnesota
Denise J. Wedel MD
Mayo Cl i ni c Coll ege of Medici ne, Rochester, Minnesota
Paul F. White PhD, MD, FANZCA
Professor and Holder of the Margaret Mi l am McDermott Disti ngui shed Chair
Department of Anesthesi ol ogy and Pai n Management, University of Texas Southwestern Medi cal
Center, Dal l as, Texas
Charles W. Whitten MD
Professor and Vice Presi dent of Resident Affairs
M.T. Pepper Jenki ns Professor i n Anesthesi ol ogy, Department of Anesthesi ology and Pai n
Management, Uni versi ty of Texas Southwestern Medi cal Center, Dall as, Texas
Scott W. Wolf MD
James R. Zaidan MD, MBA
Department of Anesthesi ol ogy, Associ ate Dean for GME, Emory Universi ty School of Medi cine,
Atl anta, Georgi a
> Front of Book > Preface
Preface
Transformation in the del i very of pati ent care, combined wi th changes in educati on, i s the new
paradi gm for anesthesi ol ogy i n the 21st century. Mi ni mi zi ng costs whil e i mproving effici ency and
enhanci ng patient safety are the goal s of contemporary anesthesi a practi ce. To ensure that
practi ti oners have incorporated the most-up-to-date i nformati on i n thei r practi ce, certifying and
li censing authori ti es have mandated continual educati on and testi ng both at the trainee and at the
practi ci ng anesthesi ol ogi st level . These changes are coupled wi th the need for ongoing i nnovation
as the anesthesi ol ogi st conti nues to be chall enged to adapt cli nical management to new surgi cal
procedures and technol ogi es. These developments are an extension of the observati on we made i n
the fi rst editi on of Cli nical Anesthesi a: The major achi evements of modern surgery woul d not
have taken pl ace wi thout the accompanyi ng visi on of the pioneers in anesthesi ol ogy.
Anesthesi ol ogy i s recogni zed as the speci al ty that has done the most to ensure pati ent safety.
Despi te these advances, the speci alty' s own leadershi p, i n addi tion to outsi de agenci es, has
mandated further i mprovement. No l onger does the anesthesi ologi st have the l uxury of admi tti ng
the pati ent to the hospital a day or more before the surgical procedure and of performi ng a
lei surel y workup and preoperative assessment. In the ambul atory surgery uni t, for example, the
patient may be avai labl e only mi nutes before the operati on, and deci sions must be made
immedi ately as to adequacy of the preanesthetic evaluati on and treatment pl an. In the i npati ent
setti ng, care i s percei ved as bei ng even more fragmented. For example, the health care
professi onal performing the preoperative eval uati on may not be the caregi ver i n the operating
room. In the operati ng room, where costs can reach $40 to $50 per minute, producti on pressure
has been noted to get the case goi ng. Thi s occurs i n a setti ng of dimi ni shed resources,
equi pment, drugs, and personnel , wi th the si multaneous requirement to improve patient safety i n
the OR. Thus, the anesthesiol ogi st must have i nformati on i mmediately avai l abl e for the
appropri ate i ntegrati on of care in the preincisi on peri od. In fact, the Ameri can Board of
Anesthesi ol ogy, i n its Booklet of Informati on, emphasi zes the i mportance of thi s facet of cli ni cal
management by stati ng, The abil i ty to i ndependently acqui re and process i nformation i n a ti mel y
manner i s central to assure indi vi dual responsi bili ty for al l aspects of anesthesiol ogy care.
Simul taneous with these cl ini cal requirements are si gni fi cant changes in the educational process
for trai nees and establi shed practi oners. Responsibi l i ty and accountabil i ty for one' s educati on have
i ncreased. Certi fyi ng boards use a framework, such as Mai ntenance of Certi fi cation in
Anesthesi ol ogy (MOCA), to ensure that the practi ti oner is current in aspects of pati ent care. Thi s
concept is based on l ifel ong l earni ng, assessment of professi onal standi ng, assessment of cl i ni cal
practi ce performance, and a written exami nation testi ng cogni tive experti se. These changes
requi re a si gni fi cant shift in the manner in whi ch textbooks present knowl edge. Wi th the advent of
el ectronic publ ishi ng, cl i ni cians cannot rel y sol el y on a si ngle textbook to suppl y the answers to
a cl i ni cal conundrum or a board recertificati on questi on. As a resul t, Cli nical Anesthesi a remai ns
fai thful to i ts origi nal goal : To devel op a textbook that supports effici ent and rapid acqui si ti on of
knowl edge. However, to meet thi s objecti ve, the edi tors have al so devel oped a mul ti faceted,
systemati c approach to thi s target. Cli nical Anesthesi a serves as the foundation and reference
source for the other educati onal tool s in the Cl i ni cal Anesthesi a seri es: The Handbook of Cli ni cal
Anesthesi a, Cl inical Anesthesi a for the PDA, Revi ew of Cl i ni cal Anesthesia, and The Li ppi ncott
Interactive Anesthesi a Library on CD-ROM (LIAL). Each of these provides a bri dge to cl i ni cal care
and educati on.
To recogni ze these requi rements, in thi s the fi rst edi ti on of Cli nical Anesthesi a of the 21st
century, we have total ly redesigned the textbook, from i ts cover to chapter format and i nclusion
of new and rel evant materi al. To enhance access to i nformati on, as wel l as ali gn chapters with
contemporary educati onal goals, each chapter starts wi th a detai led outl ine and Key Points. To
meet the real iti es of the worl d we l i ve i n, we have added new chapters on di saster preparedness
and weapons of mass destructi on, genomics, obesi ty (bariatri c surgery), and offi ce-based
anesthesia. We have encouraged contri butors to devel op cl i ni cal l y rel evant themes and pri ori ti ze
vari ous cl i ni cal opti ons consi dered by many the defi ni tive strength of previous edi ti ons. In
addi ti on, each contri butor emphasi zes appli cabl e areas of i mportance to pati ent safety. On
occasion, redundancy between chapters may exi st. We have made every effort to reduce repeti tion
or even disagreement between chapters. Di fferent approaches to a cl inical problem also represent
the reali ties of consul tant-level anesthesi a practi ce, however, so thi s di versi ty i n approach
remai ns i n certain i nstances.
Fi nal ly, we wish to express our grati tude to the i ndi vi dual authors whose hard work, dedicati on,
and ti mel y submi ssi ons have expedi ted the producti on of the fi fth edi ti on. In addi ti on, we
acknowl edge the contri buti ons of col leagues and readers for thei r constructi ve comments. We al so
thank our secretari es, Gai l Norup, Ruby Wi lson and Deanna Walker, each of whom gave unsel fi shl y
of their time to faci li tate the edi tori al process. We woul d al so li ke to take this opportunity to
recognize the conti nui ng support of Li ppi ncott Wil l iams & Wi lkins. It was more than 25 years ago
that Lewis Reines, the former CEO of J.B. Li ppi ncott, recogni zed the need for a major American
anesthesi ol ogy textbook focused on educati on and cl ini cal care. Throughout the intervening years,
he has been a trusted coll eague, an advi sor, and, most importantl y, a fri end. In addi ti on, we have
been bl essed wi th executi ve edi tors who have made singul ar contri buti ons to the success of
Cli nical Anesthesi a: Susan Gay, Mary Kay Smith, and Crai g Percy. The enduri ng commitment to
excel l ence in medi cal publi shi ng conti nues from Li ppi ncott Wi l li ams & Wil ki ns with Bri an Brown,
Seni or Acqui si tions Edi tor, and Davi d Murphy, Producti on Manager, with the assistance of Grace
Caputo, Project Di rector, Dovetai l Content Sol uti ons, and Chri s Mi l l er, Project Manager,
TechBooks.
Paul G. Barash MD
Bruce F. Cul l en MD
Robert K. Stoel ti ng MD
> Tabl e of Contents > Secti on I - Introducti on to Anesthesi a Practi ce > Chapter 1 - The Hi story of Anesthesi a
Chapter 1
The History of Anesthesia
Hugh M. Smith
Douglas R. Bacon
KEY POINTS
Surgery without adequate pai n control may seem cruel to the modern reader, yet this was the
Anesthesi ol ogy i s a young speci al ty historicall y, especi al l y when compared to
surgery or i nternal medi ci ne.
Discoveri es i n anesthesi ol ogy have taken decades to bui l d upon the
observations and experi ments of many people, and i n some instances we are
stil l searchi ng. For example, the i deal volatil e anestheti c has yet to be
di scovered.
Regi onal anesthesia i s the di rect outgrowth of a chance observati on by an intern
who woul d go on to become a successful ophthalmol ogist.
Pai n medi ci ne began as an outgrowth of regi onal anesthesi a.
Much of our current anesthesia equipment i s the direct resul t of
anesthesi ol ogi sts bei ng unhappy wi th and needi ng better tool s to properl y
anesthetize pati ents.
Many safety standards have been establ i shed through the work of
anesthesiol ogi sts who were frustrated by the status quo.
Organizati ons of anesthesi a professi onal s have been cri ti cal i n establ i shi ng high
standards i n education and profi ci ency, which in turn has defi ned the speci al ty.
Respi ratory cri tical care medici ne started as the need by anesthesi ol ogi sts to
use posi ti ve pressure venti l ati on to hel p poli o vi cti ms.
Surgical anesthesia, and physi ci an special izati on in its admi ni strati on, has
al lowed for i ncreasingly complex operati ons to be performed on i ncreasi ngly il l
patients.
common practi ce throughout most of hi story. Whi le anesthesi a is considered a rel ati vel y new fi eld,
surgery predates recorded human hi story. Human skull trephi nati ons occurred as earl y as 10,000
BC, with archaeol ogi c evi dence of post-procedure bone i nfecti on and heal i ng, provi ng these
pri mi ti ve surgeries were performed on li vi ng humans. Jui ce from coca leaves may have been
dri bbled onto the scal p wound but the recipi ent of these procedures was almost certai nl y awake
whi l e a hole was bored i nto his or her skul l wi th a sharp flake of vol cani c gl ass. Thi s was a uni que
si tuati on i n anesthesi a; there are no other instances in which both the operator and hi s pati ent
share the effects of the same drug.
In contemporary practice, we are prone to forget the real i ti es of pre-anesthesi a surgery. Fanny
Burney, a wel l -known li terary artist from the early ni neteenth century, described a mastectomy
she endured after recei vi ng a wi ne cordial as her sol e anestheti c. As seven male assi stants hel d
her down, the surgery commenced: When the dreadful steel was pl unged i nto the breast-cutti ng
through vei ns-arteries-flesh-nerves-I needed no i njuncti on not to restrain my cri es. I began a
scream that l asted unintermi ttentl y duri ng the whol e time of the i nci si on& I al most marvel that
it rings not in my Ears sti ll ! So excruci ati ng was the agony. Oh Heaven!I then fel t the knife
racking agai nst the breast bone-scrapi ng i t! Thi s performed whil e I yet remai ned in utterl y
speechl ess torture.
1
Burney' s descri pti on remi nds us that it i s diffi cult to overstate the i mpact of

anesthesia on the human condi ti on. An epi taph on a monument to Wil l iam T. G. Morton, one of the
founders of anesthesi a, summari zes the contribution of anesthesia: BEFORE WHOM i n al l ti me
Surgery was Agony.
2
Al though most human ci vi li zations evol ved some method for di mi ni shi ng
patient discomfort, anesthesia, i n i ts modern and effecti ve meani ng, i s a comparatively recent
di scovery with traceable origi ns i n the mi d-ni neteenth century. How we have changed perspecti ves
from one in which surgical pai n was terri bl e and expected to one where patients may fairl y
presume they wi l l be safe, pai n free, and unaware during extensive operati ons is a fasci nating
story.
Anesthesi ol ogists are l ike no other physici ans: we are experts at control l ing the airway and at
emergency resuscitati on; we are real -ti me cardiopul monol ogi sts achi evi ng hemodynami c and
respiratory stabil i ty for the anestheti zed pati ent; we are pharmacol ogists and physi ol ogi sts,
cal cul ati ng appropri ate doses and desi red responses; we are gurus of postoperative care and
patient safety; we are interni sts performi ng peri anestheti c medi cal evaluati ons; we are the pai n
experts across al l medi cal di sci pl i nes and appl y speci al i zed techniques i n pai n cl i ni cs and l abor
wards; we manage the severel y si ck or injured i n criti cal care uni ts; we are neurol ogists,
sel ecti vely bl ocki ng sympatheti c, sensory, or motor functi ons wi th our regi onal techniques; we are
trai ned researchers expl ori ng scienti fic mystery and cl inical phenomenon.
Anesthesi ol ogy i s an amal gam of speci al i zed techni ques, equipment, drugs, and knowl edge that,
li ke the growth rings of a tree, have bui lt up over ti me. Current anesthesi a practi ce i s the
summati on of i ndi vi dual effort and fortui tous di scovery of centuri es. Every component of modern
anesthesia was at some poi nt a new di scovery and reflects the experi ence, knowl edge, and
inventi veness of our predecessors. Hi stori cal exami nation enables understanding of how these
i ndi vi dual components of anesthesi a evol ved. A knowledge of the hi story of anesthesi a enhances
our appreci ati on of current practice and intimates where our speci al ty might be headed.
ANESTHESIA BEFORE ETHER
Today, major surgery without adequate anesthesi a woul d be unthi nkabl e, and probabl y
consti tute grounds for malpractice li tigation. And yet thi s paradi gm, thi s way of seei ng
anesthesia as a necessary part of surgery, is a fai rl y recent development dati ng back onl y 160
years. Scholars have sought to expl ain the comparati vel y l ate arri val of anesthesi a. In addi tion to
li mi tati ons i n techni cal knowl edge, cul tural atti tudes toward pai n are often cited as reasons
humans endured centuri es of surgery wi thout effective anesthesi a. For example, i t i s known that
the Roman writer Celsi us encouraged pi til essness as an essential characteri sti c of the surgeon,
an attitude that prevai led for centuries. Whil e there i s some proof for thi s perspecti ve, cl oser
inspecti on reveals that most cultures were, in fact, sensi ti ve to the sufferi ng caused by surgi cal
operati ons and devel oped methods for lessening pain. Vari ous techni ques and pl ant-based agents
P.4
in many parts of the worl d were empl oyed to al ter consci ousness or as anal gesics. Examinati on of
the methods of managi ng pai n before ether anesthesi a is useful for what it i l lumi nates about the
hi stori cal roots and pri nci pal advances of our special ty.
P hysi cal and P sychol ogi cal Anest hesi a
The Edwin Smi th Surgi cal Papyrus, the ol dest known wri tten surgical document, descri bes 48
cases performed by an Egyptian surgeon from 3000 to 2500 BC. Whi le this remarkabl e surgical
treatise contai ns no direct mention of measures to lessen pati ent pai n or suffering, Egyptian
pi ctographs from the same era show a surgeon compressi ng a nerve i n a pati ent' s antecubi tal
fossa whi l e operati ng on the pati ent' s hand. Another i mage di spl ays a pati ent compressi ng hi s own
brachial pl exus whi le a procedure i s performed on hi s pal m.
3
In the si xteenth century, mi li tary
surgeon Ambroi se Par became adept at nerve compression as a means of creati ng anesthesi a.
Bui l ding upon the techni que of Par, James Moore described i n 1874 the combined use of nerve
compressi on and opium. In hi s book A Method of Preventi ng or Di mi ni shi ng Pain i n Several
Operations of Surgery, Moore descri bed a machi ne devised to appl y continuous pressure on nerves
and how, with the admi ni strati on of a grai n of opi um, surgi cal pai n mi ght be l essened. Surgeon
John Hunter used Moore' s techni que at St. Georges Hospi tal duri ng the amputati on of a l eg below
the knee fol l owing compressi on of the sci ati c and anteri or crural nerves.
4
The pai n control duri ng
the surgery was judged better than wi thout the techni que.
Medi cal science has benefi ted from the natural refri gerati ng properti es of i ce and snow as wel l .
For centuri es anatomi cal di ssecti ons were performed onl y i n wi nter because col der temperatures
del ayed deteri orati on of the cadaver, and i n the Middl e Ages the anesthetic effects of col d water
and ice were recognized. It i s unclear how frequentl y col d mi ght have been used duri ng thi s era
but i n the seventeenth century, Marco Aureli o Severi no documented refrigerati on anesthesi a in
some detai l . By pl aci ng snow in parall el l ines across the i ncisi onal pl ane, he was abl e to render a
surgi cal site i nsensate wi thin minutes. The techni que never became popul ar, probabl y because of
the chal l enge of mai ntaini ng stores of snow year-round.
5
Severi no i s al so known to have saved
numerous l i ves during an epi demi c of di phtheri a by performi ng tracheostomi es and inserti ng
trochars to mai ntai n patency of the ai rway.
6

Formal manipul ati on of the psyche to rel i eve surgi cal pai n was undertaken by French physi ci ans
Charl es Dupotet and Jules Cloquet i n the late 1820s with hypnosi s, then call ed mesmeri sm.
Although the work of Anton Mesmer was discredi ted by the French Academy of Sci ence after
formal i nqui ry several decades earl ier, proponents l ike Dupotet and Cl oquet conti nued to make
mesmeri c experi ments and pl eaded to the Academi e de Medi ci ne to reconsi der i ts util i ty.
7
In a
well -attended demonstrati on i n 1828, Cloquet removed the breast of a 64-year-ol d pati ent whi le
she reportedly remai ned in a cal m, mesmeric sl eep. Thi s demonstrati on made a l asti ng i mpressi on
upon Bri ti sh physi ci an John El li otson who became a l eading fi gure of the mesmeri c movement i n
Engl and i n the 1830s and 1840s. Innovati ve and qui ck to adopt new advances, Ell i otson performed
mesmeri c demonstrati ons and in 1843 publ i shed Numerous Cases of Surgical Operati ons wi thout
Pai n i n the Mesmeri c State. In thi s work, El l iotson used the term anaesthesi a, and agai n 5 years
later when he gave the Harveian Orati on before the Royal Col lege of Physi ci ans i n London. Thi s
was 2 years before Oli ver Wendell Hol mes, who is often credited for introducing the term, but
many centuri es after Di oscori des first used the word anesthesia. El li otson was roughly cri tici zed
by hi s col l eagues for his unorthodox practi ces. Support for mesmerism faded when i n 1846
renowned surgeon Robert Li ston performed the first operati on under ether anesthesi a i n Engl and
and remarked, Thi s Yankee dodge beats mesmerism al l hol low.
8

Despi te its i nevi tabl e demi se, the mesmeric movement was an attempt to cope wi th surgical pai n
by manipulation of mental and emotional states. In modern obstetrics, the psychoprophylaxi s of
Lamaze cl asses and support provi ded to parturi ents by mi dwi ves and doul as represent forms of
psychol ogi cal anesthesi a shown to reduce pharmacol ogi c analgesi a requi rements and the need
for regional anesthesi a.

P.5
Ear l y Anal gesi cs and Sopor i f i cs
Di oscori des, a Greek physi ci an from the first century AD, commented on the anal gesi a of
mandragora, a drug prepared from the bark and leaves of the mandrake plant. He stated that the
pl ant substance coul d be boi l ed i n wi ne, strai ned, and used in the case of persons about to be
cut or cauterized, when they wish to produce anesthesia.
9
Mandragora was sti ll bei ng used to
benefi t patients as l ate as the seventeenth century. From the ni nth to the thi rteenth centuri es, the
sopori fic sponge was a domi nant mode of provi ding pain reli ef duri ng surgery. Mandrake l eaves,
al ong wi th bl ack ni ghtshade, poppies, and other herbs, were boi l ed together and cooked onto a
sponge. The sponge was then reconstituted i n hot water and pl aced under the pati ent' s nose
before surgery. Pri or to the hypodermi c syri nge and routine venous access, i ngesti on and
inhalation were the only known routes of admi nisteri ng medici nes to gai n systemi c effects.
Prepared as i ndi cated by publ i shed reports of the ti me, the sponge general l y contai ned morphine
and scopol ami ne i n varyi ng amountsdrugs used in modern anesthesi a.
10

Alcohol was another element of the pre-ether armamentari um because it was thought to i nduce
stupor and bl unt the i mpact of pain. Al though al cohol is a central nervous system depressant, in
the amounts admini stered i t produced li ttl e anal gesi a in the setti ng of true surgi cal pai n. Fanny
Burney' s account, menti oned previousl y, demonstrates the ineffecti veness of al cohol as an
anesthetic. Not only di d the alcohol provi de mi nimal pai n control , i t di d nothi ng to dul l her
recol l ection of events. Laudanum was an al cohol -based sol ution of opi um fi rst compounded by
Paracelsus in the si xteenth century. It was wi ldl y popul ar in the Vi ctori an and Romanti c peri ods,
and prescri bed for a wi de vari ety of ai l ments from the common col d to tubercul osi s. Al though
appropriately used as an analgesic i n some instances, it was frequentl y misused and abused.
Laudanum was given by nursemaids to qui et wail i ng i nfants and abused by many upper-cl ass
women, poets, and arti sts who were unaware of i ts addi cti ve potenti al .
I nhal ed Anest het i cs
The di scovery of surgical anesthetics, i n the modern era, remains li nked to i nhaled anesthetics.
The compound now known as di ethyl ether had been known for centuri es; i t may have been
compounded fi rst by an ei ghth-century Arabi an phi l osopher Jabi r i bn Hayyam, or possi bl y by
Raymond Lul l y, a thi rteenth-century European al chemi st. But diethyl ether was certainly known i n
the si xteenth century, both to Valeri us Cordus and Paracel sus, who prepared i t by di sti l li ng
sulfuric aci d (oil of vitri ol) with fortified wine to produce an ol eum vi tri ol i dul ce (sweet oil of
vitriol ). One of the fi rst mi ssed observations of the effects of inhal ed agents, Paracelsus
observed that ether caused chi ckens to fal l asl eep and awaken unharmed. He must have been
aware of its analgesi c quali ties, because he reported that i t coul d be recommended for use i n
pai nful i ll nesses.
For three centuri es thereafter, thi s si mpl e compound remai ned a therapeutic agent with only
occasional use. Some of its properti es were exami ned but wi thout sustai ned i nterest by
di sti ngui shed Bri ti sh scienti sts Robert Boyl e, Isaac Newton, and Mi chael Faraday, none of whom
made the conceptual leap to surgi cal anesthesia. Its onl y routi ne appli cati on came as an
inexpensive recreational drug among the poor of Bri tai n and Irel and, who someti mes drank an
ounce or two of ether when taxes made gi n prohi bi ti vel y expensi ve.
11
An Ameri can vari ati on of
this practice was conducted by groups of students who hel d ether-soaked towel s to thei r faces at
nocturnal ether frol i cs.
Like ether, nitrous oxi de was known for i ts abi li ty to induce li ghtheadedness and was often i nhal ed
by those seeki ng a thri ll . It was not used as frequentl y as ether because i t was more compl ex to
prepare and awkward to store. It was made by heati ng ammoni um ni trate i n the presence of i ron
fi l i ngs. The evol ved gas was passed through water to el i mi nate toxi c oxides of nitrogen before
bei ng stored. Ni trous oxide was first prepared i n 1773 by Joseph Pri estl ey, an Engl i sh cl ergyman
and sci entist, who ranks among the great pioneers of chemi stry. Wi thout formal scienti fi c training,
Pri estl ey prepared and exami ned several gases, incl udi ng ni trous oxi de, ammoni a, sul fur di oxide,
oxygen, carbon monoxide, and carbon di oxi de.
At the end of the ei ghteenth century i n Engl and, there was a strong interest i n the supposed
wholesome effects of mi neral waters and gases. Parti cul ar waters and gases were bel i eved to
prevent and treat di sease, and there was great i nterest in the potenti al use of gases as remedi es
for scurvy, tubercul osi s, and other di seases. Thomas Beddoes opened hi s Pneumati c Insti tute
cl ose to the small spa of Hotwel l s, i n the ci ty of Bri stol, to study the effect of i nhal ed gases. He
hi red Humphry Davy i n 1798 to conduct research projects for the Insti tute. Davy performed
bri ll i ant investi gati ons of several gases but focused much of hi s attention on ni trous oxi de. He
measured the rate of uptake of ni trous oxi de, i ts effect on respi ration, and other central nervous
system actions. His human experi mental results, combined wi th research on the physical
properties of the gas, were publ i shed i n Ni trous Oxide, a 580-page book publ i shed i n 1800.
Thi s impressi ve treatise i s now best remembered for a few incidental observati ons. Davy
commented that nitrous oxi de transi ently rel i eved a severe headache, obl i terated a minor
headache, and bri efl y quenched an aggravati ng toothache. The most frequentl y quoted passage
was a casual entry: As ni trous oxide i n its extensi ve operati on appears capabl e of destroyi ng
physi cal pai n, i t may probably be used with advantage duri ng surgi cal operati ons in whi ch no
great effusi on of bl ood takes pl ace.
12
This is perhaps the most famous of the missed
opportuniti es to di scover surgi cal anesthesi a. Davy' s l asting ni trous oxi de legacy was coi ni ng the
phrase l aughi ng gas to describe its unique property.
Al most Di scover y: Hi ckman, Cl ar ke, Long, and Wel l s
As the ni neteenth century wore on, soci etal attitudes toward pain changed, perhaps best
exempl i fi ed by the romanti c poets.
13
Thus, the di scovery of a means to rel i eve pai n may have
become more accepted, and several more near-breakthroughs occurred that are worthy of
menti on. An Engl i sh surgeon named Henry Hil l Hi ckman searched intenti onall y for an inhaled
anesthetic to rel i eve pai n i n his pati ents.
14
Hi ckman used hi gh concentrations of carbon di oxi de i n
hi s studi es on mi ce and dogs. Carbon di oxi de has some anestheti c properties, as shown by the
absence of response to an inci si on in the ani mals of Hi ckman's study, but i t was never determi ned
if the ani mals were insensate because of hypoxia rather than anesthesi a. Hi ckman' s concept was
magni fi cent; his choi ce of agent, regrettabl e.
Wi l li am E. Cl arke, a medi cal student from Rochester, New York, may have gi ven the fi rst ether
anesthetic i n January 1842. From techni ques l earned as a chemistry student in 1839, Cl arke
entertai ned hi s compani ons wi th nitrous oxide and ether. Emboldened by these experiences, i n
January 1842, he admini stered ether, from a towel , to a young woman named Hobbie. One of her
teeth was then extracted wi thout pain by a denti st

named El i jah Pope.
15
A second indirect reference to Cl arke' s anestheti c suggested that it was
bel i eved that her unconsciousness was due to hysteri a. Cl arke was advi sed to conduct no further
anesthetic experi ments.
16

There i s no doubt that 2 months l ater, on March 30, 1842, Crawford Wil l iamson Long administered
ether wi th a towel for surgi cal anesthesi a in Jefferson, Georgi a. Hi s pati ent, James M. Venable,
was a young man who was al ready fami li ar with ether' s exhi l arati ng effects, for he reported in a
certi fi cate that he had previ ousl y inhal ed it and was fond of i ts use. Venable had two smal l tumors
on hi s neck but refused to have them exci sed because he feared the pai n that accompani ed
surgery. Knowi ng that Venabl e was fami li ar with ether' s action, Dr. Long proposed that ether
mi ght al l evi ate pai n and gai ned his pati ent's consent to proceed. After i nhal ing ether from the
towel and havi ng the procedure successful ly compl eted, Venabl e reported that he was unaware of
the removal of the tumors.
17
In determi ning the fi rst fee for anesthesi a and surgery, Long settled
on a charge of $2.00.
18

Crawford Long, although l i mi ted by a rural surgical practi ce, conducted the first comparative tri al
of an anestheti c. He wi shed to prove that insensibi l ity to pain was caused by ether and was not
si mpl y a refl ecti on of the indi vi dual' s pain threshol d or the resul t of sel f-hypnosi s. When ether was
withhel d during amputati on of the second of two fi ngers, hi s experi mental pati ent, a slave boy,
and a second pati ent, a woman from whom he removed two tumors without ether and one with,
P.6
caused Long to observe that surgery was pai nl ess wi th ether.
19
For Long to gai n recogni ti on as the
initi al di scoverer of anesthesi a he needed to publi sh hi s fi ndi ngs. Long remai ned si lent unti l 1849,
when ether anesthesia was already wel l known. He expl ained that he practiced i n an isolated
envi ronment and had few opportuniti es for surgical or dental procedures.
Mi d-ni neteenth-century dentists practi ced on the horns of a di l emma. Patients refused beneficial
treatment of thei r teeth for fear of the pai n i nfl i cted by the procedure. From a denti st' s
perspective, pain was not so much l ife threateni ng as it was l i veli hood threateni ng. A few denti sts
searched for new ways to rel i eve pai n and one of the fi rst to di scover a soluti on was Horace
Wel l s of Hartford, Connecti cut, whose great moment of discovery came on December 10, 1844. He
observed a l ecture-exhi biti on on nitrous oxi de by an iti nerant sci enti st, Gardner Quincy Colton,
who encouraged members of the audience to i nhal e the gas. Well s observed a young man injure
hi s leg without pai n whi l e under the infl uence of ni trous oxide. Sensing that ni trous oxide mi ght
provi de pai n rel ief duri ng dental procedures, Wel ls contacted Col ton and bol dl y proposed an
experi ment i n which Wel l s was to be the subject. The fol l owi ng day, Col ton gave Wel l s ni trous
oxi de before a fell ow denti st, Wi l li am Riggs, extracted a tooth.
20
When Wel l s awoke, he decl ared
that he had not fel t any pain and deemed the experiment a success. Colton taught Wel ls to
prepare nitrous oxi de, whi ch the denti st admi nistered wi th success i n hi s practi ce. His apparatus
probabl y resembled that used by Colton, a wooden tube pl aced i n the mouth through which ni trous
oxi de was breathed from a small bag fi l l ed wi th the gas.
A few weeks later, i n January 1845, Wel l s attempted a publ ic demonstrati on i n Boston at the
Harvard Medi cal School. He had pl anned to anestheti ze a patient for an amputati on, but, when the
patient refused surgery, a dental anestheti c for a medical student was substi tuted. Wel l s, perhaps
infl uenced by a large and openly cri ti cal audi ence, began the extracti on wi thout an adequate l evel
of anesthesi a, and the tri al was judged a fail ure. The exact ci rcumstances of Wel ls' l ack of success
are not known. Hi s pati ent may not have cooperated ful l y or the dose of anestheti c may have been
inadequate. Moreover, Wel l s may not yet have l earned that ni trous oxide lacks suffi cient potency
to serve predictabl y as an anesthetic wi thout suppl ementati on. In any event, the pati ent cri ed out,
and Well s was jeered by hi s audi ence. No one offered Wel ls even condi tional encouragement. No
one recognized that, even though the presentati on had been fl awed, ni trous oxi de mi ght possess
si gni fi cant therapeutic potential . The di sappoi ntment di sturbed Wel ls deepl y, and whi l e profoundly
di stressed, he commi tted sui cide i n 1848.
P ubl i c Demonst r at i on of Et her Anest hesi a
Another New Engl ander, Wil l iam Thomas Green Morton, bri efl y shared a dental practi ce wi th
Horace Wel ls i n Hartford. Wel ls' daybook shows that he gave Morton a course of instructi on i n
anesthesia, but Morton apparentl y moved to Boston wi thout paying for the lessons.
21
In Boston,
Morton continued hi s interest i n anesthesia and sought instructi on from chemi st and physi ci an
Charl es T. Jackson. After l earni ng that ether dropped on the ski n provi ded anal gesi a, he began
experi ments wi th i nhal ed ether, an agent that proved to be much more versati le than ni trous
oxi de. Bottl es of l iqui d ether were easi l y transported, and the volati l i ty of the drug permi tted
effecti ve i nhal ati on. The concentrati ons requi red for surgi cal anesthesi a were so l ow that pati ents
di d not become hypoxi c when breathing ether vaporized i n ai r. It al so possessed what woul d l ater
be recognized as a uni que property among al l i nhal ed anestheti cs: the qual i ty of provi di ng surgi cal
anesthesia without causi ng respiratory depressi on. These properties, combi ned wi th a sl ow rate of
inducti on, gave the pati ent a si gni fi cant margi n of safety, even i n the hands of rel ati vel y unski ll ed
anesthetists.
22

After anestheti zi ng a pet dog, Morton became confi dent of hi s skil l s and anestheti zed patients i n
hi s dental offi ce. Encouraged by hi s success, Morton gai ned an i nvi tation to gi ve a publ i c
demonstrati on i n the Bull fi nch amphi theater of the Massachusetts General Hospi tal , the same si te
as Wel l s' fai l ed demonstrati on. Many detai ls of the October 16, 1846, demonstrati on are wel l
known. Morton secured permi ssi on to provide an anestheti c to Edward Gil bert Abbott, a patient of
surgeon John Coll i ns Warren. Warren pl anned to excise a vascular l esi on from the l eft si de of
Abbott' s neck and was about to proceed when Morton arri ved l ate. He had been del ayed because
he was obl i ged to wait for an i nstrument maker to compl ete a new i nhaler (Fi g. 1-1). It consi sted
of a l arge gl ass bulb containing a sponge soaked wi th col ored ether and a spout that was placed in
the pati ent's mouth. An openi ng on the opposi te si de of the bul b al l owed ai r to enter and be drawn
over the ether-soaked sponge wi th each breath.
23

The conversati ons of that morning were not accurately recorded; however, popul ar accounts state
that the surgeon responded testi ly to Morton' s apol ogy for his tardy arri val by remarking, Sir,
your pati ent is ready. Morton directed his

attenti on to hi s pati ent and fi rst conducted a very abbrevi ated preoperati ve eval uati on. He
i nqui red, Are you afrai d? Abbott responded that he was not and took the inhal er i n hi s mouth.
After a few mi nutes, Morton i s sai d to have turned to the surgeon to respond, Sir, your pati ent i s
ready. Gi l bert Abbott l ater reported that he was aware of the surgery but had experienced no
pai n. When the procedure ended, Warren immedi atel y turned to hi s audi ence and uttered that
famous li ne, Gentl emen, thi s i s no humbug.
24

What would be recognized as Ameri ca' s greatest contri bution to ni neteenth-century medi ci ne had
been real ized, but Morton, wishi ng to capi tal i ze on hi s di scovery, refused to di vul ge what agent
was i n hi s inhal er. Some weeks passed before Morton admi tted that the acti ve component of the
colored fl ui d, whi ch he had call ed Letheon, was di ethyl ether. Morton, Well s, Jackson, and their
supporters soon became drawn i nto in a contenti ous, protracted, and frui tl ess debate over pri ori ty
for the di scovery. Thi s debate has subsequently been termed the ether controversy. In short,
Morton had appl i ed for a patent for Letheon, and when i t was granted, tri ed to recei ve royalti es
for the use of ether as an anestheti c. Eventual ly, the matter came before the U.S. Congress where
the House of Representati ves voted to grant Morton a l arge sum of money for the discovery;
however, the Senate quashed the deal .
When the detail s of Morton' s anesthetic techni que became publ i c knowl edge, the i nformati on was
transmi tted by trai n, stagecoach, and coastal vessel s to other North American ci ti es, and by shi p
to the world. As ether was easy to prepare and admi ni ster, anestheti cs were performed i n Britain,
France, Russi a, South Afri ca, Australi a, and other countri es al most as soon as surgeons heard the
welcome news of the extraordi nary di scovery. Even though surgery coul d now be performed wi th
pai n put to sl eep, the frequency of operations did not ri se rapi dl y, and several years would pass
before anesthesi a was uni versal ly recommended.
Chl or of or m and Obst et r i cs
James Young Simpson was a successful obstetrici an of Edi nburgh, Scotland, and among the fi rst to
use ether for the reli ef of l abor pain. Yet he became di ssatisfi ed wi th ether and sought a more
FIGURE 1-1. Morton' s ether i nhal er (1846).
P.7
pl easant, rapid-acti ng anestheti c. He and his juni or associates conducted a bol d search by i nhal i ng
sampl es of several vol ati l e chemi cal s col l ected for Simpson by Bri ti sh apothecaries. Davi d Waldi e
suggested chl oroform, whi ch had fi rst been prepared in 1831. Si mpson and hi s fri ends i nhal ed i t
after dinner at a party in Si mpson' s home on the eveni ng of November 4, 1847. They promptl y fell
unconsci ous and, when they awoke, were del i ghted wi th thei r success. Simpson qui ckly set about
encouraging the use of chloroform. Wi thin 2 weeks, he submitted hi s fi rst account of i ts use to The
Lancet. Al though Si mpson i ntroduced chl oroform with bol dness, and enthusiasm, and defended i ts
use for women in l abor, he gave few anestheti cs hi mself. Hi s goal was si mpl y to i mprove pati ent
comfort duri ng hi s operati ve or obstetri c acti vi ti es.
In the nineteenth century, the reli ef of obstetri cal pai n had si gnifi cant social ramifi cati ons and
made anesthesi a duri ng chi ldbi rth a controversial subject. Simpson argued against the prevai li ng
view, which hel d that reli evi ng labor pai n was contrary to God's wil l . The pai n of the parturi ent
was percei ved as both a component of puni shment, and a means of atonement for the Ori ginal Sin.
Less than a year after admi ni stering the fi rst anesthesi a during chi l dbirth, Si mpson addressed
these concerns i n a pamphl et entitl ed Answers to the Reli gious Objecti ons Advanced against the
Empl oyment of Anaestheti c Agents i n Mi dwi fery and Surgery and Obstetri cs. In thi s work, Si mpson
recognized the Book of Genesis as being the root of thi s senti ment, and noted that God promi sed
to rel i eve the descendants of Adam and Eve of the curse. Addi tional ly, Si mpson asserted that
labor pain was a resul t of sci entific and anatomi c causes, and not the result of rel igi ous
condemnati on. He stated that the upri ght posi tion of humans necessi tated strong pel vi c muscles to
support the abdomi nal contents. As a resul t, he argued, the uterus necessari l y devel oped strong
muscul ature to overcome the resi stance of the pel vi c fl oor and that great contracti le power caused
great pai n. All i n al l , Si mpson' s pamphl et probabl y did not have much i mpact i n terms of changing
the prevai li ng vi ewpoi nts about control l i ng l abor pai n, but he di d articulate many concepts that hi s
contemporari es were debati ng at the ti me.
25

Chl oroform gai ned considerabl e notori ety after John Snow used it during the del i veri es of Queen
Victoria. The Queen' s consort, Prince Albert, intervi ewed John Snow before he was cal l ed to
Bucki ngham Palace to admi ni ster chl oroform at the request of the Queen' s obstetri ci an. Duri ng the
monarch' s labor, Snow gave analgesi c doses of chl oroform on a fol ded handkerchi ef. Thi s
technique was soon termed chloroform la rei ne. Vi ctori a abhorred the pai n of chi l dbi rth and
enjoyed the reli ef that chl oroform provi ded. She wrote i n her journal , Dr. Snow gave that bl essed
chloroform and the effect was soothing, qui eting, and del i ghtful beyond measure.
26
When the
Queen, as head of the Church of England, endorsed obstetri c anesthesia, rel i gi ous debate over the
appropriateness of anesthesi a for l abor pai n termi nated abruptl y. Four years l ater, Snow was to
gi ve a second anestheti c to the Queen, who was again determi ned to have chloroform. Snow' s
daybook states that by the ti me he arri ved, Prince Al bert had begun the anestheti c and had gi ven
hi s wi fe a l i ttl e chl oroform.
John Snow, al ready a respected physi ci an, took an i nterest i n anestheti c practi ce and was soon
invi ted to work wi th many l eadi ng surgeons of the day. In 1848, John Snow introduced a
chloroform i nhal er. He had recogni zed the versatil i ty of the new agent and came to prefer it i n hi s
practi ce. At the same ti me, he i ni tiated what was to become an extraordi nary seri es of
experi ments that were remarkabl e i n their scope and for antici pati ng sophi sti cated research
performed a century l ater. Snow real i zed that successful anestheti cs must not only abol ish pai n
but al so prevent movement. He anestheti zed several speci es of animal s wi th varyi ng
concentrations of ether and chl oroform to determi ne the concentration requi red to prevent
movement i n response to sharp sti mul i . Despi te the li mi tati ons of mi d-ni neteenth-century
technol ogy, thi s work approximated the modern concept of minimum al veolar concentration
(MAC).
27
Snow assessed the anestheti c acti on of a l arge number of potential anestheti cs but did
not find any to ri val chl oroform or ether. His studi es led hi m to recognize the rel ati onshi p between
sol ubi l i ty, vapor pressure, and anestheti c potency, whi ch was not ful l y appreciated unti l after
Worl d War II. He al so fabri cated an experi mental closed-ci rcuit devi ce in whi ch the subject (Snow
hi mself) breathed oxygen whi l e the exhal ed carbon di oxide was absorbed by potassi um hydroxi de.
Snow publ i shed two remarkable books, On the Inhalation of the Vapour of Ether (1847) and On
Chl oroform and Other Anaestheti cs (1858). The l atter was al most compl eted when he di ed of a
stroke at the age of 45.
THE SECOND GENERATION OF INHALED ANESTHETICS
Throughout the second half of the ni neteenth century, other compounds were exami ned for their
anesthetic potenti al. The pattern of fortui tous di scovery that brought ni trous oxi de, diethyl ether,
and chl oroform forward between 1844 and 1847 conti nued. The next i nhal ed anestheti cs to be
used routi nel y, ethyl chlori de and ethylene, were al so discovered as a resul t of

unexpected observati ons. Ethyl chlori de and ethyl ene were fi rst formul ated i n the eighteenth
century. Ethyl chlori de was used as a topical anesthetic and counterirritant; i t was so vol ati l e that
the skin transi ently froze after ethyl chl oride was sprayed on i t. Its redi scovery as an anestheti c
came i n 1894, when a Swedi sh denti st named Carl son sprayed ethyl chl ori de into a pati ent' s
mouth to freeze a dental abscess. Carlson was surpri sed to di scover that hi s pati ent suddenly
lost consci ousness.
As the mechani sms to del i ver drugs were refi ned, enti rel y new cl asses of medi cati ons were al so
developed, wi th the i ntenti on of providi ng safer, more pleasant pai n control . Ethylene gas was the
first al ternative to ether and chloroform, but it had some major di sadvantages. The redi scovery of
ethylene i n 1923 also came from a serendi pitous observati on. After i t was learned that ethyl ene
gas had been used to i nhi bit the openi ng of carnati on buds in Chi cago greenhouses, i t was
specul ated that a gas that put fl owers to sl eep mi ght also have an anestheti c action on humans.
Arno Luckhardt was the first to publ i sh a cl i ni cal study i n February 1923. Wi thin a month, Isabell a
Herb i n Chi cago and W. Easson Brown in Toronto presented two other i ndependent studi es.
Ethyl ene was not a successful anesthetic because hi gh concentrati ons were required and i t was
expl osi ve. An addi ti onal si gni fi cant shortcomi ng was a particularl y unpl easant smel l, which coul d
onl y be parti al l y di sgui sed by the use of oil of orange or a cheap perfume. When cycl opropane was
introduced, ethyl ene was abandoned.
Cyclopropane' s anestheti c acti on was i nadvertentl y di scovered i n 1929.
28
Brown and Henderson
had previ ousl y shown that propyl ene had desi rabl e properti es as an anesthetic when freshl y
prepared; but after storage i n a steel cyli nder, i t deteriorated to create a toxi c materi al that
produced nausea and cardi ac i rregul ari ti es in humans. Velyien Henderson, a professor of
pharmacol ogy at the University of Toronto, suggested that the toxi c product be i denti fi ed. After a
chemi st, George Lucas, i denti fi ed cycl opropane among the chemi cal s in the tank, he prepared a
sampl e i n low concentration wi th oxygen and admi ni stered it to two kittens. The animal s fel l
asl eep qui etl y but qui ckl y recovered unharmed. Rather than bei ng a toxic contami nant, Lucas saw
that cyclopropane was a potent anesthetic. After i ts effects i n other ani mals were studi ed and
cycl opropane proved to be stable after storage, human experi mentation began.
Henderson was the first vol unteer; Lucas fol l owed. They then arranged a publ ic demonstration in
whi ch Frederi ck Banting, a Nobel l aureate for the di scovery of i nsul i n, was anestheti zed before a
group of physici ans. Despite thi s promi si ng begi nni ng, further research was abruptl y hal ted.
Several anestheti c deaths i n Toronto had been attri buted to ethyl chloride, and concern about
Canadi an cl ini cal tri al s of cyclopropane prevented human studi es from proceedi ng. Rather than
abandon the study, Henderson encouraged an Ameri can fri end, Ral ph Waters, to use cyclopropane
at the Uni versi ty of Wi sconsin. The Wisconsi n group i nvesti gated the drug thoroughl y and reported
thei r cli ni cal success in 1934.
29

In 1930, Chauncey Leake and Mei Yu Chen performed successful laboratory tri als of vinethene
(di vi nyl ether) but were thwarted i n its further devel opment by a professor of surgery i n San
Francisco. Ironicall y, Canadians, who had lost cycl opropane to Wi sconsin, l earned of vinethene
from Leake and Chen in Cal iforni a and conducted the fi rst human study in 1932 at the Uni versity
of Al berta, Edmonton. Internati onal research col laborati on enabl ed earl y anesthetic use of both
cycl opropane and di vi nyl ether, advances that may not have occurred independentl y i n either the
Uni ted States or Canada.
All potent anesthetics of thi s peri od were explosive save for chl oroform, whose hepati c and cardiac
toxi ci ty l i mi ted use in Ameri ca. Anestheti c expl osi ons remai ned a rare but devastating risk to both
P.8
anesthesi ol ogi st and pati ent. To reduce the danger of expl osi on duri ng the incendi ary days of
Worl d War II, Bri ti sh anaestheti sts turned to tri chloroethyl ene. Thi s nonfl ammabl e anestheti c
found l i mi ted appl i cation in America, as it decomposed to rel ease phosgene when warmed i n the
presence of soda l ime. By the end of World War II, however, another class of noni nflammabl e
anesthetics was prepared for l aboratory trial s. Ten years l ater, fl uori nated hydrocarbons
revolutioni zed i nhalati on anesthesia.
FLUORINATED ANESTHETICS
Fl uori ne, the l ightest and most reacti ve hal ogen, forms excepti onal l y stabl e bonds. These bonds,
al though sometimes created wi th expl osi ve force, resi st separati on by chemi cal or thermal means.
For that reason, many earl y attempts to fluorinate hydrocarbons i n a controll ed manner were
frustrated by the marked chemi cal acti vi ty of fl uori ne. In 1930, the fi rst commerci al appli cati on of
fl uori ne chemi stry came i n the form of the refri gerant, Freon. Thi s was fol l owed by the first
attempt to prepare a fl uori nated anestheti c by Harol d Booth and E. May Bi xby in 1932. Al though
thei r drug, monochl orodifl uoromethane, was devoi d of anesthetic acti on, as were other drugs
studi ed that decade, thei r report predi cted future devel opments. A survey of the properti es of
166 known gases suggested that the best possi bi li ty of fi ndi ng a new noncombusti ble anesthetic
gas l ay i n the fiel d of organi c fl uoride compounds. Fluori ne substituti on for other hal ogens l owers
the boi l ing point, increases stabi li ty, and general ly decreases toxi city.
30

The secret demands of the Manhattan Project for refined urani um-235 served as an i mpetus to
better understandi ng of fluori ne chemistry. Researchers learned that urani um mi ght be refi ned
through the creati on of an intermedi ate compound, urani um hexafluoride. Earl McBee of Purdue
Uni versi ty, who had a long-standi ng i nterest i n the fluori dati on of hydrocarbons, undertook part of
this project. McBee also hel d a grant from the Mal l inckrodt Chemical Works, a manufacturer of
ether and cycl opropane, to prepare new fl uori nated compounds, for anesthesia testi ng. By 1945,
the Purdue team had created small amounts of 46 fl uori nated ethanes, propanes, butanes, and an
ether.
The anestheti c value of these chemi cal s woul d not have been appreci ated, however, i f Mal l i nckrodt
had not al so provi ded fi nancial support for research i n pharmacol ogy at Vanderbi lt Uni versi ty. The
chai r, Benjamin Robbi ns, was a pharmacologi st, and was better abl e to assess the new drugs than
coul d most other anesthesi ol ogists of that period. Robbins tested McBee' s compounds in mice, and
sel ected the most promi sing for eval uati on in dogs. Unfortunately, none of these compounds found
a pl ace as an anesthetic but Robbi ns' concl usi ons on the effects of fl uori nation, bromi nation, and
chlori nation in his l andmark report of 1946 encouraged later successful studi es.
31

A team at the Uni versi ty of Maryland under Professor of Pharmacology John C. Krantz Jr.
investi gated the anesthetic properti es of dozens of hydrocarbons over a peri od of several years,
but onl y one, ethyl vinyl ether, entered cl inical use i n 1947. Because i t was flammable, Krantz
requested that i t be fl uori nated. In response, Jul i us Shukys prepared several fl uorinated anal ogs.
One of these, trifluoroethyl vi nyl ether, or fluroxene, became the fi rst fl uori nated anestheti c.
Fl uroxene was marketed from 1954 unti l 1974. However, i t was wi thdrawn when a delayed
di scovery showed a metabol i te to be toxic to lower ani mals. Fl uroxene i s important for i ts
hi stori cal i nterest as the first fl uori nated anestheti c gas but our experience wi th i t al so
underscores the need for continual surveil l ance of anestheti c drug actions and adverse effects.
32

In 1951, Charles Suckli ng, a Briti sh chemi st of Imperi al Chemi cal Industri es, was asked to create
a new anestheti c. Suckli ng, who al ready had an expert understandi ng of

fl uori nati on, began by asking cli nici ans to describe the properties of an ideal anestheti c. He
learned from thi s inqui ry that his search must consi der several l i mi ting factors, i ncl udi ng the
vol ati l ity, infl ammabil i ty, stabi li ty, and potency of the compounds. After 2 years of research and
testi ng, Charles Suckli ng created hal othane. He fi rst determi ned that hal othane possessed
anesthetic acti on by anestheti zi ng meal worms and housefl i es before he forwarded i t to
pharmacol ogist James Raventos. Suckl i ng al so made accurate predi cti ons as to the concentrati ons
requi red for anesthesia in higher ani mal s. After Raventos compl eted a favorabl e revi ew, hal othane
P.9
was offered to Michael Johnstone, a respected anestheti st of Manchester, Engl and, who recogni zed
its great advantages over other anesthetics avail abl e i n 1956. After Johnstone' s endorsement,
halothane use spread quickly and wi del y wi thi n the practi ce of anesthesi a.
33

Hal othane was foll owed i n 1960 by methoxyfl urane, an anestheti c that remained popul ar for a
decade. By 1970, however, i t was l earned that dose-rel ated nephrotoxi city fol l owing protracted
methoxyfl urane anesthesi a was caused by i norgani c fl uori de. Si mi l arly, because of persisting
concern that rare cases of hepati ti s fol lowi ng anesthesi a mi ght be a resul t of a metabol ite of
halothane, the search for newer i nhaled anesthetics focused on the resi stance to metabol ic
degradation.
Two fl uori nated li qui d anestheti cs, enfl urane and its i somer isofl urane, were resul ts of the search
for i ncreased stabil i ty. They were synthesized by Ross Terrel l i n 1963 and 1965, respectivel y.
Because enfl urane was easier to create, i t preceded isofl urane. Its appli cati on was restri cted after
it was shown to be a marked cardiovascular depressant and to have some convul sant properties.
Isoflurane was nearl y abandoned because of di ffi cul ties in i ts puri fi cati on, but after Loui se Speers
overcame this probl em, several successful tri als were publ i shed i n 1971. The rel ease of i soflurane
for cli nical use was delayed again for more than hal f a decade by cal l s for repeated testi ng i n
lower animal s, owi ng to an unfounded concern that the drug might be carci nogeni c. As a
consequence, i soflurane recei ved more thorough testi ng than any other drug heretofore used in
anesthesia. The era when an anestheti c coul d be i ntroduced foll owi ng a si ngl e fortui tous
observation had gi ven way to a cauti ous program of assessment and reassessment. Remarkably,
no anestheti cs were introduced i nto cl ini cal use for another 20 years. Fi nal ly, desflurane was
rel eased i n 1992, and sevofl urane was rel eased i n 1994. Xenon, a gas havi ng many properti es of
the ideal anestheti c, was administered to a few pati ents i n the early 1950s but i t never gai ned
popul ari ty because of the extreme costs associ ated wi th i ts removal from ai r. However, i nterest in
xenon has been renewed now that gas concentrations can be accuratel y measured when
administered at l ow fl ows, and devi ces are avai l abl e to scavenge and reuse the gas.
REGIONAL ANESTHESIA
Cocaine, an extract of the coca l eaf, was the fi rst effecti ve l ocal anestheti c. After Albert
Ni emann refined the acti ve alkal oid and named i t cocai ne, i t was used i n experi ments by a
few investi gators. It was noted that cocaine provi ded topi cal anesthesi a and even produced l ocal
insensi bi li ty when injected, but Carl Kol ler, a Vi ennese surgical intern, fi rst recogni zed the uti l ity
of cocai ne i n cl i ni cal practice.
In 1884, Carl Kol l er was completi ng his medical trai ni ng at a time when many operati ons on the
eye were performed wi thout general anesthesi a. Al most four decades after the di scovery of ether,
general anesthesi a by mask sti ll had li mi tati ons for ophthal mi c surgery: l ack of patient
cooperati on, interference of the anesthesi a apparatus wi th surgi cal access, and the high incidence
of postoperative nausea and vomiting. At that ti me, si nce fi ne sutures were not avai labl e and
surgi cal i nci si ons of the eye were not cl osed, postoperati ve vomi ting threatened the extrusion of
the globe' s contents, putting the pati ent at ri sk for irrevocabl e bl i ndness.
34

Whil e a medi cal student, Kol l er had worked in a Vi ennese l aboratory in a search of a topi cal
ophthal mi c anestheti c to overcome the l i mi tati ons of general anesthesi a. Unfortunately, the
suspensi ons of morphi ne, chl oral hydrate, and other drugs that he had used had been ineffectual .
In 1884, Koll er's fri end, Si gmund Freud, became interested i n the cerebral -stimul ati ng effects of
cocai ne and gave him a smal l sample in an envel ope, whi ch he placed in his pocket. When the
envel ope l eaked, a few grains of cocai ne stuck to Kol l er' s fi nger and he absentmi ndedl y li cked his
tongue. When hi s tongue became numb, Kol l er i nstantl y reali zed that he had found the object of
hi s search. In his l ab, he made a suspension of cocai ne crystals that he and a lab associ ate tested
in the eyes of a frog, a rabbi t, and a dog. Sati sfi ed wi th the anestheti c effects seen in the ani mal
model s, Kol l er dropped the sol ution onto hi s own cornea. To hi s amazement, his eyes were
insensi tive to the touch of a pi n.
35
As an i ntern, Carl Kol l er coul d not afford to attend a Congress
of German Ophthal mol ogi sts i n Heidel berg on September 15, 1884. However, a fri end presented
hi s arti cle at the meeti ng and a revol ution in ophthal mic surgery and other surgi cal di sci pli nes
began. Withi n the next year, more than 100 articl es supporti ng the use of cocaine appeared in
European and American medical journal s. In 1888, Kol l er i mmi grated to New York, where he
practi ced ophthal mology for the remai nder of hi s career.
Ameri can surgeons qui ckly devel oped new appli cati ons for cocaine. Its effi cacy in anestheti zi ng
the nose, mouth, l arynx, trachea, rectum, and urethra was described i n October 1884. The next
month, the fi rst reports of its subcutaneous i njecti on were publ i shed. In December 1884, two
young surgeons, Wil l iam Hal sted and Richard Hall , descri bed bl ocks of the sensory nerves of the
face and arm. Hal sted even performed a brachi al pl exus bl ock but di d so under direct visi on whil e
the pati ent recei ved an i nhal ed anestheti c.
36
Unfortunately, sel f-experi mentati on with cocai ne was
hazardous, as both surgeons became addi cted.
37
Addiction was an i ll -understood but frequent
problem i n the l ate ni neteenth century, especi all y when cocaine and morphi ne were present i n
many patent medi cines and fol k remedi es.
Other regi onal anesthetic techni ques were attempted before the end of the nineteenth century.
The term spi nal anesthesi a was coined i n 1885 by Leonard Corni ng, a neurol ogi st who had
observed Hal l and Hal sted. Corni ng wanted to assess the action of cocai ne as a speci fi c therapy
for neurol ogi c probl ems. After first assessing i ts acti on i n a dog, produci ng a bl ockade of rapi d
onset that was confi ned to the ani mal' s rear l egs, he performed a neuraxial bl ock usi ng cocaine on
a man addi cted to masturbati on. Corni ng admini stered one dose wi thout effect, then after a
second dose, the pati ent's l egs felt sl eepy. The man had impaired sensibi l ity i n hi s l ower
extremi ty after about 20 mi nutes and left Corni ng' s offi ce none the worse for the experi ence.
38

Al though Corni ng di d not descri be escape of cerebrospi nal fl uid (CSF) i n ei ther case, i t is l i kely
that the dog had a spi nal anestheti c and that the man had an epi dural anestheti c. No therapeutic
benefi t was descri bed, but Corni ng cl osed hi s account and his attenti on to the subject by
suggesting that cocai ni zation mi ght i n ti me be a substitute for etheri zation in geni to-uri nary or
other branches of surgery.
39

Two other authors, August Bi er and Theodor Tuffier, descri bed authenti c spi nal anesthesi a, wi th
menti on of cerebrospinal fluid, injecti on of cocai ne, and an appropri atel y short onset of acti on. In
a comparati ve revi ew of the ori ginal arti cles by Bi er, Tuffi er, and Corni ng, i t was concl uded that
Corni ng' s i njection was extradural , and Bier meri ted the credit for introducing spi nal anesthesi a.
40

SPINAL ANESTHESIA
Fourteen years passed before spi nal anesthesi a was performed for surgery. In the i nterval ,
Heinri ch Qui ncke of Ki el, Germany, had descri bed hi s techni que of lumbar puncture. He offered the
val uabl e observati on that it was most safely performed at the l evel of the thi rd or fourth l umbar
interspace, because entry at that l evel was below the termi nation of the spi nal cord. Quincke' s
technique was used i n Kiel for the fi rst del iberate cocainizati on of the spinal cord i n 1899 by his
surgi cal col l eague, August Bier. Si x patients received small doses of cocaine i ntrathecal l y, but,
because some cri ed out during surgery whi l e others vomi ted and experi enced headaches, Bi er
consi dered it necessary to conduct further experi ments before continui ng this techni que for
surgery.
Professor Bier permi tted hi s assi stant, Dr. Hi l debrandt, to perform a lumbar puncture, but, after
the needl e penetrated the dura, Hi ldebrandt coul d not fi t the syri nge to the needl e and a l arge
vol ume of the professor' s spi nal fl ui d escaped. They were at the poi nt of abandoni ng the study
when Hi ldebrandt volunteered to be the subject of a second attempt. Their persi stence was
rewarded with an astoni shing success. Twenty-three minutes after the spinal injecti on, Bier noted:
A strong bl ow wi th an i ron hammer against the ti bia was not felt as pain. After 25 mi nutes:
Strong pressure and pull i ng on a testi cle were not pai nful .
40
They cel ebrated their success wi th
wi ne and ci gars. That ni ght, both devel oped vi ol ent headaches, whi ch they attri buted at fi rst to
thei r cel ebrati on. Bi er' s headache was rel i eved after 9 days of bedrest. Hi l debrandt, as a house
officer, did not have the l uxury of conti nued rest. Bi er postul ated that their headaches were a
resul t of the l oss of l arge volumes of CSF and urged that thi s be avoi ded i f possi bl e. The hi gh
inci dence of compl icati ons foll owing l umbar puncture with wi de-bore needl es and the toxi c
P.10
reacti ons attri buted to cocaine expl ai n hi s l ater loss of interest i n spi nal anesthesi a.
41

Surgeons i n several other countri es soon practiced spinal anesthesi a and progress occurred by
many smal l contributi ons to the techni que. Theodor Tuffi er publi shed the first series of 125 spinal
anesthetics from France and he later counsel ed that the solution should not be injected before CSF
was seen. The first Ameri can report was by Rudol ph Matas of New Orl eans, whose fi rst pati ent
developed postanestheti c meni ngi smus, a frequent compli cation that was overcome i n part by the
use of hermeticall y sealed steri l e sol utions recommended by E. W. Lee of Phi l adel phi a and steri l e
gl oves as advocated by Hal sted. During 1899, Dudl ey Tai t and Gui dl o Cagl i eri of San Franci sco
performed experi mental studi es i n ani mal s and therapeuti c spi nal s for orthopedi c pati ents. They
encouraged the use of fine needl es to l essen the escape of CSF and urged that the ski n and
deeper tissues be i nfi l trated beforehand wi th l ocal anesthesi a.
42
Thi s had been suggested earl ier
by Wi ll i am Halsted and the foremost advocate of infi l trati on anesthesi a, Carl Ludwi g Schlei ch of
Berl i n. An earl y Ameri can speci ali st in anesthesi a, Ormond Gol dan, publi shed an anesthesi a record
appropriate for recording the course of intraspi nal cocai ni zation in 1900. In the same year,
Heinri ch Braun l earned of a newl y descri bed extract of the adrenal gl and, epinephrine, whi ch he
used to prol ong the acti on of l ocal anesthetics wi th great success. Braun devel oped several new
nerve blocks, coi ned the term conducti on anesthesi a, and is remembered by European wri ters as
the father of conduction anesthesi a. Braun was the fi rst person to use procai ne, whi ch, al ong
with stovaine, was one of the fi rst synthetic l ocal anestheti cs produced to reduce the toxici ty of
cocai ne. Further advances in spinal anesthesia fol lowed the introducti on of these and other
synthetic l ocal anesthetics.
Before 1907, anesthesi ologi sts were sometimes disappoi nted to observe that thei r spi nal
anesthetics were i ncomplete. Most bel ieved that the drug spread sol ely by l ocal di ffusi on before
the property of barici ty was investi gated by Arthur Barker, a London surgeon.
43
Barker
constructed a glass tube shaped to fol low the curves of the human spi ne and used i t to
demonstrate the l i mi ted spread of col ored sol uti ons that he had i njected through a T-pi ece i n the
lumbar regi on. Barker appli ed thi s observati on to use sol uti ons of stovai ne made hyperbari c by the
addi ti on of 5% glucose, which worked i n a more predi ctabl e fashi on. After the i njecti on was
compl ete, Barker pl aced his pati ent' s head on pi l lows to contain the anestheti c bel ow the ni ppl e
li ne. Lincol n Si se acknowledged Barker's work in 1935 when he introduced the use of hyperbaric
solutions of pontocaine. John Adriani advanced the concept further in 1946 when he used a
hyperbari c sol uti on to produce saddl e bl ock, or peri neal anesthesi a. Adri ani ' s patients remai ned
seated after injecti on as the drug descended to the sacral nerves.
Tai t, Jonnesco, and other early masters of spi nal anesthesi a used a cervi cal approach for
thyroi dectomy and thoraci c procedures, but this radi cal approach was suppl anted i n 1928 by the
lumbar i njecti on of hypobari c sol uti ons of li ght nupercai ne by G. P. Pi tki n. Although the use of
hypobari c sol uti ons i s now l i mi ted pri mari l y to patients posi tioned i n the jackknife position, their
former use for thoraci c procedures demanded skil l and preci se timing. The enthusi asts of
hypobari c anesthesia devi sed formul as to attempt to predict the ti me in seconds needed for a
warmed soluti on of hypobari c nupercai ne to spread in pati ents of varying si ze from i ts si te of
injecti on i n the lumbar area to the level of the fourth thoraci c dermatome.
The recurring probl em of i nadequate durati on of singl e-injecti on spi nal anesthesi a l ed a
Phi ladelphi a surgeon, Wi l li am Lemmon, to devi se an apparatus for conti nuous spi nal anesthesi a in
1940.
44
Lemmon began wi th the patient in the l ateral posi ti on. The spinal tap was performed wi th
a mal l eabl e sil ver needl e, whi ch was left i n posi ti on. As the pati ent was turned supi ne, the needle
was positi oned through a hol e in the mattress and tabl e. Addi ti onal injecti ons of l ocal anestheti c
coul d be performed as requi red. Mal leable si l ver needles al so found a less cumbersome and more
common appl i cation in 1942 when Waldo Edwards and Robert Hingson encouraged the use of
Lemmon' s needl es for continuous caudal anesthesi a in obstetri cs. In 1944 Edward Tuohy of the
Mayo Cl i ni c i ntroduced two important modifi cati ons of the conti nuous spi nal techni ques. He
devel oped the now famil i ar Tuohy needl e
45
as a means of improvi ng the ease of passage of
lacquered si lk ureteral catheters through which he i njected i ncremental doses of l ocal
anesthetic.
46

In 1949, Marti nez Curbel o of Havana, Cuba, used Tuohy's needl e and a ureteral catheter to
perform the fi rst continuous epi dural anestheti c. Si lk and gum el astic catheters were di fficul t to
steri l ize and someti mes caused dural infecti ons before bei ng superseded by di sposabl e pl asti cs.
Yet del iberate si ngle-injecti on peri dural anesthesi a had been practi ced occasi onal l y for decades
before conti nuous techniques brought it greater popul ari ty. At the beginni ng of the twentieth
century, two French cl i ni ci ans experimented independentl y with caudal anesthesi a. The neurol ogi st
Jean Athanase Si card appl i ed the techni que for a nonsurgi cal purpose, the rel ief of back pai n.
Fernand Cathel i n used caudal anesthesi a as a l ess dangerous al ternative to spi nal anesthesi a for
hernia repai rs. He also demonstrated that the epi dural space termi nated in the neck by injecti ng a
solution of India i nk i nto the caudal canal of a dog. The lumbar approach was fi rst used solel y for
mul tipl e paravertebral nerve bl ocks before the Pags-Dogl i otti si ngl e-injecti on techni que became
accepted. As they worked separatel y, the techni que carries the names of both men. Captai n Fi del
Pags prepared an el egant demonstrati on of segmental si ngle-injecti on peri dural anesthesia i n
1921, but died soon after his paper appeared i n a Spani sh mi l itary journal.
47
Ten years l ater,
Achil l e M. Dogl iotti of Turi n, Ital y, wrote a cl assi c study

that made the epi dural technique wel l known.
48
Whereas Pags used a tacti le approach to i denti fy
the epidural space, Dogli otti identi fi ed i t by the loss-of-resistance technique.
Surgery on the extremiti es l ent i tsel f to other regional anesthesi a techni ques. In 1902, Harvey
Cushi ng coi ned the phrase regi onal anesthesi a for hi s techni que of bl ocki ng either the brachial
or sci ati c plexus under di rect vi si on duri ng general anesthesi a to reduce anesthesi a requirements
and provi de postoperati ve pai n rel i ef.
49
Fi fteen years before his publ i cati on, George Cri l e
advanced a simi lar approach to reduce the stress and shock of surgery. Cri le, a dedi cated
advocate of regi onal and infi l trati on techni ques duri ng general anesthesia, coined the term anoci -
association.
50

An i ntravenous regi onal techni que with procaine was reported in 1908 by August Bi er, the surgeon
who had pi oneered spi nal anesthesi a. Bi er injected procaine i nto a vei n of the upper l i mb between
two tourni quets. Even though the techni que i s termed the Bi er bl ock, it was not used for many
decades unti l it was rei ntroduced 55 years later by Macki nnon Hol mes, who modified the technique
by exsangui nation before applying a single proximal cuff. Holmes used lidocaine, the very
successful ami de local anestheti c synthesi zed i n 1943 by Lofgren and Lundquist of Sweden.
Several investi gators achi eved upper extremity anesthesi a by percutaneous injecti ons of the
brachial pl exus. In 1911, based on his i nti mate knowl edge of the anatomy of the axi l lary area,
Hirschel promoted a bl i nd axi l lary i njection. In the same year, Kul enkampff descri bed a
supracl avi cul ar approach i n which the operator sought out paresthesias of the pl exus whi le
keeping the needl e at a poi nt superfi ci al to the fi rst rib and the pleura. The ri sk of pneumothorax
wi th Kul enkampff's approach l ed Mul l ey to attempt bl ocks more proximall y by a l ateral
paravertebral approach, the precursor of what i s now popul arl y known as the Wi nni e block.
Heinri ch Braun wrote the earl i est textbook of l ocal anesthesi a, whi ch appeared i n its fi rst Engli sh
transl ati on i n 1914. After 1922, Gaston Labat's Regi onal Anesthesia domi nated the Ameri can
market. Labat mi grated from France to the Mayo Cl ini c in Mi nnesota, where he served briefly
before taki ng a permanent posi ti on at the Bel l evue Hospital in New York. He formed the fi rst
Ameri can Soci ety for Regi onal Anesthesi a.
51
After Labat' s death, Emery A. Rovensti ne was
recruited to Bell evue to continue Labat' s work, among other responsi bi li ties. Rovenstei n created
the fi rst American cl ini c for the treatment of chroni c pai n, where he and hi s associ ates refined
techniques of lyti c and therapeuti c injecti ons and used the American Soci ety of Regi onal
Anesthesi a to further the knowl edge of pain management across the United States.
52

The devel opment of the mul ti di sci pli nary pai n cl i ni c was one of many contri butions to
anesthesi ol ogy made by John J. Boni ca, a renowned teacher of regi onal techniques. Duri ng
hi s peri ods of mil i tary, ci vi l ian, and uni versi ty servi ce at the Uni versi ty of Washi ngton, Boni ca
formulated a series of i mprovements i n the management of patients wi th chroni c pai n. Hi s cl assi c
text The Management of Pain, now i n its thi rd edi tion, is regarded as a cl assic of the li terature of
anesthesia.
P.11
ANESTHESIA MACHINES AND MECHANICAL VENTILATION
Ear l y Anest hesi a Del i ver y Syst ems
The transi ti on from ether i nhal ers and chl oroform-soaked handkerchi efs to more sophisticated
anesthesia del i very equi pment occurred gradual ly, wi th i ncremental advances suppl anti ng
ol der methods. One of the earl i est anesthesi a apparatus designs was that of John Snow, who had
reali zed the inadequaci es of ether i nhal ers through whi ch patients rebreathed via a mouthpiece.
After practici ng anesthesia for only 2 weeks, Snow created the first of hi s series of i ngenious
ether i nhal ers.
53
Hi s best-known apparatus featured unidi rectional valves within a mall eable, well -
fitting mask of hi s own design, which cl osel y resembles the form of a modern face mask. The face
pi ece was connected to the vaporizer by a breathi ng tube, whi ch Snow del iberatel y desi gned to be
wider than the human trachea so that even rapi d respi rations would not be i mpeded. A metal coi l
within the vapori zer ensured that the pati ent's i nspi red breath was drawn over a l arge surface
area to promote the uptake of ether. The device also incorporated a warm water bath to maintai n
the volatil i ty of the agent (Fi g. 1-2). Snow di d not attempt to capitali ze on hi s creati vi ty, in
contrast to Wi ll i am Morton; he closed hi s account of i ts preparati on wi th the generous
observation, There i s no restriction respecti ng the making of it.
54

Joseph Cl over, another Bri ti sh physici an, was the fi rst anestheti st to admini ster chl oroform in
known concentrati ons through the Clover bag. He obtained a 4.5% concentrati on of chl oroform
in air by pumpi ng a measured vol ume of ai r wi th a bel lows through a warmed evaporati ng vessel
contai ning a known volume of l i qui d chl oroform.
55
Al though i t was reali zed that nitrous oxi de
di l uted i n ai r often gave a hypoxi c mi xture, and that the oxygen-ni trous oxide mi xture was safer,
Chi cago surgeon Edmund Andrews compl ained about the physi cal l imitati ons of del iveri ng
anesthesia to pati ents in thei r homes. The

large bag was conspi cuous and awkward to carry al ong busy streets. He observed that, In city
practi ce, among the hi gher cl asses, however, thi s i s no obstacl e as the bag can al ways be taken i n
a carri age, wi thout attracti ng attenti on.
56
In 1872, Andrews was del i ghted to report the
avai labi li ty of l i quefi ed nitrous oxide compressed under 750 pounds of pressure, which allowed a
FIGURE 1-2. John Snow's ether inhal er (1847). The ether chamber (B) contained a spi ral coi l
so that the ai r enteri ng through the brass tube (D) was saturated by ether before ascendi ng
the fl exi ble tube (F) to the face mask (G). The ether chamber rested in a bath of warm water
(A).
P.12
supply suffi ci ent for three pati ents to be carried in a si ngle cyl i nder.
Cri tical to i ncreasi ng pati ent safety was the development of a machi ne capabl e of del i veri ng a
cali brated amount of gas and vol ati le anestheti c. In the l ate nineteenth century, demands i n
denti stry insti gated development of the fi rst freestandi ng anesthesia machi nes. Three Ameri can
denti st-entrepreneurs, Samuel S. White, Charl es Teter, and Jay Hei dbri nk, devel oped the ori gi nal
series of U.S. i nstruments that used compressed cyl inders of ni trous oxi de and oxygen. Before
1900, the S. S. White Company modi fi ed Frederi ck Hewitt's apparatus and marketed i ts
conti nuous-flow machine, which was refi ned by Teter i n 1903. Hei dbri nk added reduci ng val ves i n
1912. In the same year, physi ci ans i ni ti ated other important devel opments. Water-bubbl e fl ow
meters, i ntroduced by Frederi ck Cotton and Wal ter Boothby of Harvard Uni versi ty, al l owed the
proporti on of gases and their fl ow rate to be approximated. The Cotton and Boothby apparatus
was transformed i nto a practi cal portabl e machi ne by James Tayloe Gwathmey of New York. The
Gwathmey machi ne caught the attention of a London anestheti st Henry E. G. Cocki e Boyle, who
acknowl edged hi s debt to the Ameri can when he i ncorporated Gwathmey' s concepts in the first of
the series of Boyle machines that were marketed by Coxeter and Bri ti sh Oxygen Corporati on.
During the same period in Lubeck, Germany, Hei nri ch Draeger and hi s son, Bernhaard, adapted
compressed-gas technology, whi ch they had ori gi nal l y devel oped for mi ne rescue equi pment, to
manufacture ether and chloroform-oxygen machi nes.
In the years after Worl d War I, several U.S. manufacturers conti nued to bri ng forward wi del y
admired anesthesi a machi nes. Some companies were founded by denti sts, i ncl udi ng Hei dbri nk and
Teter. Karl Connel l and El mer Gatch were surgeons. Ri chard von Foregger was an engi neer who
was exceptional ly recepti ve to cli ni cians' suggestions for addi tional features for hi s machi nes.
El mer McKesson became one of the country' s fi rst speci al i sts i n anesthesiology in 1910 and
developed a seri es of gas machi nes. In an era of fl ammabl e anestheti cs, McKesson carri ed
nonfl ammabl e ni trous oxi de anesthesi a to i ts therapeutic l i mi t by performing i nductions with 100%
ni trous oxide and thereafter addi ng smal l vol umes of oxygen. If the resultant cyanosi s became too
profound, McKesson depressed a valve on his machi ne that fl ushed a smal l vol ume of oxygen into
the ci rcuit. Even though hi s techniques of pri mary and secondary saturati on wi th nitrous oxi de are
no longer used, the oxygen flush val ve i s part of McKesson' s l egacy.
Car bon Di oxi de Absor pt i on
Carbon di oxide (CO
2
) absorbance is a basi c el ement of modern anesthetic machines. It was
initi al l y devel oped to all ow rebreathi ng of gas and mi ni mi ze l oss of flammabl e gases i nto the
room, thereby reduci ng the ri sk of expl osi on. In current practice, i t permi ts decreased uti l i zati on
of anestheti c and reduced cost. The fi rst CO
2
absorber in anesthesi a came in 1906 from the work
of Franz Kuhn, a German surgeon. His use of canisters devel oped for mi ne rescues by Draeger was
innovati ve, but hi s ci rcuit had unfortunate l imitati ons. The excepti onal l y narrow breathi ng tubes
and a large dead space explai n i ts very l imited use, and Kuhn's devi ce was i gnored.
A few years later, the first American machine with a CO
2
absorber was i ndependentl y fabri cated by
a pharmacol ogi st named Denni s Jackson. In 1915, Jackson devel oped an earl y techni que of CO
2

absorpti on that permitted the use of a closed anesthesi a ci rcuit. He used sol uti ons of sodi um and
calci um hydroxi de to absorb CO
2
. As hi s l aboratory was l ocated i n an area of St. Loui s, Missouri ,
heavil y laden with coal smoke, Jackson reported that the apparatus all owed hi m the fi rst breaths
of absol utel y fresh ai r he had ever enjoyed i n that city. The compl exity of Jackson's apparatus
li mi ted its use in hospi tal practi ce, but hi s pi oneeri ng work i n thi s fiel d encouraged Ral ph Waters
to i ntroduce a simpler devi ce usi ng soda l i me granul es 9 years l ater. Waters posi tioned a soda
li me cani ster (Fi g. 1-3) between a face mask and an adjacent breathi ng bag to which was attached
the fresh gas flow. As long as the mask was hel d agai nst the face, onl y small vol umes of fresh gas
flow were requi red and no val ves were needed.
57

When Waters made hi s fi rst to-and-fro device, he was attempting to devel op a speci al ist practi ce
in anesthesi a in Si oux City, Iowa, and had achi eved l i mi ted fi nanci al success. Waters bel i eved that
hi s device had advantages for both cl inici an and patient. Economy of operation was crucial when
pri vate patients and i nsurance compani es were reluctant to pay for speci ali st' s servi ces, drugs,
and suppl ies. Waters estimated that hi s new cani ster woul d reduce costs for gases and soda l ime
to l ess than $.50 per hour. Thi s portabl e apparatus could be easi ly carri ed to pri vate residences
and hospi tal setti ngs, preventi ng contami nation of the operati ng envi ronments with the
mal odorous and expl osi ve vapors of ethyl ene. Waters even recognized that the cani ster suppl i ed
the added benefi ts of conservi ng body heat and humi di fyi ng i nspi red gases.
Waters' devi ce featured awkward posi ti oni ng of the cani ster close to the patient' s face. Brian
Sword overcame thi s l imitati on i n 1930 with a freestanding machi ne with unidi rectional val ves to
create a circl e system and an in-li ne CO
2
absorber.
58
James Elam and his co-workers at the
Roswell Park Cancer Insti tute in Buffalo, New York, further refined the CO
2
absorber, i ncreasi ng
the efficiency of CO
2
removal wi th a minimum of resi stance for breathing.
59
Consequentl y, the
ci rcl e system introduced by Sword i n the 1930s, wi th a few refi nements, became the standard
anesthesia ci rcuit i n North Ameri ca.

Al t er nat i ve Ci r cui t s
A valveless devi ce, the Ayre' s T-pi ece, has found wi de appl i cati on i n the management of i ntubated
patients. Phi ll i p Ayre practi ced anesthesi a in England when the l imi tati ons of equi pment for
pedi atri c pati ents produced what he descri bed as a protracted and sangui ne battl e between
surgeon and anaesthetist, wi th the poor unfortunate baby as the battl efi eld.
60
In 1937, Ayre
introduced hi s valvel ess T-pi ece to reduce the effort of breathi ng i n neurosurgi cal pati ents. The T-
pi ece soon became parti cul arl y popul ar for cl eft pal ate repai rs, as the surgeon had free access to
the mouth. Positi ve pressure venti l ati on could be achi eved when the anestheti st obstructed the
expiratory li mb. In ti me, thi s i ngeni ous, li ghtwei ght, nonrebreathi ng devi ce evol ved through more
FIGURE 1-3. Waters' carbon di oxide absorbance canister.
P.13
than 100 modificati ons for a variety of special situations. A si gni fi cant al terati on was Gordon
Jackson Rees' circui t, whi ch permi tted i mproved control of ventil ati on by substi tuti ng a breathi ng
bag on the outflow li mb.
61
An al ternative method to reduce the amount of equi pment near the
patient is provi ded by the coaxi al circui t of the Bai n-Spoerel apparatus.
62
Thi s l i ghtwei ght tube-
within-a-tube has served very wel l i n many ci rcumstances si nce i ts Canadi an i nnovators described
it i n 1972.
Fl ow Met er s
As cl osed and semi cl osed circui ts became practi cal , gas fl ow could be measured wi th greater
accuracy. Bubbl e fl ow meters were repl aced wi th dry bobbi ns or bal l -bearing fl ow meters, whi ch,
al though they di d not l eak fl uids, coul d cause i naccurate measurements i f they adhered to the
gl ass column. In 1910, M. Neu had been the fi rst to appl y rotameters i n anesthesia for the
administrati on of ni trous oxide and oxygen, but hi s machi ne was not a commerci al success,
perhaps because of the great cost of nitrous oxi de i n Germany at that ti me. Rotameters desi gned
for use i n German industry were first empl oyed in Britain i n 1937 by Richard Sal t; but as Worl d
War II approached, the Engl i sh were deni ed access to these sophi sti cated fl ow meters. After World
War II rotameters became regul arly empl oyed i n Bri tish anesthesi a machines, al though most
Ameri can equi pment sti ll featured nonrotati ng fl oats. The now uni versal practi ce of displ aying gas
flow in l iters per mi nute was not a customary part of al l Ameri can machines unti l more than a
decade after Worl d War II. Some anesthesi ol ogi sts stil l i n practi ce l earned to cal cul ate gas fl ows
in the cumbersome proporti ons of gall ons per hour.
Vapor i zer s
The art of a smooth inducti on with a potent anestheti c was a great chal l enge, parti cul arly i f the
inspi red concentration coul d not be determined wi th accuracy. Thi s l imitati on was parti cularl y true
of chloroform, as an excessi ve rate of admi ni strati on produced a l ethal cardi ac depressi on. Even
the cl i ni cal i ntroduction of hal othane after 1956 might have been si mil arl y thwarted except for a
fortunate coi ncidence: the pri or devel opment of cal i brated vapori zers. Two types of cal i brated
vapori zers desi gned for other anesthetics had become avai l abl e i n the hal f decade before
halothane was marketed. The prompt acceptance of halothane was i n part because of an abil i ty to
provi de it in carefull y ti trated concentrati ons.
The Copper Kettl e was the fi rst temperature-compensated, accurate vaporizer. It had been
developed by Lucien Morri s at the University of Wi sconsi n in response to Ral ph Waters' plan to
test chloroform by giving i t in control l ed concentrati ons.
63
Morri s achi eved thi s goal by passi ng a
metered flow of oxygen through a vapori zer chamber that contai ned a porex di sk to separate the
oxygen i nto mi nute bubbl es. The gas became ful ly saturated wi th anesthetic vapor as i t percol ated
through the l iqui d. The concentrati on of the anestheti c i nspired by the pati ent could be cal cul ated
by knowi ng the vapor pressure of the l i qui d anestheti c, the vol ume of oxygen fl owing through the
li qui d, and the total vol ume of gases from all sources enteri ng the anesthesi a ci rcuit. Al though
experi mental models of Morri s' vaporizer used a water bath to mai ntain stabi li ty, the excel lent
thermal conducti vi ty of copper was substi tuted in l ater model s. When fi rst marketed, the Copper
Kettl e di d not feature a mechanism to i ndi cate changes i n the temperature (and vapor pressure) of
the li quid. Shuh-Hsun Ngai proposed the i ncorporation of a thermometer, a suggesti on that was
l ater added to al l vapori zers of that cl ass.
64

The Copper Kettl e (Foregger Company) and the Verni trol (Ohi o Medical Products) were universal
vapori zersa property that remai ned a di sti nct advantage as new anesthetics were marketed.
Uni versal vapori zers coul d be charged wi th any anestheti c l i qui d, and, provi ded that i ts vapor
pressure and temperature were known, the i nspired concentrati on could be cal cul ated qui ckl y. Thi s
feature gave an unanti ci pated advantage to Ameri can investi gators. They were not dependent on
the constructi on of new agent-specific vapori zers.
When hal othane was fi rst marketed i n Britain, an effecti ve temperature-compensated, agent-
specific vapori zer had recentl y been pl aced i n cl i ni cal use. The TECOTA (TEmperature
COmpensated Trichl oroethyl ene Ai r) vapori zer had been created by engi neers who had been
frustrated by a gi ant corporati on's unresponsi veness. Thei r vaporizer featured a bimetal li c strip
composed of brass and a ni ckel steel al loy, two metal s wi th di fferent coeffi cients of expansi on. As
the anestheti c vapor cooled, the strip bent to move away from the ori fi ce, thereby permi tting
more fresh gas to enter the vaporizing chamber. Thi s mai ntai ned a constant inspi red concentration
despi te changes in temperature and vapor pressure. After thei r TECOTA vapori zer was accepted
into anestheti c practi ce, the technology was used to create the Fl uotec, the fi rst of a series of
agent-specific tec vapori zers for use in the operati ng room.
Vent i l at or s
Mechani cal ventil ators are now an i ntegral part of the anesthesia machi ne. Pati ents are ventil ated
duri ng general anesthesi a by el ectrical or gas-powered devi ces that are simpl e to control yet
sophi sti cated i n thei r functi on. The hi story of mechani cal positi ve pressure venti l ation began wi th
attempts to resuscitate victims of drowni ng by a bel lows attached to a mask or tracheal tube.
These experi ments found l ittle role in anestheti c care for many years. At the begi nni ng of the
twenti eth century, however, several modal i ti es were explored before i ntermittent posi ti ve pressure
machines evolved.
A seri es of arti fi ci al envi ronments were created i n response to the frustrati on experi enced by
thoraci c surgeons who found that the l ung col l apsed when they inci sed the pl eura. Between 1900
and 1910, conti nuous positi ve or negati ve pressure devi ces were created to mai ntain i nflati on of
the lungs of a spontaneously breathi ng patient once the chest was opened. Brauer (1904) and
Murphy (1905) pl aced the pati ent's head and neck i n a box in whi ch posi ti ve pressure was
conti nual ly mai ntai ned. Sauerbruch (1904) created a negati ve-pressure operating chamber
encompassi ng both the surgical team and the pati ent's body and from which only the pati ent' s
head projected.
66

In 1907, the fi rst i ntermittent posi ti ve-pressure device, the Draeger Pul motor, was devel oped to
rhythmi cal l y i nflate the l ungs. Thi s instrument and l ater American model s such as the E & J
Resuscitator were used almost exclusivel y by fi refighters and mine rescue workers. A few
European medi cal

workers had an earl y i nterest i n rhythmi c infl ati on of the l ungs. In 1934 a Swedi sh team
devel oped the Spi ropul sator, whi ch C. Crafoord l ater modi fi ed for use during cyclopropane
anesthesia.
65
Its acti on was control led by a magneti c control valve cal led the fl asher, a type fi rst
used to provide i ntermi ttent gas fl ow for the l i ghts of navigati onal buoys. When Trier Morch, a
Danish anesthesi ol ogi st, coul d not obtai n a Spi ropulsator during Worl d War II, he fabricated the
Morch Respi rator, whi ch used a pi ston pump to rhythmi cal l y del i ver a fi xed vol ume of gas to the
patient.
66

A major stimul us to the devel opment of venti l ators came as a consequence of a devastati ng
epi demi c of poli omyel iti s that struck Copenhagen, Denmark, i n 1952. As scores of pati ents were
admitted, the onl y effective venti latory support that coul d be provi ded to patients wi th bul bar
paral ysi s was conti nuous manual venti l ati on vi a a tracheostomy empl oying devi ces such as Waters'
to-and-fro ci rcuit. This succeeded only through the dedi cated efforts of hundreds of vol unteers.
Medi cal students served i n rel ays to venti l ate paralyzed pati ents. The Copenhagen cri sis
sti mul ated a broad European i nterest i n the devel opment of portabl e ventil ators i n anti ci pation of
another epidemic of pol i omyel iti s. At this ti me, the common practi ce in North Ameri can hospital s
was to place pol i o pati ents with respiratory i nvol vement i n iron l ungs, metal cyli nders that
encased the body bel ow the neck. Inspi rati on was caused by intermi ttent negati ve pressure
created by an electri c motor acting on a piston-l i ke devi ce occupyi ng the foot of the chamber.
Some early Ameri can ventil ators were adaptati ons of respi ratory-assi st machi nes ori ginal l y
desi gned for the del ivery of aerosoli zed drugs for respi ratory therapy. Two types empl oyed the
Bennett or Bird flow-sensi ti ve val ves. The Bennett val ve was desi gned duri ng Worl d War II when
a team of physiol ogi sts at the University of Southern California encountered difficulties in
separati ng inspirati on from expi ration in an experi mental apparatus desi gned to provide positi ve
pressure breathi ng for avi ators at hi gh al titude. An engineer, Ray Bennett, vi sited thei r
P.14
laboratory, observed thei r probl em, and resol ved i t wi th a mechani cal flow-sensi ti ve automatic
val ve. A second val vi ng mechani sm was l ater desi gned by an aeronautical engi neer, Forrest Bi rd.
The use of the Bi rd and Bennett val ves gained an anestheti c appl i cation when the gas flow from
the valve was directed i nto a ri gid pl asti c jar contai ni ng a breathi ng bag or bel l ows as part of an
anesthesia ci rcui t. These bag-in-bottl e devices mi mi cked the acti on of the cl i ni ci an' s hand as the
gas fl ow compressed the bag, thereby provi di ng posi ti ve pressure inspi rati on. Passive exhal ati on
was promoted by the descent of a wei ght on the bag or bel l ows.
SAFETY STANDARDS
The i ntroduction of safety features was coordinated by the Ameri can Nati onal Standards
Insti tute (ANSI) Commi ttee Z79, whi ch was sponsored from 1956 until 1983 by the American
Society of Anesthesi ologists. Si nce 1983, representati ves from i ndustry, government, and
heal thcare professi ons have met on Committee Z79 of the Ameri can Soci ety for Testing and
Materi al s. They establi sh vol untary goal s that may become accepted nati onal standards for the
safety of anesthesi a equi pment.
Ral ph Tovel l voi ced the fi rst call for standards duri ng Worl d War II whi le he was the U.S. Army
Consul tant i n Anesthesi ol ogy for Europe. Tovell found that, as there were four different
di mensions for connectors, tubes, masks, and breathi ng bags, suppl i es di spatched to fi el d
hospi tal s mi ght not match their anesthesi a machi nes. As Tovel l observed, When a sudden need
for accessory equi pment arose, nurses and corpsmen were l i kel y to respond to i t by bri ngi ng parts
that woul d not fi t.
67
Al though Tovel l ' s reports did not gain an immedi ate response, after the war
Vincent Coll i ns and Hamil ton Davi s took up hi s concern and formed the ANSI Commi ttee Z79. One
of the commi ttee's most active members, Lesli e Rendel l -Baker, wrote an account of the
committee' s domesti c and i nternati onal achi evements.
68
He reported that Tovell encouraged al l
manufacturers to sel ect the now uniform orifice of 22 mm for al l adul t and pedi atri c face masks
and to make every tracheal tube connector 15 mm i n diameter. For the fi rst time, a Z79-desi gned
mask-tube elbow adapter woul d fi t every mask and tracheal tube connector.
The Z79 Commi ttee i ntroduced other advances. Tracheal tubes of nontoxic pl asti c bear a Z79 or IT
(Implantation Tested) mark. The committee al so mandated touch identi fi cation of oxygen flow
control at Roderi ck Cal verl ey' s suggesti on, which reduced the ri sk that the wrong gas woul d be
sel ected before internal mechani cal controls prevented the sel ection of an hypoxic mixture.
69
Pi n
i ndexi ng reduced the hazard of attachi ng a wrong cyl i nder i n the pl ace of oxygen. Di ameter
indexing of connectors prevented si mil ar errors i n hi gh-pressure tubi ng. For many years, however,
errors commi tted i n reassembl ing hospital oxygen suppl y li nes l ed to a seri es of tragedi es before
pol arographi c oxygen anal yzers were added to the i nspiratory li mb of the anesthesi a circui t.
Cont r ol of the Ai r way
Pri or to devel opment of techniques and equi pment for safel y and effecti vel y i ntubati ng the
trachea, ai rway management l eft much to be desi red. Inhal ers, drop techni ques, and mask
anesthesia functioned equal l y when induci ng unconsciousness, but unfortunatel y, were equal l y
incapabl e of preventi ng obstructi on of airways. Defi ni ti ve control of the ai rway, a ski l l
anesthesiol ogi sts now consi der paramount, devel oped onl y after many harrowi ng and apnei c
epi sodes spurred the devel opment of safer ai rway management techni ques. Preceding tracheal
i ntubati on, however, several i mportant techni ques were proposed toward the end of the
ni neteenth century that remai n integral to anesthesi ol ogy educati on and practi ce.
Joseph Cl over was the first Engl i shman to urge the now uni versal practi ce of thrusti ng the
patient' s jaw forward to overcome obstructi on of the upper ai rway by the tongue. Cl over al so
publ ished a l andmark case report in 1877 in whi ch he performed a surgi cal ai rway. Once hi s
patient was asleep, Clover discovered that hi s pati ent had a tumor of the mouth that obstructed
the ai rway compl etel y, despi te hi s trusted jaw thrust maneuver. He averted di saster by i nserti ng a
smal l curved cannula of his design through the cri cothyroi d membrane. He conti nued anesthesi a
via the cannul a unti l the tumor was excised. Cl over, the model of the prepared anesthesiologi st,
remarked, I have never used the cannula before al though it has been my compani on at some
thousands of anaesthetic cases.
70

Tr acheal I nt ubat i on i n Anest hesi a
The devel opment of techni ques and i nstruments for intubati on ranks among the major advances i n
the hi story of anesthesi ol ogy. The fi rst tracheal tubes were devel oped for the resuscitati on of
drowni ng vi cti ms, but were not used i n anesthesia until 1878. The fi rst use of el ecti ve oral
intubation for an anesthetic was undertaken by Scotti sh surgeon Wil l iam Macewan. He had
practi ced passing fl exi bl e metal tubes through the larynx of a cadaver before attempting the
maneuver on an awake pati ent wi th an oral tumor at the Glasgow Royal Infi rmary, on Jul y 5,
1878.
71
Because topical anesthesi a was not yet known,

the experi ence must have demanded forti tude on the part of Macewan' s patient. Once the tube
was correctl y posi tioned, an assistant began a chloroformai r anesthetic via the tube. Once
anesthetized, the pati ent soon stopped coughi ng. Unfortunately, Macewan abandoned the practi ce
fol l owing a fatal ity i n which a patient had been successfull y intubated whi le awake but the tube
became di sl odged once the pati ent was asl eep. After the tube was removed, an attempt to provide
chloroform by mask anesthesi a was unsuccessful and the patient died.
Although there was a sporadic i nterest i n tracheal anesthesi a i n Edi nburgh and other European
centers after Macewan, an American surgeon named Joseph O' Dwyer i s remembered for hi s
extraordinary dedi cati on to the advancement of tracheal i ntubation. In 1885, O'Dwyer desi gned a
series of metal laryngeal tubes, whi ch he i nserted bl indl y between the vocal cords of chil dren
suffering a diphtheri tic cri si s. Three years later, O' Dwyer desi gned a second ri gi d tube wi th a
coni cal tip that occl uded the larynx so effectively that i t could be used for arti fi ci al venti lation
when appl i ed wi th the bel l ows and T-pi ece tube desi gned by George Fel l . The Fel l -O' Dwyer
apparatus, as i t came to be known, was used duri ng thoraci c surgery by Rudol ph Matas of New
Orleans. Matas was so pleased wi th i t that he predi cted, The procedure that promi ses the most
benefi t in preventing pulmonary coll apse i n operati ons on the chest is the rhythmi cal
maintenance of arti fi cial respi rati on by a tube i n the glotti s directl y connected wi th a bel l ows.
After O' Dwyer's death, the outstandi ng pi oneer of tracheal intubati on was Franz Kuhn, a surgeon
of Kassel , Germany. From 1900 unti l 1912, Kuhn publ i shed several papers and a classic
monograph, Di e peroral e Intubati on, whi ch were not wel l known i n hi s li fetime but have si nce
become wi del y appreci ated.
72
Hi s work mi ght have had a more profound i mpact i f i t had been
transl ated i nto Engl ish. Kuhn descri bed techni ques of oral and nasal intubati on that he performed
with fl exi ble metal tubes composed of coi led tubing simil ar to those now used for the spout of
metal gasol ine cans. After applying cocaine to the ai rway, Kuhn introduced hi s tube over a curved
metal stylet that he di rected toward the larynx with his left index finger. While he was aware of
the subglotti c cuffs that had been used bri efl y by Victor Ei senmenger, Kuhn preferred to seal the
l arynx by posi ti oni ng a supral aryngeal fl ange near the tube' s ti p before packi ng the pharynx wi th
gauze. Kuhn even moni tored the pati ent' s breath sounds conti nuousl y through a monaural
earpiece connected to an extensi on of the tracheal tube by a narrow tube.
68

Intubati on of the trachea by pal pati on was an uncertai n and someti mes traumatic act. For some
years, surgeons even bel ieved that i t woul d be anatomi cal ly i mpossi ble to vi suali ze the vocal cords
di rectl y. This mi sapprehensi on was overcome i n 1895 by Alfred Kirstei n i n Berli n who devi sed the
first direct-visi on l aryngoscope.
73
Ki rstei n was moti vated by a fri end' s report that a patient' s
trachea had been acci dental l y i ntubated duri ng esophagoscopy. Ki rstei n promptl y fabri cated a
hand-hel d instrument that at fi rst resembl ed a shortened cyl i ndrical esophagoscope. He soon
substi tuted a semi circul ar bl ade that opened i nferi orl y. Ki rstein could now exami ne the l arynx
whi l e standi ng behind his seated pati ent, whose head had been placed i n an atti tude
approxi mati ng the sniffi ng posi ti on. Al though Al fred Ki rstein's autoscope was not used by
anesthesiol ogi sts, i t was the forerunner of al l modern l aryngoscopes. Endoscopy was refi ned by
Cheval ier Jackson i n Phil adelphia, who desi gned a U-shaped l aryngoscope by addi ng a handgri p
that was parall el to the bl ade. The Jackson blade has remained a standard i nstrument for
endoscopi sts but was not favored by anesthesi ologi sts. Two l aryngoscopes that cl osely resembl ed
modern L-shaped i nstruments were desi gned in 1910 and 1913 by two Ameri can surgeons, Henry
P.15
Janeway and George Dorrance, but nei ther instrument achi eved l asti ng use despi te thei r excell ent
desi gns.
74

Anest hesi ol ogi st - I nspi r ed Lar yngoscopes
Before the i ntroducti on of muscl e relaxants in the 1940s, intubati on of the trachea could be
chal l engi ng. This chal l enge was made somewhat easi er, however, wi th the advent of l aryngoscope
bl ades specificall y desi gned to increase visual izati on of the vocal cords. Robert Mil l er of San
Antonio, Texas, and Robert Maci ntosh of Oxford Uni versi ty created thei r respecti vel y named blades
within an i nterval of 2 years. In 1941, Mi ll er brought forward the sl ender, straight blade wi th a
sl i ght curve near the tip to ease the passage of the tube through the larynx. Al though Mi l ler' s
bl ade was a refi nement, the techni que of i ts use was identi cal to that of earl i er model s as the
epi gl ottis was li fted to expose the l arynx.
75

The Maci ntosh bl ade, whi ch i s pl aced i n the val l ecul a, rather than under the epi gl ottis, was
invented as an i ncidental resul t of a tonsi l lectomy. Si r Robert Maci ntosh l ater descri bed the
ci rcumstances of i ts di scovery i n an appreci ati on of the career of his techni cian, Mr. Ri chard Sal t,
who constructed the bl ade. As Sir Robert recal l ed, A Boyl e-Davi s gag, a size larger than intended,
was i nserted for tonsi l lectomy, and when the mouth was ful l y opened the cords came into vi ew.
Thi s was a surpri se since conventi onal laryngoscopy, at that depth of anaesthesi a, woul d have
been i mpossi ble i n those pre-rel axant days. Withi n a matter of hours, Sal t had modi fi ed the bl ade
of the Davis gag and attached a l aryngoscope handl e to i t; and streamli ned (after testi ng several
model s), the end resul t came i nto wi despread use.
76
Maci ntosh underesti mated the popul arity of
the blade as more than 800,000 have been produced, and many speci al -purpose versi ons have
been marketed.
The most distingui shed i nnovator i n tracheal i ntubati on was the sel f-trai ned Bri tish anestheti st
Ivan (l ater, Si r Ivan) Magi ll .
77
In 1919, whil e serving i n the Royal Army as a general medi cal
officer, Magi l l was assi gned to a mi l itary hospi tal near London. Al though he had onl y rudi mentary
trai ni ng in anesthesi a, Magil l was obl i ged to accept an assi gnment to the anesthesi a servi ce,
where he worked wi th another neophyte, Stanl ey Rowbotham.
78
Together, Magi l l and Rowbotham
attended casual ti es disfi gured by severe facial injuri es who underwent repeated restorati ve
operations. These procedures required that the surgeon, Harold Gi l li es, have unrestricted access
to the face and airway. These pati ents presented formi dabl e chal l enges, but both Magi l l and
Rowbotham became adept at tracheal i ntubati on and qui ckl y understood i ts current li mi tati ons.
Because they learned from fortuitous observati ons, they soon extended the scope of tracheal
anesthesia.
They gai ned experti se wi th bl i nd nasal intubati on after they l earned to soften semi ri gi d
insuffl ati on tubes for passage through the nostril . Even though their ori gi nal intent was to posi ti on
the ti ps of the nasal tubes i n the posteri or pharynx, the sl ender tubes frequently ended up i n the
trachea. Sti mul ated by this chance experi ence, they devel oped techni ques of del i berate
nasotracheal i ntubation. In 1920, Magi l l devi sed an ai d to mani pul ati ng the catheter ti p, the
Magi ll angul ated forceps, whi ch continue to be manufactured according to hi s origi nal design of
75 years ago.
Wi th the war over, Magi l l entered ci vi li an practice and set out to devel op a wi de-bore tube that
would resist ki nking but be conformabl e to the contours of the upper airway. Whil e i n a hardware
store, he found mi neral i zed red rubber tubi ng that he cut, bevel ed, and smoothed to produce
tubes that cl i ni cians around the world woul d come to cal l Magi ll tubes. His tubes remai ned the
uni versal standard for more than 40 years unti l rubber products were suppl anted by i nert pl asti cs.
Magi l l al so redi scovered the advantage of appl yi ng cocai ne to the nasal mucosa, a techni que that
greatl y faci li tated awake bli nd nasal i ntubation.

In 1926, Arthur Guedel began a series of experi ments that l ed to the i ntroduction of the cuffed
tube. Hi s goal was to combine the safety of tracheal i ntubation with the safety and economy of the
cl osed-ci rcuit anesthesi a, recently refined by hi s cl ose fri end Ralph Waters.
79
Guedel transformed
the basement of hi s Indi anapoli s home into a l aboratory, where he subjected each step of the
P.16
preparati on and appl icati on of his cuffs to a vigorous revi ew.
80
He fashioned cuffs from the rubber
of dental dams, condoms, and surgi cal gl oves that were gl ued onto the outer wal l of tubes. Usi ng
ani mal tracheas donated by the fami l y butcher as his model , he consi dered whether the cuff
should be posi ti oned above, below, or at the level of the vocal cords. He recommended that the
cuff be positi oned just bel ow the vocal cords to seal the airway. Waters l ater recommended that
cuffs be constructed of two layers of soft rubber cemented together. These detachable cuffs were
fi rst manufactured by Waters' chi ldren, who sol d them to the Foregger Company.
Guedel sought ways to show the safety and uti l i ty of the cuffed tube. He first fil l ed the mouth of
an anestheti zed and i ntubated pati ent wi th water and showed that the cuff seal ed the ai rway.
Even though this exhi biti on was successful , he searched for a more dramatic techni que to capture
the attention of those unfami l iar wi th the advantages of intubation. He reasoned that if the cuff
prevented water from enteri ng the trachea of an intubated pati ent, i t should al so prevent an
animal from drowning, even if it were submerged under water. To encourage physi ci ans attendi ng
a medical convention to use hi s tracheal techni ques, Guedel prepared the first of several dunked
dog demonstrati ons (Fi g. 1-4). An anestheti zed and i ntubated dog, Guedel' s own pet, Airway,
was i mmersed i n an aquari um. After the demonstrati on was completed, the anestheti c was
di sconti nued before the ani mal was removed from the water. Ai rway awoke promptly, shook water
over the onlookers, saluted a post, then trotted from the hall to the appl ause of the audi ence.
Endobr onchi al TubesThe Next St ep
After a pati ent experienced an acci dental endobronchi al intubati on, Ral ph Waters reasoned that a
very long cuffed tube coul d be used to venti l ate the dependent l ung whi le the upper lung was
bei ng resected.
81
On l earni ng of hi s friend' s success with intenti onal one-lung anesthesia, Arthur
Guedel proposed an i mportant modificati on for chest surgery, the doubl e-cuffed si ngl e-lumen
tube, which was introduced by Emery Rovensti ne. These tubes were easil y posi ti oned, an
advantage over bronchi al bl ockers that had to be inserted by a skil l ed bronchoscopi st.
Foll owi ng Worl d War II, several doubl e-cuffed si ngl e-lumen tubes were used for thoraci c surgery,
but after 1953, these were supplanted by double-lumen endobronchi al tubes. The doubl e-lumen
tube currentl y most popul ar was desi gned by Frank Robertshaw of Manchester, Engl and, and i s
prepared i n both ri ght- and l eft-si ded versi ons. Robertshaw tubes were first manufactured from
mi neral i zed red rubber but are now made of extruded pl asti c, a techni que refi ned by Davi d
FIGURE 1-4. The dunked dog. Arthur Guedel demonstrated the safety of endotracheal
intubation with a cuffed tube by submergi ng his anesthetized pet, Ai rway, in an aquarium
whi l e the ani mal breathed an ethyl ene-oxygen anestheti c through an underwater Waters' to-
and-fro anesthesia ci rcuit.
Sheri dan. Sheri dan was al so the first person to embed centi meter markings al ong the si de of
tracheal tubes, a safety feature that reduced the ri sk of the tube' s bei ng i ncorrectl y posi ti oned.
Ai r way Management Devi ces
Conventi onal l aryngoscopes proved inadequate for pati ents with di fficul t airways. A few
cl i ni ci ans credi t harrowing i ntubati ng experi ences as the i ncentive for i nventi on. In 1928, a rigi d
bronchoscope was specificall y desi gned for exami nation of the l arge airways. Ri gi d bronchoscopes
were refi ned and used by pul monol ogi sts. Al though it was known i n 1870 that a thread of gl ass
coul d transmi t l ight al ong i ts length, technological li mitati ons were not overcome unti l 1964 when
Shi geto Ikeda developed the first flexi bl e fi beropti c bronchoscope. Fi beropti c-assi sted tracheal
intubati on has become a common approach i n the management of pati ents with diffi cult ai rways
havi ng surgery.
Roger Bul l ard desired a devi ce to simul taneousl y examine the l arynx and i ntubate the vocal cords.
He had been frustrated by fai l ed attempts to vi sual i ze the larynx of a pati ent wi th Pi erre-Robi n
syndrome. In response, he devel oped the Bul l ard l aryngoscope, whose fi beropti c bundl es l i e
besi de a curved blade. Si mi l arl y, the Wu-scope was desi gned by Tzu-Lang Wu i n 1994 to combine
and faci l itate visual i zati on and i ntubation of the trachea in pati ents wi th diffi cult ai rways.
82

The passage of fl exi bl e fi beropti c bronchoscopes has been ai ded by intubati ng ai rways such as
those desi gned by Berman, Ovassapi an, Augustine, Wil l iams, Luomanen, and Pati l . Pati ents
requi ring conti nuous-oxygen admini stration during fi beropti c bronchoscopy may breathe through
the Patil face mask, which features a separate ori fi ce through which the scope i s advanced. The
Patil face mask i s onl y one of an extensive series of ai des to i ntubati on created by the i nnovati ve
Vijay Patil.
Dr. A. I. J. Archi e Brai n first recognized the pri nci pl e of the l aryngeal mask airway (LMA) i n
1981 when, li ke many Bri tish cl i ni cians, he provi ded dental anesthesia via a Gol dman nasal mask.
However, unl i ke any before hi m, he real i zed that just as the dental mask coul d be fi tted cl osel y
about the nose, a comparabl e mask attached to a wi de-bore tube mi ght be positi oned around the
larynx. He not onl y concei ved of this radical departure i n ai rway management, whi ch he fi rst
descri bed i n 1983,
83
but also spent years i n si ngl e-handedl y fabri cati ng and testing scores of
incremental modificati ons. Scores of Brai n' s prototypes are displayed i n the Royal Berkshi re
Hospi tal , Readi ng, Engl and, where they provide a detail ed record of the evolution of the LMA. He
fabricated his first model s from Magi l l tubes and Gol dman masks, then refi ned thei r shape by
performing postmortem studi es of the hypopharynx to determi ne the form of cuff that woul d be
most functi onal . Before si l i cone rubber was sel ected, Brai n had even mastered the techni que of
formi ng masks from li qui d l atex. Every detail of the LMA, the number and posi ti on of the aperture
bars, the shape and the si ze of the masks, requi red repeated modi fi cati on.

PATIENT MONITORING
In many ways, the history of l ate-ni neteenth- and early-twenti eth-century anesthesi ol ogy i s the
quest for the safest anestheti c. The di scovery and widespread use of el ectrocardi ography, pul se
oxi metry, bl ood gas anal ysi s, capnography, and neuromuscular blockade moni toring have reduced
patient morbi dity and mortali ty and revol utioni zed anesthesia practice. Whil e safer machi nes
assured cl i ni ci ans that appropri ate gas mi xtures were del i vered to the patient, moni tors provided
an earl y warni ng of acute physi ol ogi c deteri orati on before pati ents suffered i rrevocabl e damage.
Joseph Cl over was one of the fi rst cl i ni cians to routi nel y perform basi c hemodynamic monitori ng.
Cl over devel oped the habi t of monitori ng hi s pati ents' pulse but surprisi ngl y, this was a
contentious i ssue at the ti me. Promi nent Scotti sh surgeons scorned Cl over' s emphasis on the
acti on of chl oroform on the heart. Baron Li ster and others preferred that seni or medical students
gi ve anesthetics and urged them to stri ctl y carry out certain simpl e instructi ons, among whi ch i s
that of never touchi ng the pul se, i n order that their attenti on may not be distracted from the
respirati on.
84
Lister al so counsel ed, it appears that prel i mi nary exami nati on of the chest, often
consi dered i ndi spensabl e, i s qui te unnecessary, and more li kel y to i nduce the dreaded syncope, by
P.17
al armi ng the pati ents, than to avert it.
84
Little progress in anesthesi a could come from such
reacti onary statements. In contrast, Clover had observed the effect of chl oroform on ani mal s and
urged other anestheti sts to moni tor the pulse at al l ti mes and to di scontinue the anestheti c
temporaril y if any i rregul ari ty or weakness was observed i n the strength of the pul se.
Two Ameri can surgeons, George W. Cri l e and Harvey Cushi ng, devel oped a strong i nterest i n
measuri ng bl ood pressure duri ng anesthesi a. Both men wrote thorough and detai l ed exami nati ons
of bl ood pressure moni tori ng; however, Cushi ng' s contributi on i s better remembered because he
was the first American to appl y the Riva Rocci cuff, which he saw while visiting Italy. Cushing
introduced the concept i n 1902 and had blood pressure measurements recorded on anesthesia
records.
85
In 1894, Cushing and a fel l ow student at Harvard Medi cal School , Charl es Codman,
initi ated a system of recordi ng patients' pul ses to assess the course of the anestheti cs they
administered. In 1902, Cushi ng conti nued the practice of moni tori ng and recordi ng pati ent bl ood
pressures and pulses. The transi tion from manual to automated blood pressure devices, which fi rst
appeared i n 1936 and operate on an oscil l ometric pri ncipl e, has been gradual . The devel opment of
inexpensive mi croprocessors has enabled routine use of automati c cuffs i n cl i ni cal setti ngs.
The fi rst precordi al stethoscope was bel ieved to have been used by S. Griffith Davis at Johns
Hopkins Uni versi ty.
65
He adapted a techni que devel oped by Harvey Cushi ng in a l aboratory i n
whi ch dogs wi th surgicall y induced val vul ar l esions had stethoscopes attached to thei r chest wal l
so that medi cal students mi ght l isten to brui ts characteri sti c of a specific mal formati on. Davi s'
technique was forgotten but was rehabi li tated by Dr. Robert Smi th, an energetic pi oneer of
pedi atric anesthesiol ogy in Boston. A Canadi an contemporary, Al bert Codesmi th, of the Hospi tal
for Si ck Chi l dren, Toronto, became frustrated by the repeated dislodgi ng of the chest piece under
the surgi cal drapes and fabri cated hi s fi rst esophageal stethoscope from urethral catheters and
Penrose drai ns. Hi s bri ef report heralded i ts cl i ni cal rol e as a moni tor of both normal and
adventi tious respi ratory and cardi ac sounds.
86
An addi ti onal benefi t was that the stethoscope
coul d protect agai nst the ri sk of di sconnection of a paral yzed pati ent from the anesthesia circui t.
In the era before audi bl e ci rcuit di sconnect al arms, the patient' s survi val depended upon the
anesthesiol ogi st' s recogni ti on of the sudden di sappearance of breath sounds.
El ect r ocar di ogr aphy, P ul se Oxi met r y, and Capnogr aphy
Cli nical el ectrocardi ography began wi th Wi ll em Ei nthoven' s appl i cation of the string galvanometer
in 1903. Withi n two decades, Thomas Lewis had described its rol e in the di agnosi s of di sturbances
of cardi ac rhythm, whi l e James Herrick and Harold Pardee fi rst drew attention to the changes
produced by myocardi al i schemi a. After 1928, cathode ray oscil l oscopes were avai l abl e, but the
ri sk of expl osi on owi ng to the presence of flammabl e anestheti cs forestall ed the i ntroduction of
the electrocardi ogram i nto routi ne anesthetic practice until after Worl d War II. At that ti me, the
smal l screen of the heavil y shiel ded bul let osci l loscope di spl ayed onl y 3 seconds of data, but
that i nformati on was hi ghl y pri zed.
Pul se oxi metry, the opti cal measurement of oxygen saturati on i n ti ssues, is one of the more recent
addi ti ons to the anesthesi ol ogi st' s array of routi ne monitors. Severinghaus states, Pul se oxi metry
is arguabl y the most important technol ogi cal advance ever made i n moni tori ng the wel l -bei ng and
safety of pati ents duri ng anesthesia, recovery, and criti cal care.
87
Although research in this area
began in 1932, i ts fi rst practi cal appli cati on came during Worl d War II. An American physiol ogi st,
Gl en Mil l ikan, responded to a request from Briti sh col l eagues i n aviation research. Mi l li kan set
about prepari ng a seri es of devi ces to i mprove the suppl y of oxygen that was provi ded to pi l ots
fl ying at hi gh al ti tude i n unpressuri zed ai rcraft. To moni tor oxygen del i very and to prevent the
pi l ot from succumbing to an unrecogni zed fai lure of hi s oxygen supply, Mil l i kan created an
oxygen-sensi ng moni tor worn on the pi l ot' s earlobe, and coined the name oxi meter to descri be i ts
acti on. Before his tragi c death i n a cl i mbi ng acci dent i n 1947, Mil l ikan had begun to assess
anesthetic appl i cations of oxi metry.
For the next three decades, oxi metry was rarel y used by anesthesi ol ogi sts, and then pri mari l y i n
research studies such as those of Al bert Faulconer and John Pender. Refi nements of oximetry by a
Japanese engi neer, Takuo Aoyagi , l ed to the devel opment of pul se oximetry. As John Severi nghaus
recounted the epi sode, Aoyagi had attempted to el iminate the changes i n a si gnal caused by
pul satil e vari ati ons when he real ized that this fluctuation could be used to measure both the pulse
and oxygen saturation.
87

Although pul se oximetry gives second-by-second data about oxygen saturati on, anesthesi ol ogists
have recogni zed a need for breath-by-breath measurement of respi ratory and anesthetic gases.
After 1954, i nfrared absorpti on techni ques gave immedi ate di splays of the exhaled concentration
of CO
2
. Cl ini ci ans qui ckl y l earned to rel ate abnormal concentrations of CO
2
to threateni ng
si tuati ons such as the i nappropri ate pl acement of a tracheal tube i n the esophagus, abrupt
al terati ons in pulmonary bl ood flow, and other factors. More recentl y, i nfrared anal ysis has been
perfected to enabl e breath-by-breath measurement of anestheti c gases as well . This technol ogy
has largel y repl aced mass spectrometry, which initi al l y had only i ndustri al appl i cations before
Albert Faul coner of the Mayo Cli ni c fi rst used i t to monitor the concentrati on of an exhaled
anesthetic i n 1954.
The abil i ty to confi rm endotracheal i ntubati on and monitor venti lation, as refl ected by
concentrations of CO
2
in respi red gas, began i n 1943. At that ti me, K. Luft descri bed the pri nci pl e
of infrared absorption by CO
2
and he devel oped an apparatus for measurement.
88
Routi ne
appl i cati on of capnography i n anesthesi a practi ce was pi oneered by Dr. Bob Smal hout and Dr.
Zden Kal enda i n the Netherl ands. Breath-to-breath conti nuous moni toring and a waveform di splay
of CO
2
level s hel p

anesthesiol ogi sts recogni ze abnormali ties i n metabol ism, venti lation, and circul ati on.
INTRAVENOUS MEDICATIONS IN ANESTHESIA
Pri or to Wi l li am Harvey' s descripti on of a complete and continuous intravascul ar ci rcui t i n De Motu
Cordi s (1628), i t was wi dely hel d that blood emanated from the heart and was propel led to the
peri phery where i t was consumed. The idea that substances coul d be i njected intravascul arl y and
travel systemi cal ly probably ori ginated wi th Christopher Wren. In 1657, Wren i njected aqueous
opi um i nto a dog through a goose quil l attached to a pi g' s bl adder, renderi ng the ani mal
stupefi ed.
89
Wren si mil arl y i njected i ntravenous crocus mettalorum, an i mpure preparati on of
anti mony, and observed the ani mals to vomi t and then die. Knowl edge of a circul atory system and
intravascul ar access spurred i nvestigati ons i n other areas, and Wren' s contemporary, Ri chard
Lower, performed the fi rst bl ood transfusi ons of lamb' s blood i nto dogs and other animal s.
In the mid-ni neteenth century, equipment necessary for effecti ve intravascul ar i njecti ons was
conceived. Vacci nati on l ancets were used i n the 1830s to puncture the ski n and force morphi ne
paste subcutaneousl y for anal gesia.
90
The hol l ow needl e and hypodermi c syri nge were devel oped
in the fol lowi ng decades but were not initi al l y designed for i ntravenous use. In 1845, Dubl in
surgeon Franci s Rynd created the hol l ow needl e for i njecti on of morphi ne i nto nerves in the
treatment of neural gi as. Simil arl y, Charl es Gabri el Pravaz designed the fi rst functi onal syri nge i n
1853 for perineural i njections. Alexander Wood, however, is generall y credited wi th perfecting the
hypodermic gl ass syringe. In 1855, Wood publ ished a paper on the injecti on of opi ates into painful
spots by use of hol l ow needl e and hi s gl ass syri nge.
91

In 1872, Pierre Or of Lyons performed what i s perhaps the fi rst successful i ntravenous surgi cal
anesthetic by i njecti ng chl oral hydrate immedi atel y prior to i nci si on. His 1875 publi cation
descri bes its use i n 36 pati ents but several postoperative deaths l ent l i ttl e to recommend thi s
method to other practi ti oners.
92
In 1909, Ludwig Burkhardt produced surgical anesthesi a by
intravenous i njecti ons of chl oroform and ether in Germany. Seven years later, Eli sabeth
Bredenfeld of Swi tzerl and reported the use of intravenous morphi ne and scopol amine. The tri al s
fai l ed to show an i mprovement over i nhal ed techni ques. Intravenous anesthesia found l i ttle
appl i cati on or popul ari ty, pri mari l y because of a lack of sui tabl e drugs. In the fol l owi ng decades,
thi s woul d change.
INDUCTION AGENTS
The fi rst barbi turate, barbi tal , was synthesi zed i n 1903 by Fischer and von Meri ng. Phenobarbi tal
P.18
and al l other successors of barbi tal had very protracted acti on and found l i ttle use i n anesthesia.
After 1929, oral pentobarbi tal was used as a sedative before surgery, but when i t was given i n
anesthetic concentrati ons, l ong peri ods of unconsciousness foll owed. The fi rst short-acti ng
oxybarbiturate was hexobarbital (Evipal ), avai l abl e cli nical l y i n 1932. Hexobarbital was
enthusi asticall y recei ved by the anesthesia communi ti es in Europe and North America because i ts
abbrevi ated i nducti on ti me was unri val ed by any other techni que. A London anestheti st, Ronal d
Jarman, found that it had a dramatic advantage over i nhal ati on i nducti ons for minor procedures.
Jarman instructed hi s pati ents to rai se one arm whi l e he i njected hexobarbi tal i nto a vei n of the
opposi te forearm. When the upraised arm fell, indicating the onset of hypnosi s, the surgeon could
begi n. Pati ents were al so amazed i n that many awoke unabl e to bel i eve they had been
anesthetized.
93
(Soon after Evi pal was i ntroduced, Robert Maci ntosh admini stered i t to Si r Wil l i am
Morri s, the manufacturer of the Morris Garages [MG] automobil es. When Morri s awoke, he learned
that his surgery was compl eted, and was amazed by this magic experience, whi ch he contrasted
with hi s vi vi d recoll ecti ons of the terror of undergoi ng a mask inducti on as a chi ld in a denti st' s
office. Morris [l ater, Viscount Nuffi el d] i nsisted, over the objections of Oxford's medical
establ i shment, on endowi ng a department of anesthesi a for the uni versi ty as a precondi ti on of hi s
support for a postgraduate medi cal center. In 1937, Si r Robert Maci ntosh became Oxford' s fi rst
professor of anesthesiol ogy. He l ed the growth of the first uni versity department i n Europe from
the fi rst ful l y endowed Chai r of Anaesthesi a and hel ped establi sh one of the most di sti ngui shed
anesthesia centers i n the worl d.)
Even though the prompt acti on of hexobarbi tal had a dramati c effect on the conduct of anesthesi a,
it was soon replaced by two thi obarbiturates. In 1932, Donal ee Tabern and Ernest H. Vol wi ler of
the Abbott Company synthesi zed thi opental (Pentothal ) and thi amyl al (Suri tal ). The sulfated
barbiturates proved to be more sati sfactory, potent, and rapi d acting than were their
oxybarbiturate anal ogs. Thi opental was fi rst admini stered to a pati ent at the Uni versi ty of
Wi sconsi n i n March 1934, but the successful i ntroduction of thiopental into cl i ni cal practice
fol l owed a thorough i nvesti gati on conducted by John Lundy and hi s col leagues at the Mayo Cl inic
in June 1934.
When first i ntroduced, thiopental was often gi ven i n repeated increments as the primary
anesthetic for protracted procedures. Its hazards were soon appreci ated. At fi rst, depressi on of
respirati on was moni tored by the si mple expedi ent of observi ng the moti on of a wisp of cotton
pl aced over the nose. Only a few ski l l ed practi ti oners were prepared to pass a tracheal tube i f the
pati ent stopped breathi ng. Such practi tioners real ized that thi opental wi thout suppl ementati on di d
not suppress ai rway refl exes, and they therefore encouraged the prophyl actic provisi on of topi cal
anesthesia of the ai rway beforehand. The vasodi l atory effects of thi obarbi turates were wi del y
appreci ated only when thi opental caused cardi ovascul ar coll apse in hypovol emi c burned ci vi l ian
and mi l itary pati ents i n World War II. In response, fl ui d replacement was used more aggressi vely
and thi opental administered with greater cauti on.
In 1962, ketamine was synthesized by Dr. Cal vi n Stevens at the Parke Davis l aboratories i n Ann
Arbor, Mi chi gan. One of the cycl ohexylami ne compounds that i ncl udes phencycl i di ne (PCP),
ketami ne was the only drug of thi s group that gained cli ni cal uti l i ty. The other compounds
produced undesi rabl e postanesthetic del i ri um and psychomi meti c reacti ons. In 1966, the
neol ogism di ssociative anesthesi a was created by Guenter Corrsen and Edward Domino to
descri be the trance-li ke state of profound anal gesi a produced by ketami ne.
94
It was rel eased for
use in 1970 and al though i t remai ns primari ly an agent for anestheti c inducti on, i ts anal gesic
properties are i ncreasingly studied and uti li zed by pai n speci al i sts.
Etomi date was first descri bed by Paul Janssen and hi s coll eagues i n 1964, and ori ginal l y gi ven the
name Hypnomi date. Its key advantages, minimal hemodynami c depressi on and l ack of hi stami ne
rel ease, account for i ts ongoing uti li ty i n cl i ni cal practi ce. It was released for use in 1974 and
despi te i ts drawbacks (pai n on injecti on, myocl onus, postoperati ve nausea and vomi ti ng, and
i nhi bi ti on of adrenal steroi dogenesi s), etomi date i s often the drug of choice for anesthetizing
hemodynamicall y unstabl e pati ents.

P.19
Propofol , or 2,-6 di -isopropyl phenol , was fi rst synthesi zed by Imperi al Chemi cal Industries and
tested cl ini cal ly i n 1977. Investigators found that i t produced hypnosis quickl y wi th mi ni mal
exci tati on and that pati ents awoke promptly once the drug was di sconti nued. In addi ti on to i ts
excel l ent induction characteri sti cs, propofol ' s anti emeti c acti on made i t an agent of choi ce i n
pati ent popul ati ons prone to nausea and emesi s. Regrettabl y, Cremophor EL, the sol vent wi th
whi ch i t was formul ated, produced several severe anaphyl actic reactions and it was wi thdrawn
from use. Once propofol was reformul ated wi th egg l eci thi n, gl ycerol , and soybean oil , the drug
reentered cl i ni cal practice and gai ned great success. Its popul ari ty i n Bri tai n coi ncided wi th the
introducti on of the LMA, and i t was soon noted that propofol suppressed pharyngeal refl exes to a
degree that permi tted the i nserti on of an LMA wi thout a need for either muscl e relaxants or potent
inhaled anesthetics.
Opi oi ds
Opi oi ds (hi stori cal ly referred to as narcoti cs, al though semanti cal l y i ncorrectsee Chapter 14)
remai n the anal gesic workhorse i n anesthesi a practi ce. They are used routi nel y i n the
peri operative peri od, i n the management of acute pai n, and i n a variety of termi nal and chroni c
pai n states. The avai labi li ty of short-, medium-, and long-acti ng opi oids, as wel l as the many
routes of administrati on, gives physi cians considerabl e fl exi bi li ty i n the use of these agents. The
anal gesi c and sedati ng properti es of opi um have been known for over two mil l ennia. Certainl y the
Greeks and Chi nese ci vi l izati ons harnessed these properti es i n medi cal and cul tural practices.
Opi um i s deri ved from the seeds of the poppy (Papaver somniferum), and i s an amalgam of over
25 pharmacol ogic al kal oids. The fi rst al kal oi d i sol ated, morphi ne, was extracted by Prussian
chemi st Frei drich A.W. Sertrner i n 1803. He named this alkal oid after the Greek god of dreams,
Morpheus. Morphine became commonl y used as a suppl ement to inhaled anesthesia and for
postoperative pai n control duri ng the latter hal f of the ni neteenth century. Codeine, another
al kaloi d of opium, was i sol ated i n 1832 by Robi quet but i ts relatively weaker anal gesi c potency
and nausea at hi gher doses li mi ts its rol e i n managi ng moderate to severe perioperative surgi cal
pai n.
Meperidi ne was the fi rst synthetic opi oi d and was devel oped in 1939 by two German researchers at
IG Farben, Otto Ei sl eb and O. Schaumann. Al though many pharmacol ogi sts are remembered for
the introducti on of a si ngl e drug, one prol ifi c researcher, Paul Janssen, has since 1953 brought
forward more than 70 agents from among 70,000 chemicals created i n his l aboratory. Hi s products
have had profound effects on di sci pli nes as disparate as parasitol ogy and psychi atry. The pace of
producti ve i nnovati on i n Janssen' s research l aboratory i s astonishi ng. Chemi cal R4263 (fentanyl),
synthesized in 1960, was foll owed onl y a year l ater by R4749 (droperi dol ), and then etomidate in
1964. Innovar, the fixed combi nation of fentanyl and droperi dol , i s l ess popul ar now but Janssen's
phenyl peperi di ne deri vati ves, fentanyl, sufentani l and al fentani l , are stapl es in the anesthesia
pharmacopoeia. Remifentanil , an ul tra short-acti ng opi oid introduced by Gl axo-Wel l come i n 1996,
i s a departure from other opioi ds i n that it has very rapid onset and equal l y rapi d offset due to
metaboli sm by nonspeci fi c tissue esterases. Ketorolac, a nonsteroidal antii nflammatory drug
(NSAID) approved for use in 1990, was the fi rst parenteral NSAID i ndi cated for postoperati ve
pai n. Wi th a 6- to 8-mg morphi ne equival ent anal gesi c potency, Ketorol ac provi des si gni fi cant
postoperative pai n control , and has parti cul ar use as a sole i ntravenous agent in minor
procedures, or for pain attenuati on when an opi oi d-spari ng approach i s essenti al . Ketorol ac use is
l i mi ted by si de effects and may be i nappropri ate i n pati ents wi th underl yi ng renal dysfunction,
bl eedi ng probl ems, or compromi sed bone heal i ng.
Ant i emet i cs
Effective treatment for postoperati ve nausea and vomi ti ng (PONV) evol ved rel ati vel y recentl y and
has been dri ven by incenti ves to li mi t hospi tal i zati on expenses and i mprove pati ent sati sfaction.
But PONV i s an ol d probl em for whi ch l ate-ni neteenth-century practi ti oners recognized many
causes including anxiety, severe pai n, sudden changes i n bl ood pressure, i l eus, i ngesti on of bl ood,
and the resi dual effects of opi oi ds and i nhal ati onal anestheti cs. Ri sk of pulmonary aspirati on of
gastri c contents and subsequent death from asphyxi a or aspi rati on pneumonia was a feared
consequence of anestheti cs, especiall y those precedi ng use of cuffed endotracheal tubes. Vomi ti ng
and aspi rati on duri ng anesthesi a led to the practice of mai ntaining an empty stomach
preoperati vel y, a pol i cy that conti nues today despi te evi dence that cl ear fl ui ds up to 3 hours
before surgery do not i ncrease gastri c volumes, change gastri c pH, or i ncrease the ri sk of
aspirati on.
A vari ety of treatments for nausea and vomi ti ng were proposed by early anestheti sts. James
Gwathemy' s 1914 publ icati on, Anesthesi a, commented that Bri tish surgeons customari ly gave
ti ncture of iodi ne i n a teaspoonful of water every hal f hour for three or four doses. Inhal ati on of
vinegar fumes, and rectal injecti on of 30 to 40 drops of tincture of opium with 60 grains of sodium
bromi de were al so felt to qui et the vomi ti ng center.
95
Other practiti oners attempted ol factory
control by pl aci ng a pi ece of gauze moistened wi th essence of orange or an aromati c oi l on the
upper l i p of the pati ent.
96
A 1937 anesthesi a textbook encouraged treatment of PONV with lateral
positi oning, iced soda water, strong bl ack coffee, and chl oretone.
97
Counterirri tati on, such as
mustard l eaf on the epi gastri um, was also beli eved useful i n l i mi ti ng emesis.
98
As late as 1951,
anesthesia texts recommended oxygen admi nistrati on, whi ffs of ammonia spi ri ts, and control of
bl ood pressure and posi ti oni ng.
99
The compl ex central mechani sms of nausea and vomi ting were
l argel y unaffected by most of these treatments. Newer drugs capable of i nterveni ng at speci fi c
pathways were needed to have an i mpact on PONV. As more short-acti ng anestheti cs were
devel oped, the probl em recei ved sharper focus i n awake postoperative pati ents in the recovery
room. The nausea attending use of newer chemotherapy agents provi ded additi onal i mpetus to the
development of anti emetic medicati ons.
In 1955, a nonrandomized study usi ng the anti histamine cycli zi ne showed a reducti on i n PONV
from 27% to 21% i n a group of 3,000 pati ents. The foll owing year, a more ri gorous study by
Knapp and Beecher reported a si gni fi cant benefi t from prophyl axi s wi th the neurol epti c
chlorpromazi ne. In 1957, promethazi ne (Phenergan) and chl orpromazine were both found to
reduce PONV when used prophyl acticall y. Thi rteen years later, a doubl e-bl i nd study evaluati ng
metocl oprami de was publ i shed and i t became a fi rst-l i ne drug in the management of PONV.
Droperi dol , released in the earl y 1960s, became wi dely used unti l 2001 when concerns regarding
prolongation of QT i nterval s prompted a warning from the Food and Drug Admi nistrati on about its
conti nued use.
The antiemeti c effects of corti costeroi ds were first recognized by oncol ogi sts treati ng i ntracrani al
edema from tumors.
100
Subsequent studi es have borne out the antiemeti c properti es of this cl ass
of drugs i n treati ng PONV. Recogniti on of the serotoni n 5-HT3 pathway i n PONV has l ed to a
uni que cl ass of drugs devoted onl y to addressi ng thi s parti cul ar probl em. Ondansetron, the fi rst
representati ve of

this drug cl ass, was FDA approved i n 1991. Additi onal serotonin 5-HT3 antagoni sts have been
approved and are avail able today.
Muscl e Rel axant s
Muscl e rel axants entered anesthesi a practi ce nearl y a century after inhal ati onal anestheti cs. (See
Tabl e 1-1.) Curare, the fi rst known neuromuscular blocki ng agent, was ori ginall y used in hunti ng
and tri bal warfare by nati ve peopl es of South America. The curares are alkaloi ds prepared from
pl ants nati ve to equatorial rai n forests. The refi nement of the harmless sap of several species of
vines into toxi ns that were l ethal only when injected was an extraordinary triumph introduced by
pal eopharmacol ogi sts i n loi ncl oths. Thei r di scovery was the more remarkabl e because it was
i ndependentl y repeated on three separate continentsSouth Ameri ca, Afri ca, and Asi a. These
jungle tribes also devel oped nearly i dentical methods of del i veri ng the toxi n by darts, whi ch, after
bei ng di pped i n curare, mai ntai ned their potency indefi ni tel y unti l they were propel led through
bl owpi pes to stri ke the fl esh of monkeys and other ani mal s of the treetops. Moreover, the
Ameri can Indi ans knew of the juice of an herb that would counteract the effects of the poi son i f
administered i n ti me.
101

P.20
TABLE 1-1 Events in the Development of Muscle Relaxants
Year Event
1516 Peter Martyr d' Anghera, De orbe novo, publ i shed account of South Ameri can
Indi an arrow poi sons
1596 Sir Wal ter Ral ei gh provi des detai led account of arrow poi son effects and
anti dote
1745 Charl es-Mari e de l a Condami ne returns from Ecuador and conducts curare
experi ments wi th chi ckens and attempted to use sugar as an anti dote
1780 Abbe Fel i x Fontana inserts curare di rectly i nto exposed sciati c nerve of rabbi t
without effect, concludes that mechani sm i s the destruction of the i rritabil i ty
of voluntary muscles. Publishes On the Ameri can Poi son Ticunas (name of
South Ameri can tribe)
1811 Benjami n Coll i ns Brodi e demonstrates that ani mal s mechani cal l y venti l ated
may survi ve si gni fi cant doses of curare
1812 Wi l li am Sewel l suggests use of curare in hydrophobi a (rabies) and tetanus
1844 Cl aude Bernard determi nes that death occurs by respi ratory fai lure, motor
nerves are unabl e to transmi t stimul i from hi gher centers, di fferenti al effect
on muscl es with peri pheral and thoracic muscl es bei ng affected before
respiratory muscl es. Bernard concludes that the si te of action is the junction
between muscl es and nerves, neuromuscul ar juncti on
1858 Loui s Al bert Sayres, New York physici an, uses curare to treat tetanus i n two
patients
1864 Physostigmi ne i sol ated from Calabar beans by Si r T.R. Fraser, a Scottish
pharmacol ogist
1886
1897
R. Boehm, a German chemi st, demonstrated three separate classes of
al kaloi ds in each of three types of i ndi genous containers: tube-curares, pot-
curares, and calabash-curares
1900 Jacob Pal recogni zes that physosti gmi ne can antagoni ze the effects of curare
1906 Succi nylchol i ne prepared by Rei d Hunt and R. Taveau, experi mented on
rabbits pretreated wi th curare to l earn of cardiac effects and so paral ysi s
went unrecogni zed
Accounts from sixteenth-century expl orers of South Ameri ca incl ude reports of the poison-arrow
darts used by the nati ves. In 1564, Si r Wal ter Ral eigh descri bed the effects of curare upon thei r
targets, as wel l as the use of an anti dote. Later, expl orers brought home sampl es of the poison-
ti pped darts to Europe and Great Bri tai n where sci entific studi es were undertaken. Earl y
experi ments on bi rds, cats, rabbits, and dogs in the 1780s veri fi ed that the poi son worked by
aboli shi ng muscle functi on, i ncl udi ng respi ratory muscles, and that di rect i nserti on into nerves had
no effect. In 1811, Benjami n C. Brodi e demonstrated that l arge ani mals such as horses and
donkeys treated with curare could be kept al i ve i f venti l ated for several hours through a bell ows
sewn directl y to the trachea.
101

The earl iest cli ni cal use of curare in humans was to amel i orate the tortuous muscle spasms of
infecti ous tetanus. In 1858, New York physici an Loui s Al bert Sayres reported two cases i n whi ch
he attempted to treat severe tetanus wi th curare at the Bel levue Hospital . Both of hi s pati ents
1912 Arthur Lawen uses curare in surgery but report publ i shed i n German and goes
largel y unrecogni zed
1938 Ri chard and Ruth Gi l l bri ng l arge quantity of curare to New York for further
study by pharmaceuti cal company
1939 Abram E. Bennett uses curare in chi ldren with spasti c disorders and to
prevent trauma from metrazol therapy (precursor to ECT)
1942 Harol d Griffi th and Eni d Johnson use curare for abdomi nal rel axati on i n
surgery
1942 H. A. Hal ody devel ops Rabbi t drop head Assay for standardi zati on and large-
scal e producti on of curare and d-tubocurari ne
1948 Decamethoni um, a depol ari zi ng rel axant, is synthesized
1949 Succi nylchol i ne prepared by Dani el Bovet, the fol l owi ng year by J.C. Casti l l o
and Edwi n de Beer
1956 Di sti ncti on between depol ari zi ng and nondepol ari zi ng neuromuscul ar bl ockade
i s made by Wi l l i am D. M. Paton
1964 Pancuroni um rel eased for use i n humans, synthesi zed by Savage and Hewett
1979 Vecuroni um i ntroduced, speci fi cal l y designed to be more hepati cal ly
metabol i zed than pancuroni um
1993 Mi vacurium rel eased for cl i ni cal use
1994 Rocuronium i ntroduced to cli ni cal practi ce
di ed. Si mil ar efforts were undertaken to use muscl e rel axants to treat epi l epsy, rabi es, and
choreaform di sorders. Treatment of Parki nson-li ke ri gi di ty and the preventi on of trauma from
sei zure therapy al so preceded the use of curare i n anesthesi a.
102

Interesti ngl y, curare antagonists were devel oped wel l before muscl e rel axants were ever used i n
surgery. In 1900, Jacob Pal , a Vi ennese physi cian, recogni zed that curare coul d be antagonized by
physosti gmi ne. Thi s substance had been i sol ated from the calabar bean some 36 years earli er by
Scotti sh pharmacol ogi st Si r T.R. Fraser. Neostigmine methylsulphate was synthesi zed i n 1931 and
was si gni fi cantl y more potent i n antagoni zi ng the effects of curare.
103

In 1938, Richard and Ruth Gil l returned to New York from South America, bringing wi th them 11.9
kg of crude curare col lected near thei r Ecuadori an ranch. Thei r moti vation was a mixture of
personal and al trui sti c goal s. Some months before, whi l e on an earli er vi si t to the Uni ted States,
Ri chard Gi l l learned that he had mul tipl e scl erosis. His physici an, Dr. Walter Freeman, menti oned
the possibi l ity that curare mi ght have a therapeuti c role i n the management of spasti c di sorders.
When the Gi l ls returned to the Uni ted States with their suppl y of crude curare, they encouraged
sci enti sts at E. R. Squi bb & Co. Squibb to take an i nterest in i ts uni que properti es. Squibb soon
offered semi refi ned curare to two groups of Ameri can anesthesi ol ogists, who assessed i ts acti on
but qui ckl y abandoned thei r studi es when i t caused total respi ratory paralysi s i n two pati ents and
the death of l aboratory ani mals.
The earl iest effecti ve cl i ni cal appli cati on of curare i n medici ne occurred i n physi atry. After A. R.
McIntyre refi ned a porti on of the raw curare in 1939, Abram. E. Bennett of Omaha, Nebraska,
injected i t into chi l dren wi th spasti c di sorders. Whi le no persi stent benefit coul d be observed i n
these pati ents, he next admini stered i t to patients about to recei ve metrazol , a precursor to
el ectroconvulsi ve therapy. Because it el i mi nated sei zure-induced fractures, they termed i t a
shock absorber. By 1941, other psychiatri sts foll owed thi s practice and, when they found that
the action of curare was protracted, occasi onall y used neosti gmi ne as an anti dote.
Curare was used i ni tial ly in surgery by Arthur Lawen in 1912, but the publ i shed report was wri tten
i n German and was i gnored for decades. Lawen, a physi ol ogi st and physi ci an from Lei pzi g, used
curare i n hi s l aboratory before bol dl y produci ng abdomi nal rel axati on at a li ght l evel of anesthesi a
in a surgi cal patient. Lawen' s efforts were not appreci ated for decades, and whi l e hi s pi oneeri ng
work anti ci pated l ater cl i nical appl icati on, safe use would have to await the introducti on of regul ar
intubati on of the trachea and controll ed venti lation of the l ungs.
104

Thi rty years after Lawen, Harol d Griffith, the chi ef anesthetist of the Montreal Homeopathi c
Hospi tal , l earned of A. E. Bennett' s successful use of curare and resolved to apply i t in anesthesi a.
As Gri ffi th was al ready a master of tracheal i ntubation, he was much better prepared than were
most of his contemporaries to attend to potential compl i cations. On January 23, 1942, Gri ffi th and
hi s resident, Eni d Johnson, anesthetized and i ntubated the trachea of a young man before
injecti ng curare earl y in the course of his appendectomy. Sati sfactory abdomi nal rel axation was
obtai ned and the surgery proceeded without incident. Griffith and Johnson' s report of the
successful use of curare i n the 25 pati ents of their seri es launched a revol uti on i n anesthetic
care.
105

Anesthesi ol ogists who practiced before muscle rel axants recall the anxi ety they felt when a
premature attempt to i ntubate the trachea under cycl opropane caused persisting l aryngospasm.
Before 1942, abdominal relaxation was possi bl e onl y i f the pati ent tol erated hi gh concentrati ons of
an i nhal ed anestheti c, whi ch mi ght bri ng profound respi ratory depressi on and protracted recovery.
Curare and the drugs that fol lowed transformed anesthesi a profoundly. Because intubati on of the
trachea coul d now be taught i n a deli berate manner, a neophyte coul d fail on a first attempt
without compromisi ng the safety of the pati ent. For the first ti me, abdomi nal rel axation coul d be
attai ned when curare was supplemented by l i ght pl anes of i nhal ed anesthetics or by a combi nati on
of intravenous agents provi ding bal anced anesthesi a. New fronti ers opened. Sedated and
paral yzed pati ents coul d now successful ly undergo the major physi ol ogic trespasses of
cardi opul monary bypass, del i berate hypothermia, or long-term respi ratory support after surgery.
P.21
Credi t for successful and safe introducti on of curare and d-tubocurari ne i nto anesthesi a must i n
part be gi ven to a Squi bb researcher named H. A. Hol aday. Crude, unstandardized preparati ons of
curare produced uncertai n cl ini cal effects and undesi rabl e si de effects rel ated to vari ous
impuriti es. Isol ati on of d-tubocurari ne i n 1935 renewed cl i ni cal i nterest but a method for
standardi zi ng Intocostri n and its purer deri vati ve, d-tubocurari ne, had yet to be devi sed. In the
early 1940s, i n part as a result of Griffi th and Johnson's successful tri al s, Squi bb embarked upon
wi de-scal e producti on. Hol aday devel oped a rel i abl e, easi l y reproduci ble method for standardizing
curare doses that became known as the Rabbi t head drop assay (Fi g. 1-5). The assay consisted of
aqueous curare soluti on i njected intravenousl y i n 0.1-mL doses every 15 seconds unti l the
endpoi nt, when the rabbi t became unable to rai se its head, was reached.
106

Successful cl inical use of curare l ed to the i ntroducti on of other muscl e rel axants. By 1948,
gal l ami ne and decamethoni um had been synthesi zed. Metubi ne, a curare redi scovered in the
1970s, was used cli nicall y in the same year. Succi nylchol ine was prepared by the Nobel l aureate
Daniel Bovet i n 1949 and was i n wide i nternati onal use before historians noted that the drug had
been synthesi zed and tested l ong beforehand.

In 1906, Rei d Hunt and R. Taveaux prepared succi nylchol ine among a series of chol i ne esters,
whi ch they had i njected into rabbi ts to observe their cardi ac effects. If thei r rabbi ts had not been
previ ously paralyzed wi th curare, the depol arizing acti on of succinyl chol i ne mi ght have been
recogni zed decades earl i er.
The abil i ty to monitor i ntraoperative neuromuscul ar bl ockade with nerve sti mul ators began i n
1958. Working at St. Thomas' Hospital in London, T. H. Christie and H. Churchi ll -Davidson
devel oped a method for moni tori ng peri pheral neuromuscul ar bl ockade duri ng anesthesi a. It was
not unti l 1970, however, that H. H. Al i and col leagues devi sed the techni que of del i veri ng four
supramaxi mal impul ses del i vered at 2 Hz (0.5 seconds apart), or a Train of Four, as a method of
quanti fyi ng the degree of residual neuromuscul ar bl ockade.
107

Research i n rel axants was reki ndl ed in 1960, when researchers became aware of the acti on of
maloeti ne, a rel axant from the Congo basi n. It was remarkable i n that i t had a steroi dal nucl eus.
Investi gati ons of maloetine led to pancuroni um in 1968. In the 1970s and 1980s, research shifted
toward identi fi cati on of speci fi c receptor biochemi stry and devel opment of receptor-specific drugs.
From these isoqui nol ones, four rel ated products emerged: vecuroni um, pi pecuroni um, rocuroni um,
and rapacuroni um. Rapacuronium, rel eased i n the early 1990s, was withdrawn from cl i ni cal use
FIGURE 1-5. The rabbi t head drop assay. H. A. Hal l oday of Squi bb pharmaceutical company
devel oped a method for standardi zi ng doses of curare and d-tubocurari ne by i njecti ng 0.1 mL
of aqueous curare soluti on every 15 seconds unti l the rabbi t coul d no longer rai se its head.
P.22
after several cases of i ntractable bronchospasm l ed to brai n damage or death. Four cl i ni cal
products based upon the steroi d parent drug d-tubocurari ne (atracuri um, mi vacuri um, doxacuri um,
and ci s-atracurium) also made i t to cli ni cal use. Recogni ti on that atracurium and cis-atracurium
undergo spontaneous degradati on by Hoffmann eli mi nation has defi ned a rol e for these muscle
rel axants i n patients with li ver and renal i nsuffi ciency.
BLOOD, FLUIDS, AND HEMODYNAMIC CONTROL
Pal eol i thic cave drawi ngs found i n France depi ct a bear l osi ng bl ood from mul ti pl e spear wounds,
indicati ng that primiti ve man understood the si mple relationship between bl ood and l i fe.
108
Over
10,000 years later, modern anesthesiol ogi sts attempt to preserve thi s intimate rel ati onshi p by
repl aci ng fl ui ds and bl ood products when faced with intravascul ar vol ume depl eti on or di mi nished
oxygen-carryi ng capacity from blood l oss. Interesti ngl y, knowl edge of bl ood and vol ume defi ci ts
rel ated to symptomati c hypovolemia and anemi a was probabl y first understood and connected wi th
the anci ent art of phl ebotomy, or bl oodl etti ng. Si nce before Hi ppocrates in the fi fth century BC,
bl oodl etti ng was practi ced to restore bal ance to the body's four humors: bl ood, phl egm, bl ack and
yell ow bi l e. From the mi ddle ages, Barbers performing venesection adverti sed thei r services wi th
the red (bl ood) and white (tourniquet) stri ped pol e that pati ents squeezed and used to steady
thei r arms duri ng the procedure. One to four pints of bl ood was typi cal ly drai ned at a ti me and the
procedure was stopped i f the patient became fai nt. Thi s amount i s intri gui ng in that it i s
consi stent wi th current understandi ng of acute bl ood l oss and the vol ume necessary to produce
symptoms secondary to anemi c hypovol emi c states. Recogni tion that phlebotomi zi ng more than 3
to 4 pi nts of bl ood l ed to undesi rabl e symptoms undoubtedl y occurred by process of tri al and
error.
109
The obvi ous probl em wi th bloodletti ng, erroneous therapeutic assumptions aside, was
that overzeal ous phl ebotomy coul d l ead to hypovol emi a and shock wi th no method avai l abl e for
restori ng fl ui ds to the i ntravascul ar compartment. Unrestrai ned venesecti on ki ll ed U.S. presi dent
George Washi ngton when i n 1799 he was drai ned of ni ne pints of bl ood i n 24 hours fol l owi ng a
throat i nfection.
The techni que that mi ght have saved Washi ngton from thi s fate, blood transfusi on, was fi rst
attempted i n 1667 by physi ci an to Loui s XIV, Jean Bapti ste Deni s. Deni s had l earned of Ri chard
Lower' s transfusion of l amb' s bl ood into a dog the previ ous year. Lamb' s bl ood was most
frequently used because the donating ani mal ' s essential qual iti es were thought to be transferred
to the reci pient. Despi te this dangerous trans-species transfusi on, Deni s' first pati ent got better.
His next two pati ents were not as fortunate, however, and Deni s avoi ded further attempts. Given
the poor outcomes of these early bl ood transfusi ons, and heated rel i gious controversy regardi ng
the impli cati ons of transferri ng ani mal -specific qual i ti es across speci es, blood transfusi on i n
humans was banned for over a hundred years i n both France and Engl and begi nni ng in 1670.
90

In 1900, Karl Landsteiner and Samuel Shattock i ndependentl y hel ped lay the sci enti fic basis of al l
subsequent transfusi ons by recogni zi ng that blood compatibi l ity was based upon di fferent bl ood
groups. Landstei ner, an Austri an physici an, ori ginal l y organized human blood i nto three groups
based upon substances present on the red bl ood cel l s. The fourth type, AB group, was i denti fi ed i n
1902 by two students, A. Decastrell o and A. Sturl i . Based upon these findi ngs, Reuben Ottenberg
performed the fi rst type-specific bl ood transfusi on i n 1907.
Transfusi on of physiologi c sol utions occurred i n 1831, independentl y performed by O'Shaughnessy
and Lewi ns i n Great Bri tai n. In hi s letter to The Lancet, Lewi ns descri bed transfusi ng l arge
vol umes of sal ine sol uti ons into pati ents wi th chol era. He reported that he would inject i nto adul ts
from 5 to 10 pounds of sal i ne sol uti on and repeat as needed.
110
Despi te i ts publi cation in a
promi nent journal , Lewi ns' techni que was apparentl y overl ooked for decades and bal anced
physi ol ogi c sol uti on avai l abi l i ty woul d have to awai t the coming of anal yti cal chemi stry.
ANESTHESIA ORGANIZATION AND EDUCATION
Anesthesi ol ogy evol ved slowl y as a medi cal speci al ty i n the United States. Whi le ether
remai ned the domi nant anesthetic i n America, the provisi on of anesthesi a was often a servi ce
rel egated to medical students, junior house offi cers, nurses, and nonprofessi onal s. The
subordinate status of anesthesi a was refl ected i n Ameri can art. Thomas Eaki ns' great studi es, The
Gross Cl i ni c of 1876 and The Agnew Cl i ni c of 1889, both present the surgeon as the focus of
attenti on, whereas the person administeri ng the anestheti c is seen among the supporti ng fi gures.
During the l ate nineteenth century, small communi ties were often served by a single physi ci an,
who assi gned a nurse to drop ether under hi s directi on. In larger towns, doctors practi ced
i ndependentl y and di d not wel come bei ng pl aced i n what they percei ved to be the subordi nate rol e
of anesthetist whil e thei r competi tors enhanced their surgi cal reputati ons and coll ected the larger
fees. Many Ameri can surgeons recal led the si mple techni ques they had practiced as junior house
officers and regarded anesthesi a as a techni cal craft that coul d be l eft to anyone. Some hospi tals
preferred to pay a sal ary to an anesthesi a nurse whi le gai ni ng a profit from the fees charged for
that person' s servi ces. The most compel l i ng argument to be advanced i n favor of nurse anesthesi a
was that of ski ll : a trained nurse who admini stered anesthetics every worki ng day was to be
preferred to a physi ci an who gave anesthesia i nfrequentl y.
Before the begi nni ng of the twenti eth century, Mary Botsford and Isabell a Herb
111
were among the
first Ameri cans to become speci al i sts i n anesthesia. Both women were highly regarded as
cl i ni ci ans and al so were i nfl uenti al in the formati on of special ty societi es. Dr. Botsford is bel ieved
to have been the

first woman to establ i sh a practi ce as a speci al i st i n anesthesi a. In 1897, she became the
anesthesiol ogi st at a chi ldren' s hospital i n San Franci sco. Fol l owing her exampl e, several other
Cal i fornian female physi ci ans entered the speci al ty. Botsford l ater received the fi rst academi c
appointment i n anesthesia i n the western Uni ted States when she became cl i ni cal professor of
anesthesia at the Universi ty of California, San Francisco. Dr. Botsford al so served as the president
of the Associ ated Anestheti sts of the Uni ted States and Canada.
112

One of the fi rst physi cians to actual ly decl are himsel f a special ist i n anesthesia was Sydney
Ormond Goldan of New York, who publ i shed seven arti cl es i n 1900, i ncl udi ng an early descripti on
of the use of cocaine for spi nal anesthesi a. After studying Gol dan' s earl y career, Raymond Fink
recognized in him some of the qual iti es of many modern anesthesi ol ogists: He was bri mful of
enthusi asm for anesthesia, an excel l ent communicator and a prol ific wri ter, a gadgeteer and the
owner of several patents of anesthesia equipment.
113
At a time when many surgeons considered
that spi nal anesthesi a di d away with their need for an anesthesi ol ogist, Gol dan was particul arl y
bol d i n his wri tten opi ni ons. He cal led for equal ity between surgeon and anesthesi ol ogist and was
among the fi rst to state that the anesthesi ol ogi st had a ri ght to establi sh and col lect hi s own fee.
Gol dan regarded the anesthesi ol ogi st as bei ng more i mportant than the surgeon to the wel fare of
the pati ent.
Since the training of physi ci an anestheti sts around the turn of the century l acked uni formity,
many promi nent surgeons preferred nurse anestheti sts and di rected the training of the most able
candi dates they coul d recrui t. At the Mayo Cli nic, there were no medi cal students or resi dents to
gi ve anesthetics i n the earl y 1890s. The Mayo brothers turned to Edith Graham to admini ster
anesthesia. After she marri ed Charl es Mayo, Al i ce Magaw became thei r personal anestheti st. In
turn, Magaw trai ned Fl orence Henderson and many others in the art of anesthesi a.
114
George W.
Cri l e rel i ed on the ski ll s of Agatha Hodgi ns. During Worl d War I, Agatha Hodgins, Geraldi ne
Gerrard, Ann Penl and, and Sophi e Gran were among the more than 100 nurse anestheti sts who
attended thousands of American and All i ed casualties in France. On thei r return to the United
States, many devel oped schools of nurse anesthesi a.
115

ORGANIZED ANESTHESIOLOGY
Physi ci an anestheti sts sought to obtain respect among their surgi cal coll eagues by organi zi ng
professi onal soci eti es and i mprovi ng the qual i ty of trai ni ng. The first Ameri can organi zati on was
founded by ni ne members on October 6, 1905, and cal led the Long Isl and Soci ety of Anestheti sts
with annual dues of $1.00. In 1911, the annual assessment rose to $3.00 when the Long Isl and
Society became the New York Soci ety of Anestheti sts. Al though the new organi zati on sti l l carri ed a
local titl e, i t drew members from several states and had a membershi p of 70 physi ci ans i n
P.23
1915.
116

One of the most noteworthy fi gures in the struggle to professi onali ze anesthesiol ogy was Francis
Hoffer McMechan. McMechan had been a practi cing anesthesi ol ogist i n Cinci nnati until 1911, when
he suffered a severe fi rst attack of rheumatoi d arthri ti s, which eventual ly left hi m confi ned to a
wheel chai r and forced his reti rement from the operating room i n 1915. McMechan had been i n
practi ce onl y fi fteen years, but he had wri tten eighteen cli ni cal articl es i n thi s short ti me. A
proli fi c researcher and wri ter, McMechan di d not permi t hi s cri ppl i ng di sease to si del i ne hi s career.
Instead of pursui ng goal s in cl inical medi ci ne, he appli ed his talents to establ i shi ng anesthesi ology
soci eties.
117

McMechan supported himsel f and hi s devoted wi fe through edi ti ng the Quarterly Anesthesi a
Suppl ement from 1914 unti l August 1926. He became editor of the fi rst journal devoted to
anesthesia, Current Researches i n Anesthesia and Analgesia, the precursor of Anesthesi a and
Anal gesi a, the oldest journal of the speci al ty. As wel l as fosteri ng the organi zati on of the
Internati onal Anesthesi a Research Soci ety (IARS) i n 1925, McMechan and his wife, Laurette,
became overseas ambassadors of Ameri can anesthesi a. Since Laurette was French, i t was
understandable that McMechan combined hi s own ideas about anesthesi ol ogy wi th concepts from
abroad.
118

In 1926, McMechan hel d the Congress of Anestheti sts i n a joi nt conference with the Secti on on
Anaesthetics of the Bri tish Medi cal Associ ati on. Subsequentl y, he travel ed throughout Europe,
gi vi ng l ectures and networki ng physi cians i n the fi eld. Upon his final return to Ameri ca, he was
gravely i ll and was confi ned to bed for 2 years. Hi s hard work and constant travel pai d di vi dends,
however: i n 1929, the IARS, whi ch McMechan founded i n 1922, had members not only from North
America, but also from several European countri es, Japan, Indi a, Argenti na, and Brazi l.
119

In the 1930s, McMechan expanded hi s mi ssi on from organi zing anesthesi ol ogi sts to promoting the
academic aspects of the speci al ty. In 1931, work began on what woul d become the Internati onal
Col l ege of Anestheti sts. Thi s body began to award fel lowshi ps in 1935. For the first ti me,
physi ci ans were recogni zed as special ists in anesthesi ology. The certificati on qual i fi cati ons were
uni versal , and fell ows were recognized as speciali sts i n several countri es. Al though the criteri a for
certi fi cation were not stri ct, the Coll ege was a success in rai sing the standards of anesthesi a
practi ce i n many nations.
120
In 1939, McMechan fi nal ly succumbed to il l ness, and the anesthesia
worl d lost its tireless leader.
Other Americans promoted the growth of organi zed anesthesi ology. Ral ph Waters and John Lundy,
among others, partici pated i n evol vi ng organized anesthesi a. Waters' greatest contri bution to the
special ty was rai si ng its academi c standards. After compl eting hi s i nternship in 1913, he entered
medi cal practi ce i n Si oux Ci ty, Iowa, where he gradual l y l i mi ted his practice to anesthesi a. Hi s
personal experience and extensive reading were suppl emented by the onl y postgraduate trai ni ng
avai labl e, a 1-month course conducted i n Ohi o by E. I. McKesson. At that ti me, the custom of
becomi ng a sel f-procl aimed speci al i st i n medi ci ne and surgery was not uncommon. Waters, who
was frustrated by l ow standards and who would eventuall y have a great i nfl uence on establi shi ng
both anesthesia resi dency trai ni ng and the formal exami nati on process, recal l ed that before 1920,
The requi rements for speci al i zati on i n many Midwestern hospi tal s consi sted of the possessi on of
suffi ci ent audacity to attempt a procedure and persuasi ve power adequate to gain the consent of
the pati ent or hi s fami ly.
121

In an effort to i mprove anestheti c care, Waters regularly corresponded wi th Denni s Jackson and
other sci entists. In 1925, he rel ocated to Kansas City wi th a goal of gaining an academic post at
the Uni versity of Kansas, but the professor of surgery fail ed to support hi s proposal. The l arger
ci ty di d al l ow hi m to i ni tiate hi s freestanding outpati ent surgi cal faci li ty, The Downtown Surgi cal
Cli nic, whi ch featured one of the fi rst postanestheti c recovery rooms.
122
In 1927, Erwi n Schmi dt,
professor of surgery at the University of Wi sconsi n' s medi cal school , encouraged Dean Charl es
Bardeen to recrui t Waters.
In accepti ng the fi rst Ameri can academic positi on i n anesthesi a, Waters descri bed four objectives
that have been since adopted by many other academi c departments. Hi s goals were as fol l ows:
(1) to provi de the best possibl e service to patients of the insti tuti on; (2) to teach what is known
of the pri nci pl es of Anesthesi ol ogy to al l candidates for thei r medi cal degree; (3) to hel p l ong-
term graduate students not only to gai n a fundamental knowledge of the subject and to master
the art of admi ni stration, but also to l earn as much as possible of the effective methods of
teaching; (4) to accompany these efforts

with the encouragement of as much cooperati ve investi gati on as is consistent wi th achi evi ng the
first objectives.
123

Waters' personal and professi onal quali ties i mpressed tal ented young men and women who sought
residency posts in hi s department. He encouraged resi dents to i ni ti ate research i nterests i n whi ch
they col l aborated wi th two pharmacologi sts whom Waters had known before arriving i n Wi sconsi n,
Arthur Loevenhart and Chauncey Leake, as well as others wi th whom he became associated in
Madi son. Cl ini cal concerns were al so investi gated. As an example, anesthesi a records were coded
onto punch cards to form a database that was used to anal yze departmental acti vi ties. Morbi di ty
and mortali ty meeti ngs, now a requi rement of al l traini ng programs, also ori ginated i n Madi son.
Members of the department and distingui shed visi tors from other centers attended them. As a
consequence of their cri tical revi ews of the conduct of anesthesi a, responsi bil i ty for an operati ve
tragedy gradual l y passed from the pati ent to the physi cian. In more casual ti mes, a practiti oner
coul d compl ai n, The pati ent di ed because he di d not take a good anesthetic. Alternati vel y, the
death might be attri buted to a mysteri ous force such as status l ymphaticus, of whi ch Arthur
Guedel, a master of sardonic humor, observed, Certai nly status lymphaticus is at ti mes a great
hel p to the anesthetist. When he has a fatal i ty under anesthesia with no other cl eansing
explanation he i s glad to recogni ze the condi ti on as an enti ty.
123

In 1929, John Lundy at the Mayo Cl i ni c organi zed the Anaestheti sts' Travel Cl ub, whose members
were l eadi ng American or Canadian teachers of anesthesi a. Each year one member was the host
for a group of 20 to 40 anesthesi ol ogi sts who gathered for a program of informal di scussi ons.
There were demonstrati ons of promi sing i nnovations for the operati ng room and l aboratory, whi ch
were al l subjected to what i s remembered as a hi gh-spi ri ted, energeti c, cri ti cal revi ew.
124
The
Travel Cl ub would be cri ti cal i n the upcomi ng battl e to form the American Board of Anesthesi ology.
Even during the l ean years of the Depressi on, internati onal guests al so vi si ted Waters'
department. For Geoffrey Kaye of Austral i a, Torsten Gordh of Sweden, Robert Macintosh and
Mi chael Nosworthy of England, and scores of others, Waters' department was thei r mecca of
anesthesia. Ral ph Waters trained 60 resi dents duri ng the 22 years he was the Chi ef. From 1937
onward, the al umni , who decl ared themsel ves the Aqualumni in hi s honor, returned annual ly for
a professi onal and soci al reuni on. Thi rty-four Aqualumni took academi c posi ti ons, and, of these,
14 became chai rpersons of departments of anesthesia. They maintai ned Waters' professi onal
pri nci pl es and encouraged teaching careers for many of thei r own graduates.
125
Hi s enduri ng
legacy was once recognized by the dean who had recruited hi m i n 1927, Charles Bardeen, who
observed, Ral ph Waters was the fi rst person the Uni versi ty hi red to put peopl e to sl eep, but,
instead, he awakened a worl d-wide interest i n anesthesi a.
127

Waters and Lundy al ong with Paul Wood, of New York City, had an important role i n establi shi ng
organi zed anesthesi a, and the defi ni tion of the speci al ty. In the heart of the Great Depressi on,
these three physi cians real i zed that anesthesiol ogy needed to have a process to determi ne who
was an anestheti c speci al i st wi th Ameri can Medi cal Associ ati on (AMA) backing. Usi ng the New York
Society of Anestheti sts, of whi ch Paul Wood was secretary-treasurer, a new cl ass of members,
Fel lows, was created. The Fel lows criteri a fol lowed establ ished AMA guidel ines for special ty
certi fi cation. However, the AMA wanted a nati onal organi zati on to sponsor a speci alty board. The
New York Soci ety of Anestheti sts changed i ts name to the Ameri can Soci ety of Anestheti sts (ASA)
in 1936. Combi ned wi th the Ameri can Soci ety of Regional Anesthesia, whose presi dent was Emery
Rovenstein, the Ameri can Board of Anesthesi ol ogy (ABA) was organi zed as a subordi nate board to
the American Board of Surgery in 1938. Wi th McMechan' s death in 1939, the AMA favored
independence for the ABA, and i n 1940, independence was granted.
122, 127

A few years later, the officers of the Ameri can Soci ety of Anestheti sts were chal lenged by Dr. M. J.
P.24
Sei fert, who wrote, An Anestheti st i s a technici an and an Anesthesi ologi st i s the speci fi c authori ty
on anesthesi a and anestheti cs. I cannot understand why you do not term yoursel ves the Ameri can
Society of Anesthesi ologists.
126
Ral ph Waters was decl ared the first presi dent of the newl y named
ASA i n 1945. In that year, when Worl d War II ended, 739 (37%) of 1,977 ASA members were i n
the armed forces. In the same year, the ASA' s fi rst Di sti ngui shed Servi ce Award (DSA) was
presented to Paul M. Wood for his ti rel ess service to the speci al ty, one el ement of which can be
exami ned today i n the extensi ve archi ves preserved i n the Soci ety's Wood Li brary Museum at ASA
headquarters, Park Ri dge, Il l i noi s.
127

After Worl d War II, speci al ties withi n the real m of anesthesiol ogy began to thri ve. Kathl een Belton
was a superb pediatri c speci al i st. In 1948, whi l e working i n Montreal , Bel ton and her coll eague,
Digby Leigh, wrote the cl assi c text Pedi atric Anesthesi a. At the same ti me, a second pedi atric
anesthesiol ogi st, Margot Demi ng, was the Di rector of Anesthesia at the Chi l dren' s Hospital of
Phi l adel phi a. Pedi atri c anesthesia al so fi gured i n the career of Doreen Vermeul en-Cranch, who had
earli er initi ated thoracic anesthesi a in The Netherlands and pioneered hypothermi c anesthesia.
Obstetri c anesthesi a al so figured promi nentl y i n the career of Vi rginia Apgar. After encounteri ng
severe fi nanci al and professi onal frustrations duri ng her training and whil e serving as Director of
the Di visi on of Anesthesi a at Columbi a University, Apgar turned to obstetric anesthesi a i n 1949.
She dedi cated the next decade of her mul ti faceted career to the care of mothers and thei r
infants.
128

ANESTHESIA PRACTICE TODAY AND TOMORROW
Thi s overvi ew of the development of anesthesi ol ogy coul d be extended al most i ndefi ni tel y by an
expl orati on of each subspeci al ty area, but an assessment of our current rol es can be seen by a
personal survey of the areas i n whi ch anesthesiol ogi sts serve in hospitals, cl ini cs, and
laboratori es. The operati ng room and obstetri c del i very sui te remai n the central i nterest of most
special ists. Asi de from bei ng the locati on where the techni ques descri bed i n thi s chapter find
regul ar appl icati on, service i n these areas bri ngs us i nto regul ar contact wi th new advances in
pharmacol ogy and bi oengi neeri ng.
After surgery, pati ents are transported to the postanesthesi a care uni t or recovery room, an
area that i s now considered the anesthesi ol ogi st' s ward. Fi fty years ago, pati ents were
carri ed directl y from the operati ng room to a surgi cal ward to be attended onl y by a juni or nurse.
That person l acked both the ski l l s and equi pment to intervene when compl i cations occurred. After
the experi ences of World War II taught the value of central ized care, physi cians and nurses
created recovery rooms, which were soon mandated for al l major hospi tal s. By 1960 the evoluti on
of criti cal care progressed through the use of mechanical venti lators. Pati ents who requi red many
days of i ntensi ve medi cal and nursi ng management were cared for in a curtai ned corner of the
recovery room. In ti me, curtai ns drawn about one or two beds gave way to fi xed parti ti ons and the
rel ocati on of those areas to form intensi ve care uni ts. The pri nci ples of resusci tative and
supporti ve care establ i shed by anesthesiol ogi sts transformed criti cal care medi cine.
The future of anesthesi ol ogy i s a bri ght one. The safer drugs that once revol uti oni zed the
care of patients undergoi ng surgery are constantl y bei ng i mproved upon. The rol e of

the anesthesi ol ogi st conti nues to broaden, as physi ci ans wi th backgrounds i n the special ty have
developed cli ni cs for chroni c pai n control and outpati ent surgery. Anesthesia practice wi l l conti nue
to increase in scope, both inside and outside of the operati ng sui te, such that anesthesi ol ogi sts
wi l l become even more of an i ntegral part of the entire peri operati ve experience.
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87. Severi nghaus JC, Honda Y: Pul se oximetry. Int Anesthesi ol Cl in 25:205, 1987
88. Luft K. Methode der registri eren gas anal yse mi t hi l fe der absorption ul traroten Strahl en
ohne spectral e Zerlegung. Z Tech Phys 1943;24:97.
89. Wren PC: Phi losophical Transactions, Vol I. London, Anno, 1665 and 1666
90. Keys TE: The Hi story of Surgi cal Anesthesi a, p 38. New York, Dover Publ i cati ons, 1945
91. Dundee J, Wyant G: Intravenous Anesthesia, p 1. Hong Kong, Churchil l Livingstone, 1974
92. Or PC: Etudes, cli ni ques sur l ' anesthsi e chi rurgi cal e par l a methode des injecti on de
choral dans l es vei nes. Pari s,: JB Ball i ere et Fi ls 1875, As quoted in: Hemel ri jck JV, Ki ssi n I:
History of Intravenous Anesthesi a. In: PF Whi te (ed): Textbook of Intravenous Anesthesi a, p
3. Balti more, Wi l li ams & Wil ki ns, 1997
93. Macintosh RR: Modern anaesthesi a, wi th special reference to the chai r of anaesthetics i n
Oxford. In, Rupreht J, van Lieburg MJ, Lee JA, Erdmann W (eds.): Anaesthesi a: Essays on Its
History, p 352. Berli n, Spri nger-Verl ag, 1985
94. Hemel ri jck JV, Kissi n I: Hi story of Intravenous Anesthesi a. In: Whi te PF (ed): Textbook of
Intravenous Anesthesia, p 3. Balti more, Wi l li ams & Wil ki ns, 1997
95. Gwathmey JT: Anesthesi a, p 379. New York, D. Appl eton and Company, 1914
96. Fl agg PJ: The Art of Anaesthesia, p 80. Phi l adel phi a, JB Li ppincott Company, 1918
97. Chl oretone (chl orobutanol ) i s prepared by mixing chloroform and acetone, and has a
camphor-l i ke odor that some fi nd pl easant. Chloretone i s now commonl y used for euthani zi ng
repti l es and amphi bi ans
98. Hewer CL: Recent Advances i n Anaesthesi a and Anal gesi a, p 237. Phi l adel phi a: P
Bl aki ston' s Son & Co. Inc., 1937
99. Col l ins VJ: Pri ncipl es and Practice of Anesthesi ol ogy, p 327. Phi l adel phi a, Lea & Febi ger,
1952
100. Raeder J: Hi story of Postoperati ve Nausea and Vomiti ng. Int Anesthesi ol Cli n 41(4):1,
2003
101. McIntyre AR: Curare, Its History, Nature, and Cl i ni cal Use, p 6, 131. Chi cago, Uni versi ty
of Chi cago Press, 1947
102. Thomas BK: Curare: Its History and Usage, p 90. Phi l adel phi a, JB Li ppi ncott Company,
1963
103. Rushman GB, Davi es NJH, Atkinson RS: A Short History of Anaesthesia, p 78. Oxford,
Butterworth-Heinemann, 1996
104. Knoefel PK: Fel ice Fontana: Li fe and Works, p 284. Trento, Societa de Studi Trenti ni ,
1985
105. Gri ffi th HR, Johnson GE: The use of curare in general anesthesi a. Anesthesi ology 3:418,
1942
106. McIntyre AR: Hi stori cal background, early use and devel opment of muscl e rel axants.
Anesthesi ol ogy 20: 412, 1959
107. Al i HH, Utti ng JE, Gray C: Quanti tati ve assessment of resi dual anti depol ari zi ng block
(part II). Br J Anaesth 43:478, 1971
108. Gottl i eb AM: A Pi ctori al Hi story of Blood Practi ces and Transfusi on, p 2. Scottsdal e, AZ,
Arcane Publ i cations, 1992
109. For further detai l s regardi ng bl oodl etti ng, see CK Wi l bur: Anti que Medical Instruments,
1987, or G. Pendergraph: Handbook of Phlebotomy. Phi l adel phi a Lea and Febi ger, 1984
110. Jenki ns MT: Epochs in i ntravenous flui d therapy: from the goose qui l l and pi g bl adder to
bal anced sal t soluti ons, p 4. The Lewi s H. Wri ght Memori al Lecture, Wood Li brary-Museum
Col l ecti on, Park Ri dge, IL, 1993
111. Strickl and RA: Isabel la Col er Herb, MD: an early leader in anesthesi ol ogy. Anesth Anal g.
80(3):600, 1995
112. Cal mes SH: Anesthesi ol ogy i n Cal i fornia: the earl y years. Bul letin of the History of
Anesthesi ol ogy 17(1):8, 1999
113. Fi nk BR: Leaves and needl es: the i ntroducti on of surgi cal l ocal anesthesi a.
114. Harri s NA, Hunziker-Dean J: Fl orence Henderson. Nursi ng History Revi ew 9:159, 2001
115. Bankert M: Watchful Care: A Hi story of America's Nurse Anestheti sts. New York,
Conti nuum, 1989
116. Betcher AM, Ci l i berti BJ, Wood PM, Wri ght LH: The jubi l ee year of organized anesthesi a.
117. Bacon DR: The promi se of one great anesthesi a society. Anesthesi ology 80:929, 1994
118. Sel don TH: Franci s Hoeffer McMechan. In: Volpi tto PP, Vandam LD (eds): Genesi s of
Ameri can Anesthesiol ogy, p 5. Springfi el d, IL, Charles C Thomas, 1982
119. Bacon DR: The worl d federati on of societi es of anesthesi ol ogi sts: McMechan's final
legacy? Anesth Analg 84:1131, 1997
120. Bacon DR, Lema MJ: To defi ne a special ty: A bri ef hi story of the American Board of
Anesthesi ol ogy' s fi rst written exami nation. J Cl in Anesth 1992;4:489
121. Waters RM: Pioneering in anesthesiology. Postgrad Med 4:265, 1948
122. Waters RM: The down-town anesthesia clinic. Am J Surg 33:71, 1919
123. Guedel AE: Inhal ati on Anesthesia: A Fundamental Gui de, p 129. New York: MacMi ll an,
1937
124. MacKenzi e RA, Bacon DR, Martin DP: Anaestheti sts' Travel Club: a transformation of the
soci ety of cl inical surgery? Bul l Anesth Hist Jul ;22(3):7, 2004
125. Bacon DR, Ament R: Ralph Waters and the beginni ngs of academi c anesthesiol ogy i n the
Uni ted States: the Wi sconsi n templ ate. J Cli n Anesth 7:534, 1995
126. Littl e DM Jr, Betcher AM: The Di amond Jubil ee 19051980, p 8. Park Ridge, IL, Ameri can
Society of Anesthesi ologists, 1980
127. Bamforth BJ, Si ebecker KL: Ral ph M. Waters. In: Vol pi tto PP, Vandam LD (eds): Genesi s
of Ameri can Anesthesi ol ogy,. Spri ngfi el d, IL: Charles C Thomas, 1982
128. Cal mes SH: Development of the Apgar Score. In: Rupreht J, van Lei gurgh MJ, Lee JA,
Erdman W (eds.): Anaesthesi a: Essays on Its Hi story, p 45. Berli n, Spri nger-Verl ag, 1985
> Tabl e of Contents > Secti on I - Introducti on to Anesthesi a Practi ce > Chapter 2 - Practi ce and Operati ng
Room Management
Chapter 2
Practice and Operating Room Management
Richard L. Lock
John H. Eichhorn
KEY POINTS
Anesthesi ol ogy resi dents, and many postgraduates al so, tend to l ack suffi ci ent
knowl edge (with someti mes unfortunate resul ts) about practi ce structures,
financial matters of al l types, and contracti ng i n parti cul ar. They must educate
themsel ves and al so seek expert advi ce and counsel to survi ve (and hopefull y
flouri sh) in today' s exceedingly complex medi cal practi ce mi l ieu.
There are several very hel pful detail ed i nformati on resources on practice and OR
management avai l abl e from the Ameri can Soci ety of Anesthesi ol ogi sts (ASA)
and other sources.
Securi ng hospi tal privil eges is far more than a bureaucrati c annoyance and must
be taken seri ousl y by anesthesi ol ogi sts.
Anesthesi ol ogists need to be involved, concerned, active parti ci pants and
leaders i n thei r i nsti tution and communi ty to enhance thei r practice function and
image.
Anesthesi ol ogy i s the l eadi ng medi cal speci al ty i n establi shi ng and promulgating
standards of practi ce, which have si gnifi cantly posi ti vel y i nfluenced practi ce.
The i mmedi ate response to a major adverse anesthesia event i s cri ti cal to the
eventual resul t and an extremel y val uable protocol i s avai l abl e at
www.apsf.org , Resources: Cli nical Safety.
Managed care' s i nfl uence waxes, wanes, and changes but i t must always be
consi dered by modern anesthesi ol ogi sts. Whil e cost, value, outcome, and quali ty
issues are certai nly central to al l anesthesi ol ogy practices, di ffi cul ti es in
constructing and appl yi ng defini ti ve measurements and rigorous stati sti cal
anal ysi s of these parameters have prevented, so far at least, some of the
potential negati ve infl uences of the core features of ful ly managed health care
on anesthesi ol ogy practi ce i n most circumstances.
Ongoi ng evol uti on of medical practice i n the United States has accelerated to such a pace that
consi derati ons of organi zati on, admi nistrati on, and management requi re constant updati ng.
Functi ons and detai l s across the whole spectrum of the health care system or enterprise, from
the bri efest and si mplest pri mary care encounter of a si ngl e patient, through the admi ni strati on
and management of an anesthesi ol ogy practi ce group and i ts envi ronment, all the way up to
nati onal pol i ci es for fi nanci ng the care of the enti re popul ati on, demand more attenti on and effort
than ever before.

In the past, anesthesiol ogi sts traditi onal l y were l i ttle involved in the management of many
components of thei r practi ce beyond the stri ctl y medi cal el ements of appl i ed physi ol ogy and
pharmacol ogy, pathophysi ol ogy, and therapeutics. This was, perhaps, somewhat understandable
because anesthesi ol ogi sts tradi ti onall y spent the vast majority of thei r usual l y very long work
hours i n a hospi tal OR. Busi ness matters were often left to the one or two group members
i nterested or wil l i ng to deal wi th an outsi de contractor bil l ing agency. Often there were few if any
support personnel (someti mes no office base at al l other than a corner desk i n the doctors'
lounge). In many ci rcumstances, there was li ttl e or no ti me to even consi der or attempt
management functions. Rel uctant compl iance with criti cal mandatory processes such as
credential ing was secured onl y by the i nsi stence of a hospi tal staff admini strator. In that era, very
little formal teaching of or trai ni ng in practi ce management of any ki nd occurred i n anesthesi ol ogy
residency programs. Word-of-mouth handing down of what was mostl y fol kl ore was often all an
anesthesi ol ogy resi dent had to go on after compl eting traini ng and begi nni ng practi ce.
Interesti ngl y i n this regard, the Anesthesi ol ogy Resi dency Review Commi ttee of the Accreditati on
Counci l on Graduate Medi cal Educati on now requires that the di dacti c curri cula of anesthesiology
residenci es include materi al on practice management. Today, most resi dency programs offer at
least a cursory introducti on to issues of practice management, but these can be insuffici ent to
prepare sati sfactoril y the resi dent being graduated for the real infrastructure, admi ni strati ve,
busi ness, and management chal l enges of the modern practi ce of anesthesi ol ogy.
Thi s chapter, whi ch draws si gnifi cantly from i ts predecessor
1
and also i ncorporates concepts
from a rel ated chapter
2
in the previ ous editi on, presents a wi de vari ety of topi cs that, until
very recentl y, were not i n anesthesiology textbooks. Several basi c components of the
administrati ve, organizati onal (i ncl udi ng dai l y functioni ng of the OR), and fi nanci al aspects of
anesthesi ol ogy practi ce are outl i ned. Incl uded is mention of some of the issues associ ated with
practi ce arrangements i n the modern environment heavil y infl uenced by vari ous types of managed
care and i ts permutati ons and combinati ons. Al though certain of these issues are undergoi ng
al most constant change, it i s i mportant to understand the basi c vocabul ary and pri nci pl es i n thi s
Anesthesi ol ogists must partici pate i n operating room (OR) management i n their
faci li ties and should play a central leadershi p rol e. Operating room schedul i ng,
staffi ng, uti l i zati on, and pati ent fl ow i ssues are compl ex and anesthesi ol ogists
should work hard to both thoroughl y understand and posi ti vel y infl uence them.
Anesthesi ol ogy personnel issues i nvol ve an el aborate bal ancing act and
groups/departments shoul d gi ve these i ssues, as wel l as thei r constituent
personnel , more attenti on and energy than has been tradi ti onal in the past or
the anesthesi a provi der shortage wi ll l i kel y conti nue to worsen.
Attention to the many often-underemphasized detai ls of i nfrastructure,
organizati on, and admi ni strati on can transform a merel y endurable anesthesia
practi ce i nto one that is effi ci ent, effecti ve, producti ve, col legi al , and even fun.
P.28
dynami c universe. Lack of understandi ng of these issues may put anesthesi ol ogists at a
di sadvantage when attempting to maximi ze the effici ency and i mpact of their dai ly activiti es, to
create and execute practice arrangements, and to secure fai r compensation i n an increasi ngl y
compl ex heal th care system wi th greater and greater competi tion for scarcer and scarcer
resources.
ADMINISTRATIVE COMPONENTS OF ANESTHESIOLOGY
PRACTICE
Oper at i onal and I nf or mat i on Resour ces
Whil e i t may be rel ati vely rare, there are sti l l si tuati ons in whi ch a brand-new anesthesiol ogy
practi ce i s created and there i s no previ ousl y exi sti ng i nfrastructure, protocol , organi zation,
habits, or tradi ti on to draw on for guidance. Li kewise, mergers and spi n-offs of anesthesi ol ogy
practi ces occur, just as i n the busi ness worl d. How can anesthesiol ogi sts and the
administrati ve/support personnel they hi re learn from the coll ecti ve experi ence of the profession
and thus avoid havi ng to rei nvent the wheel in faci l itati ng their practice? Simil arl y, practi ci ng
anesthesiol ogi sts frequentl y recognize the need to exami ne and, it i s hoped, i mprove the functi on
of their practi ces through comparabl e efforts.
Overvi ew summari es such as thi s chapter are intended as an introducti on. Further,
fortunatel y, the Ameri can Society of Anesthesiol ogi sts (ASA), the professi onal associ ati on for
physi ci an anesthesi ol ogi sts i n the United States, for many years has made avail able to i ts
members extensi ve resource materi al regarding practice i n general and speci fi c arrangements for
its execution. Ci tati on and avai l abi l ity of thi s materi al can be found on the ASA websi te,
http://www.asahq.org. El ements are updated peri odi cal l y by the ASA through i ts physi ci an
officers, commi ttees, task forces, administrative and support staff, and vari ous offi ces. Al though
many of the documents generated and even the advice gi ven in response to members' questi ons
contai n broad-brush general i ti es that must be i nterpreted i n each i ndi vi dual practice situation,
these nonetheless stand as a sol id foundation on whi ch anesthesiol ogy practi ce can be formul ated.
In the past, many ASA members were unaware of the exi stence of these resources and di scovered
them only when referred to them during an appeal to the ASA for hel p resol vi ng some si gni fi cant
practi ce or fi nanci al probl em. Prospecti ve fami l i arity wi th the princi pl es outl i ned i n the ASA
material l ikel y coul d help avoi d some of the probl ems l eadi ng to cal l s for hel p. Selected key
documents are compi l ed and bound i nto a vol ume that can be purchased.
3
Each spri ng, the ASA
offers a Practi ce Management Conference, fol l owi ng whi ch the l ecture materi als are publ i shed in
an annual vol ume (see http://www.asahq.org, Publ icati ons and Servi ces, Publ icati ons on
Practi ce Management).
Background
The current atmosphere i n American medici ne, whi ch creates the impression that al l of a sudden,
al l the rul es and understandi ngs are changi ng, makes it virtual l y mandatory that
anesthesi ol ogi sts be fami l i ar wi th the fundamental background of thei r professi on. The ASA
Guidel i nes for the Ethi cal Practice of Anesthesi ol ogy
3
includes sections on the pri nci ples of
medical ethics; the defi ni ti on of medical directi on of nonphysi ci an personnel (i ncl udi ng the speci fi c
statement that an anesthesi ol ogi st engaged in medi cal di recti on shoul d not personal l y be
administeri ng another anestheti c); the anesthesi ologi st' s rel ationship to pati ents and other
physi ci ans; the anesthesi ol ogist's duti es, responsibi l iti es, and rel ati onshi p to the hospi tal ; and the
anesthesiol ogi st' s rel ati onshi p to nurse anestheti sts and other nonphysici an personnel . Further,
the ASA publ i shes The Organi zati on of an Anesthesi a Department
3
and states through it that the
ASA has adopted a Statement of Pol i cy, whi ch contai ns pri nci pl es that the Soci ety urges i ts
members to consider in structuri ng thei r own i ndi vi dual medical practi ces. Thi s document has
secti ons on physi cian responsibi l iti es for medi cal care and on medi cal -administrati ve organi zati on
and responsi bi l i ti es. The ASA has been parti cul arl y proacti ve i n hel pi ng i ts members keep up with
rapi dl y changi ng areas of both managed care and government programs wi th all the myriad
financial i mpl icati ons of the evol vi ng rules and requi rements. In the past, some (probabl y many)
anesthesiol ogy resi dents finishing traini ng fel t unprepared, in a busi ness and organi zati onal sense,
to enter the job and practice markets. They had to l earn compl ex diffi cult l essons through a sel f-
taught crash course during negotiations for a posi ti on, sometimes to thei r detri ment. Beyond
summaries such as thi s chapter, reference to the consi derable body of material created and
presented by the ASA (whi ch i ncl udes a thi ck volume specifi cal l y on the detai ls of busi ness
arrangements
4
) i s an excel lent starting point to help young anesthesi ol ogi sts duri ng residency
prepare for the i ncreasing ri gors of starti ng and managi ng a career in practi ce. Li kewi se, there i s
a great deal of i nformati on on the ASA websi te concerni ng the most recent governmental
regulations, rulings, and bi l l i ng codes. The ASA Newsl etter di stri buted to al l members now
contai ns the monthl y columns Washi ngton Report and

Practi ce Management, whi ch di sseminate rel ated current devel opments.
Of course, the Internet i s a very i mportant source of i nformati on. In addi ti on to the ASA, most
other anesthesi ol ogy subspeci alty soci eties and interest groups have Web l ocati ons, as do most
journal s. Certai n anesthesiology and other journal s that exist only on the Internet are now in
exi stence, and more wi l l l i kel y be devel oped. Parti cul arly, the websi te of the Anesthesia Pati ent
Safety Foundati on, http://www.apsf.org, has been ci ted as especi al l y useful i n promoti ng safe
cl i ni cal practi ce. El ectronic bull etin boards al l ow anesthesi ol ogy practi tioners from around the
worl d to i mmedi atel y exchange i deas on di verse topi cs, both medi cal and admi ni strati ve.
Traditi onal l y, the ASA has not maintai ned one. However, one of the ori ginal si tes that remai ns
very popul ar i s http://www.gasnet.org and a web search (anesthesiol ogy + bul l eti n board) using
a search engine such as http://www.googl e.com reveal s a great number of si tes that contai n a
vari ety of discussions about al l manner of anesthesi ol ogy-rel ated topi cs, i ncl udi ng practi ce
organizati on, admi ni strati on, and management. Additi onal l y, references to the enti rety of the
medical li terature are readi ly accessi ble to any practi ti oner (such as by starti ng with
http://www.nl m.ni h.gov to access Medl i ne). A modern anesthesi ol ogy practi ce cannot reasonabl y
exist wi thout readi ly avai l abl e hi gh-speed Internet connecti ons.
The Cr edent i al i ng P r ocess and Cl i ni cal P r i vi l eges
The system of credenti al i ng a heal th care professi onal and granti ng cl i ni cal pri vi l eges i n a
heal th care faci li ty i s moti vated by a fundamental assumpti on that appropri ate educati on,
trai ni ng, and experi ence, al ong wi th the absence of excessi ve numbers of bad patient outcomes,
increase the chances that the i ndi vi dual wi ll del iver acceptabl e-quali ty care. As a resul t, the
systems have recei ved consi derably i ncreased emphasi s i n recent years.
5
The process of
credential ing heal th care professi onals has been the focus of consi derabl e publ ic attenti on
(parti cularly in the mass medi a), in part the result of very rare inci dents of untrai ned persons
(i mpostors) infi l trati ng the heal th care system and sometimes harming pati ents. The more
common situation, however, involves health professi onals who exaggerate past experi ence and
credential s or fail to disclose adverse past experiences. There has been some justi fi ed publ i city
concerning physi cians who lost their l icenses sequential ly i n several states and simply moved on
each ti me to start practi ce el sewhere (which shoul d be much, much more diffi cult now).
The pati entphysi ci an relationshi p al so has changed radicall y, wi th a concomi tant i ncrease i n
suspi cion directed toward the medi cal professi on. There is now a pervasive publ i c percepti on that
physi ci ans are i nadequatel y pol i ced, parti cul arl y by their own professi onal organizati ons and
hospi tal s. Intense publ i c and pol i ti cal pressure has been brought to bear on various law-maki ng
bodi es, regul atory and l i censi ng agenci es, and heal th care insti tution administrati ons to discover
and purge both (1) fraudul ent, cri minal, and devi ant health care provi ders, and (2) i ncompetent or
si mpl y poor-quali ty practi tioners whose hi stori es show suffici ent poor pati ent outcomes to attract
attenti on, usuall y through mal practi ce suits. Identifying and avoi ding or correcti ng an i ncompetent
practi ti oner is the goal. Veri fi cation of appropri ate educati on, traini ng, and experi ence on the part
of a candi date for a posi ti on renderi ng anesthesia care assumes speci al i mportance i n l i ght of the
l egal doctri ne of vicari ous li abil i ty, which can be described as fol l ows: i f an i ndi vi dual , group, or
insti tuti on hires an anesthesi a provi der or even simpl y approves of that person (e.g., by granti ng
cl i ni cal pri vi l eges through a hospi tal medi cal staff), those i nvol ved i n the deci sion may l ater be
P.29
hel d li able in the courts, along wi th the i ndi vi dual , for the i ndi vi dual ' s acti ons. Thi s woul d be
especial ly true if it were l ater discovered that the offendi ng practi ti oner' s past adverse outcomes
had not been adequately i nvestigated during the credenti al i ng process.
Out of these various l ong-standi ng concerns has arisen the someti mes cumbersome process of
obtai ni ng state l i censes to practi ce and of obtaining hospital pri vi leges. It is somewhat anal ogous
to passi ng through screeni ng and metal detecti on devices at ai rports, which i s tolerated by the
individual in the interest of the safety of all, wi th the presumpti on that danger wi l l be detected
and eli mi nated. The stri ngent credential ing process i s intended both to protect patients and to
safeguard the i ntegri ty of the medical professi on. Recently, central credential ing systems have
been devel oped, including those affil i ated wi th the Ameri can Medi cal Associati on, Ameri can
Osteopathic Association, and, parti cularly, the Federati on Credenti al s Veri fi cation Service of the
Federati on of State Medi cal Boards. These systems veri fy a physi cian' s basi c credenti al s (identi ty,
ci ti zenshi p or i mmigrati on status, medi cal educati on, postgraduate trai ni ng, l i censure examinati on
hi story, pri or l i censes, board acti ons, etc.) once and then, thereafter, can certify the validity of
these credenti als to a state l i censi ng board or medical facil i ty. Some states do not yet accept thi s
veri fi cation and most states seek speci fi c suppl emental i nformation.
There are checkli sts of the requi rements for the granti ng of medi cal staff pri vi l eges by hospi tal s
(see the Ameri can Hospi tal Association Resource Center, http://www.aharc.l ibrary.net). In
addi ti on, the National Practi tioner Data Bank and reporti ng system admini stered by the U.S.
government now has many years' worth of i nformati on i n it. This data bank i s a central reposi tory
of li censing and credenti als i nformati on about physi cians. Many adverse situations i nvol vi ng a
physi ci anparti cul arl y i nstances of substance abuse, malpracti ce l i ti gati on, or the revocati on,
suspensi on, or li mi tati on of that physici an' s li cense to practi ce medi ci ne or to hol d hospi tal
pri vi legesmust be reported (vi a the state board of medi cal regi strati on/l i censure) to the National
Practi ti oner Data Bank. It i s a statutory requi rement that al l appl icati ons for hospi tal staff
pri vi leges be cross-checked against this nati onal data bank. The potenti al medi col egal li abil i ty on
the part of a faci l ity' s medi cal staff, and the anesthesiol ogy group i n parti cul ar, for fai l i ng to do so
is signi fi cant. The Data Bank, however, i s not a compl ete substitute for di rect documentati on and
background checking. Often, practiti oners reach negoti ated sol uti ons foll owing quali ty-dri ven
medical staff probl ems, thereby avoi ding the mandatory reporting. In such cases, a suspect
physi ci an may be gi ven the opti on to resi gn medi cal staff pri vi leges and avoi d Data Bank reporti ng
rather than undergo full involuntary pri vi l ege revocation.
Documentation
The documentati on for the credenti al i ng process for each anesthesi a practi tioner must be
compl ete. Pri vi leges to administer anesthesia must be offi ci all y granted and del ineated i n wri ting.
3

Thi s can be strai ghtforward or i t can be more compl ex to accommodate insti tutional needs to
identi fy practi ti oners special ly qual ified to practi ce i n desi gnated anesthesi a subspeci al ty areas
such as cardi ac, infant/pedi atric, obstetric, i ntensi ve care, or pai n management. Speci fi c
documentation of the process of granti ng or renewi ng cl ini cal pri vi l eges i s requi red and, unl i ke
some other records, the documentation li kel y is protected as confidenti al peer review informati on.
Any questi ons about compl ex sensiti ve i ssues such as this shoul d be referred to an experi enced
attorney famil i ar wi th appl icable federal and state law. Veri fi cation of an appli cant' s credenti al s
and experi ence i s mandatory. Because of another type of l egal case, some

exampl es of whi ch have been hi ghly publ i ci zed, medical practi ti oners may be hesi tant to gi ve an
honest eval uation (or any eval uation at all ) of i ndi vi dual s known to them who are seeki ng a
professi onal positi on elsewhere. Obvi ously, someone wri ting a reference for a current or former
coworker shoul d be honest. Sti cking to cl earl y documentable facts i s advi sabl e. Stati ng a fact that
is i n the publ i c record (such as a malpracti ce case lost at tri al ) shoul d not justify an objecti on
from the subject of the reference. Whether omitting such a fact is di shonest on the part of the
reference writer is more of a gray area. Incl udi ng posi ti ve opi ni ons and enthusi asti c
recommendations, of course, i s no probl em. Some fear that including facts that may be percei ved
as negative (e.g., the l ost malpracti ce case or personal probl ems such as a history of treatment
P.30
for substance abuse) and negati ve opi ni ons wi ll provoke retal i atory lawsui ts (such as for l ibel ,
defamati on of character, or l oss of l i veli hood) from the subject. As a resul t, many reference
wri ters i n these questionabl e situations confi ne thei r written materi al to bri ef, si mpl e facts such as
dates empl oyed and posi ti on held. As al ways, questi ons about complex sensi tive i ssues such as
this should be referred to an experi enced attorney fami li ar with appl i cabl e federal and state l aw.
Because there shoul d be no hesi tati on for a reference wri ter to i nclude posi ti ve opi ni ons, recei pt
of a reference that i ncl udes nothi ng more than dates worked and posi ti on hel d shoul d be a
suggestion that there may be more to the story. Recei pt of such a reference about a person
appl yi ng for a posi ti on shoul d al ways lead to a tel ephone cal l to the writer. A tel ephone cal l is
li kel y advi sabl e i n al l cases, i ndependent of whatever the wri tten reference contains. Frequentl y,
pertinent questi ons over the tel ephone can el i ci t more candi d i nformation. In rare instances, there
may be di shonesty through omi ssi on by the reference giver even at this l evel . This may involve an
appl i cant who an i ndi vi dual , a department or group, or an i nsti tuti on would li ke to see leave. The
subject appl i cant may have poor-quali ty practice, but there may al so be rel uctance by the
reference giver(s) to approach l i censi ng or di sci pl inary authori ti es (because of the unpl easantness
and al so out of concern about retal i atory legal action). This type of sandbaggi ng i s fortunatel y
infrequent. The best way to avoi d i t is to tel ephone an independent observer or source (such as a
former empl oyer or associ ate who no l onger has a personal stake i n the appl i cant' s success or
even the head nurse of an OR i n whi ch the appl icant worked) when any question exi sts. Because
the ul ti mate goal i s opti mum pati ent care, the subjects appl yi ng for posi ti ons general l y should not
object to such cal ls bei ng made. Di scovery of a hi story of unsafe practi ces and/or habi ts or of
causi ng preventable anesthesia morbidi ty or mortal i ty shoul d el ici t careful evaluati on as to
whether the appli cant can be appropri atel y assi gned, trai ned, and/or supervised to be maximally
safe i n the proposed new environment.
In al l cases, new personnel i n an anesthesi a practi ce envi ronment must be gi ven a thorough
orientati on and checkout. Pol i cy, procedures, and equi pment may be unfami l iar to even the most
thoroughl y trai ned, experi enced, and safe practi ti oner. Thi s may occasional ly seem tedious, but it
is both sound and cri ticall y i mportant safety pol i cy. Bei ng in the midst of a cri si s situation caused
by unfami l iari ty with a new setti ng is not the opti mal ori entati on session.
After the i ni tial granti ng of cl i ni cal privil eges to practice anesthesi a, anesthesi ol ogi sts must
peri odi cal ly renew thei r pri vi l eges withi n the i nsti tution or facil i ty (e.g., annuall y or every other
year). There are moral , ethi cal , and soci etal obl i gati ons on the part of the pri vi lege-granting
enti ty to take this process seri ousl y. State l i censi ng bodi es often become aware of probl ems wi th
heal th professi onal s very l ate i n the evoluti on of the diffi culti es. An anesthesia provider's peers in
the hospi tal or faci l ity are much more li kel y to notice untoward devel opments as they first appear.
However, pri vi l ege renewal s are often essenti all y automatic and recei ve li ttl e of the necessary
attenti on. Judici ous checki ng of renewal appl icati ons and awareness of rel evant peer revi ew
information is absol utely necessary. The physi ci ans or admini strators responsi bl e for eval uating
staff members and revi ewi ng their practi ces and pri vi l eges may be justi fi abl y concerned about
retal i atory l egal action by a staff member who is censured or denied pri vi lege renewal .
Accordi ngl y, such evaluati ng groups must be thoroughl y objecti ve (total l y eli mi nating any hi nt of
pol iti cal or financi al moti ves) and must have documentati on that the staff person i n questi on is i n
fact practi cing bel ow the standard of care. Court deci si ons have found l i abi l ity by a hospital, its
medi cal staff group, or both when the i ncompetence of a staff member was known or shoul d have
been known and was not acted upon.
6
Agai n, questions about compl ex sensi ti ve issues such as
thi s shoul d be referred to an experi enced attorney fami l iar wi th appl i cabl e federal and state l aw.
A major i ssue i n the granti ng of cl inical pri vi l eges, especi all y in procedure-oriented special ti es
such as anesthesiol ogy, i s whether i t i s reasonabl e to continue the common practi ce of bl anket
pri vi leges. This process in effect authori zes the practiti oner to attempt any treatment or procedure
normal ly consi dered wi thin the purvi ew of the appl i cant' s medi cal speci alty. These consi derations
may have profound pol i ti cal and economi c impli cati ons wi thin medi ci ne, such as whi ch type of
surgeon shoul d be doi ng caroti d endarterectomi es or l umbar di scectomi es. More i mportant,
however, is whether the practi tioner bei ng eval uated i s qual ified to do everything tradi ti onal l y
associated wi th the speci alty. Speci fi cal l y, shoul d the granting of privil eges to practice anesthesi a
automati cal l y approve the practi ti oner to handle pediatri c cardi ac cases, criti cal ly i ll newborns
(such as a day-ol d premature infant wi th a l arge di aphragmatic hernia), ablati ve pai n therapy
(such as an al cohol celi ac plexus bl ock under fl uoroscopy), high-ri sk obstetri c cases, and so forth?
Thi s questi on rai ses the issue of procedure-specific or li mi ted pri vi l eges. The qual ity assurance
(QA) and risk management consi derations i n thi s questi on are wei ghty if i nexperienced or
insuffi cientl y quali fi ed practi tioners are al l owed or even expected, because of peer or schedul ing
pressures, to undertake major chal lenges for which they are not prepared. The li kel i hood of
compl i cati ons and adverse outcome wi l l be hi gher, and the di ffi cul ty of defendi ng the practi ti oner
against a mal practi ce clai m i n the event of catastrophe wi ll be si gni fi cantl y i ncreased.
There i s no cl ear answer to the questi on of procedure-specific credential ing and granting of
pri vi leges. Ignori ng issues regarding quali fi cati ons to undertake complex and chal lenging
procedures has clear negati ve potential . On the other hand, stri ngent procedure-specific
credential ing i s impracti cal i n smal l er groups, and i n l arger groups encourages many small
fiefdoms, with a consequent further atrophy of the cl inical skil l s outsi de of the practiti oner' s
specific area(s). Each anesthesi a department or group needs to address these i ssues. At the very
least, the common practi ce of every appl i cant for privil eges (new or renewal ) checking off every
li ne on the pri nted l i st of anesthesi a procedures should be revi ewed. Addi ti onal l y, board
certi fi cation is now essenti al l y a standard of qual ity assurance of the mi ni mum skil l s required for
the consultant practi ce of anesthesi ol ogy. Subspeci al ty boards, such as those i n pai n
management, cri tical care, and transesophageal echocardi ography, further objecti fy the
credential ing process. This i s now si gnifi cant because i ni tial board certificati on after the year 2000
by the American Board of Anesthesi ology i s time l imited and subject to peri odi c testi ng and
recertificati on. Cl earl y, this wil l encourage an ongoi ng process of conti nuing medi cal educati on
(CME). Many states, some insti tuti ons, even some regul atory bodi es have requirements for a
mi ni mum number of hours of CME. Documentati on of meeti ng such a standard again acts as one
type of qual i ty assurance mechani sm for the i ndi vi dual

practi ti oner, whi l e provi di ng another objective credential ing measurement for those granting
li censes or pri vi l eges.
Medi cal St af f P ar t i ci pat i on and Rel at i onshi ps
All medi cal care faci li ties and practi ce setti ngs depend on thei r medi cal staffs, of course, for
dai ly acti vi ti es of the del ivery of health care; but, very i mportantl y, they al so depend on
those staffs to provi de admi ni strati ve structure and support. Medi cal staff acti vi ties are
increasi ngl y i mportant i n achi evi ng favorabl e accreditati on status (e.g., from the Joi nt Commi ssi on
for the Accredi tation of Heal thcare Organi zations [JCAHO]) and i n meeti ng a wi de vari ety of
governmental regul ati ons and reviews. Pri ncipal medi cal staff activiti es i nvol ve sometimes ti me-
consuming efforts, such as duti es as a staff officer or commi ttee member. Anesthesi ol ogists
should be partici pants i nin fact, should pl ay a si gni fi cant rol e i ncredential ing, peer revi ew,
ti ssue revi ew, transfusi on review, OR management, and medi cal di recti on of same-day surgery
uni ts, postanesthesi a care uni ts (PACUs), i ntensi ve care units (ICUs), and pai n management uni ts.
Also, i t i s very i mportant that anesthesi ol ogy personnel be involved in fund-raisi ng acti vi ties,
benefi ts, community outreach projects sponsored by the faci li ty, and soci al events of the faci l ity
staff.
The rol e these and rel ated acti vi ties pl ay i n anesthesia practice management may not be obvious
at fi rst gl ance, but thi s is a refl ection of the unfortunate fact that, all too often, anesthesiol ogi sts
have i n the past chosen to have very l ittle or no i nvol vement in such efforts. Of course, there are
excepti ons i n speci fi c setti ngs. However, it i s an unmi stakabl e reali ty that anesthesi ol ogi sts as a
group have a reputati on for l ack of involvement i n medi cal staff and faci l i ty issues because of a
lack of time (because of long hours in the OR) or simply a l ack of i nterest. In fact, anesthesi ology
personnel are all too often percei ved i n a faci l ity as the ones who sl i p i n and out of the bui l ding
essential ly anonymousl y (often dressed very casual l y or even i n the pajama-li ke comfort of scrub
suits) and vi rtual ly unnoti ced. Thi s i s an unfortunate state of affai rs, and i t has frequently come
back i n vari ous pai nful ways to haunt those who have not been i nvol ved, or even noti ced.
P.31
Anesthesi ol ogy personnel someti mes respond that the demands for anesthesi ology servi ce are so
great that they si mpl y never have the ti me or the opportuni ty to become i nvol ved in thei r faci l ity
and wi th thei r peers. If thi s is real l y true, i t is cl ear that more providers of anesthesi a care must
be added at that faci l i ty, even i f doing so sl ightl y reduces the i ncome of those al ready there.
In any case, anesthesi ol ogi sts si mpl y must make the ti me to be involved i n medical staff affai rs,
both i n health care faci l ity administrati on and also as part of the organi zati on, admi ni strati on, and
governance of the comparatively l arge multi speci alty physi ci an groups that provi de enti ti es wi th
whi ch managed care organizati ons (MCOs) and health care faci l iti es can negoti ate for physici an
servi ces. The types and styl es of these organizati ons vary wi del y and are di scussed l ater. The
poi nt here i s si mpl e. If anesthesiol ogi sts are not involved and not percei ved as interested,
dedi cated team pl ayers, they wi l l be shut out of cri tical negoti ati ons and deci si ons. Although one
obvi ous i nstance in whi ch others wi l l make decisi ons for anesthesi ologi sts is the distri buti on of
capi tated or bundl ed practi ce fee income col lected by a central umbrell a organizati on, there are
many such situations, and the anesthesi ol ogists wi ll have to compl y wi th the resulti ng mandates.
In the most basi c terms, absence from the bargaining tabl e and/or bei ng seen as uni nvol ved i n the
welfare of the large group virtuall y ensure that anesthesiol ogi sts wi l l not parti cipate in key
deci si ons or recei ve thei r fai r share of the pie.
Simil arl y, involvement wi th a facil i ty, a medi cal staff, or a multi speci al ty group goes beyond
formal organi zed governance and commi ttee activity. Col l egial rel ati onshi ps wi th physi cians of
other speci al ties and with admini strators are central to mai ntenance of a recogni zed positi on and
avoi dance of the situation of exclusi on descri bed above. Bei ng readi l y avail able for formal and
informal consults, parti cularly regardi ng preoperati ve pati ent workup and the maximal l y effici ent
way to get surgeons' patients to the OR in a ti mel y, expedi ent manner, i s extremely important. No
one i ndi vi dual can be everywhere al l the ti me, but an anesthesi ol ogy group or department shoul d
stri ve to be al ways responsi ve to any request for hel p from physici ans or admi ni strators. It often
appears that anesthesi ol ogi sts fai l to appreci ate just how great a posi ti ve i mpact a rel ati vely
si mpl e i nvol vement (starti ng an i ntravenous l i ne for a pedi atrici an, hel pi ng an interni st manage an
ICU venti l ator, or hel ping a faci l ity administrator uncl og a jammed recovery room) may have.
Unfortunatel y, anesthesi ol ogi sts i n a great many locations have a negati ve stereotype bui lt up
over years to overcome and must work hard to mai ntai n the percepti on that they deserve an equal
voi ce regardi ng the i mpact of the current changes i n the heal th care system.
Est abl i shi ng St andar ds of P r act i ce and Under st andi ng t he
St andar d of Car e
Gi ven all the current and future changes in the anesthesi ology practi ce envi ronment, i t i s more
important than ever that anesthesi ologi sts genuinely understand what i s expected of them in thei r
cl i ni cal practi ce. The increasi ng frequency and intensi ty of producti on pressure,
7
wi th the taci t
(or even expl i ci t) directi ve to anesthesi a personnel to go fast no matter what and to do more
with less, creates si tuati ons i n whi ch anesthesi ologi sts may conclude that they must cut corners
and compromi se maximall y safe care just to stay i n business. This type of pressure has become
even greater wi th the i mpl ementati on of more and more protocol s or parameters for practi ce,
some from professi onal soci eti es such as the ASA and some mandated by or devel oped i n
conjunction with purchasers of health care (government, insurance compani es, or MCOs). Many of
these protocols are devi sed to fast-track patients through the medi cal care system, especi al l y
when an el ecti ve procedure is i nvol ved, in as absol utel y l i ttl e ti me as possibl e, thus mi ni mi zi ng
costs. Do these fast-track protocol s constitute standards of care that health care provi ders are
mandated to impl ement? What are the i mpl icati ons of doing so? Of not doi ng so?
To better understand answers to such questi ons, it i s i mportant to have a basi c background i n the
concept of the standard of care. Anesthesi ology personnel are fortunate i n thi s regard because for
nearl y 20 years Ameri can anesthesi ol ogy has been recogni zed as one of the si gnifi cant leaders i n
establ i shing practice standards i ntended to maximi ze the qual i ty of patient care and hel p gui de
personnel at ti mes of di ffi cul t deci sions, i ncl udi ng the ri skbenefi t and costbenefi t deci si ons of
specific practi ces. Another i mportant component of thi s issue i s the uni que l egal system in the
Uni ted States, in which the potenti al l i abi l ity impli cati ons of most deci sions must be consi dered.
Busi nesses, groups, and i ndi vi dual s have had thei r enti re publ i c exi stences destroyed by
staggeri ng l egal settl ements and judgments al l owed by the U.S. l egal system. Major attempts at
reform of this system have occurred and wi ll continue to occur. However, although a very posi tive
restructuri ng of the tort li abil i ty system could al leviate some of the catechol ami ne-generati ng
sword over the head mental i ty exhibi ted by some physi cians, i t wi l l not reli eve anesthesiol ogy
personnel of the responsi bil i ty to provide maximal l y safe care for their pati ents. Integrati on of
systems and protocol s to help maxi mi ze the qual i ty of pati ent care, whether from formal standards
or not, is an important component of managing an anesthesiology practi ce.

The standard of care i s the conduct and skil l of a prudent practi tioner that can be expected by a
reasonable pati ent. Thi s i s a very important medi col egal concept because a bad medi cal resul t due
to a fail ure to meet the standard of care i s mal practice. Extensi ve discussi ons have attempted to
establ i sh exactl y the appl i cable standard of care. Courts have tradi ti onall y rel i ed on medi cal
experts knowl edgeabl e about the poi nt i n questi on to give opi ni ons as to what i s the standard of
care and if i t has been met i n an i ndi vi dual case. Thi s type of standard i s somewhat di fferent from
the standards promul gated by various standard-setti ng bodi es regardi ng, for example, the col or of
gas hoses connected to an anesthesi a machine or the inabi l ity to open two vaporizers on that
machine simul taneousl y. However, i gnoring the equi pment standards and tolerati ng an unsafe
si tuati on i s a vi ol ati on of the standard of care. Promul gated standards, such as the vari ous safety
codes and anesthesi a machi ne speci fi cati ons, rapi dl y become the standard of care because
patients (through their attorneys, in the case of an untoward event) expect the publ ished
standards to be observed by the prudent practi ti oner.
Understandi ng the concept of the standard of care is the key to integrati ng the numerous
standards, gui del ines, statements, practi ce parameters, and suggested protocol s appl i cable to
Ameri can anesthesi ology practice i n the unfortunately necessary constant undercurrent of concern
about potenti al l egal li abil i ty. Ul timatel y, the standard of care i s what a jury says i t is. However, it
is possi ble to antici pate, at least i n part, what knowledge and actions wi l l be expected. There are
two mai n sources of i nformation as to exactly what i s the expected standard of care. Tradi ti onall y,
the bel i efs offered by expert wi tnesses i n medical l i abi l ity lawsui ts regardi ng what was bei ng done
in real life (de facto standards of care) were the mai n i nput juri es had i n deci di ng what was
reasonable to expect from the defendant. The resul ting probl em i s wel l known: except i n the most
egregious cases, i t i s usuall y possi bl e for the lawyers to find experts who wi ll support each of the
two opposi ng si des, maki ng the process more subjecti ve than objective. (Because of this, there i s
the ASA Guidel i nes for Expert Witness Qual i fi cations and Testi mony.) Of course, there can be
l egi ti mate di fferences of opi ni on among thoughtful , i nsi ghtful experts, but even i n these cases the
jury stil l must decide who i s more bel i evabl e, l ooks better, or sounds better. The second, much
more objecti ve, source for defi ni ng certai n component parts of the standard of care has devel oped
si nce the mid 1980s i n Ameri can anesthesi ology. It i s the publ i shed standards of care, guidel i nes,
practi ce parameters, and protocol s now becomi ng more common. These serve as hard evi dence of
what can be reasonabl y expected of practiti oners and can make i t easier for a jury eval uati ng
whether a malpracti ce defendant fail ed to meet the appl i cabl e standard of care. Several types of
documents exist and have differing impli cati ons.
Leading the Way
Anesthesi ol ogy may be the medi cal special ty most involved wi th publ i shed standards of care.
It has been suggested that the nature of anesthesi a practi ce (having certai n central criti cal
functi ons rel ati vely cl earl y defined and common to al l situations and havi ng an emphasis on
technol ogy) makes it the most amenabl e of all the fiel ds of medi cine to the use of publ i shed
standards. The origi nal i ntraoperati ve monitori ng standards
8
are a cl assi c exampl e. The ASA fi rst
adopted i ts own set of basi c intraoperati ve moni toring standards in 1986 and has modi fi ed them
several ti mes (Tabl e 2-1).
P.32
TABLE 2-1 American Society of Anesthesiologists Standards for Basic Anesthetic
Monitoring
These Standards appl y to al l anesthesi a care, al though, i n emergency ci rcumstances,
appropri ate l i fe-support measures take precedence. These standards may be exceeded at
any ti me based on the judgment of the responsibl e anesthesiologi st. They are i ntended
to encourage qual i ty pati ent care, but observi ng them cannot guarantee any speci fi c
patient outcome. They are subject to revi si on from ti me to time, as warranted by the
evol uti on of technol ogy and practi ce. They appl y to al l general anestheti cs, regi onal
anesthetics, and moni tored anesthesia care. This set of standards addresses onl y the
issue of basi c anestheti c moni toring, whi ch is one component of anesthesia care. In
certai n rare or unusual ci rcumstances, (1) some of these methods of monitori ng may be
cl i ni cal ly i mpracti cal , and (2) appropri ate use of the described moni toring methods may
fai l to detect untoward cl inical developments. Bri ef i nterrupti ons of conti nual
a
monitoring
may be unavoi dabl e. Under extenuating circumstances, the responsi bl e anesthesi ol ogist
may waive the requi rements marked with an asteri sk (*); i t is recommended that when
this i s done, i t should be so stated (i ncl udi ng the reasons) i n a note i n the pati ent' s
medical record. These standards are not i ntended for appl icati on to the care of the
obstetri cal patient i n l abor or i n the conduct of pain management.
STANDARD I
Qual i fied anesthesi a personnel shal l be present in the room throughout the conduct of al l
general anestheti cs, regional anestheti cs, and moni tored anesthesi a care.
Objective
Because of the rapid changes i n pati ent status duri ng anesthesi a, quali fi ed anesthesi a
personnel shall be continuousl y present to moni tor the pati ent and provide anesthesia
care. In the event there is a di rect known hazard, for example, radiation, to the
anesthesia personnel that might require i ntermi ttent remote observati on of the pati ent,
some provision for monitoring the pati ent must be made. In the event that an
emergency requires the temporary absence of the person pri mari l y responsi ble for the
anesthetic, the best judgment of the anesthesiol ogi st wil l be exerci sed in comparing the
emergency wi th the anestheti zed pati ent' s condi tion and i n the sel ecti on of the person
left responsi ble for the anestheti c during the temporary absence.
STANDARD II
During all anestheti cs, the pati ent' s oxygenati on, venti lation, ci rculation, and
temperature shal l be conti nual l y evaluated.
OXYGENATION
Objective
To ensure adequate oxygen concentration i n the inspired gas and the bl ood duri ng al l
anesthetics.
Methods
1. Inspi red gas: Duri ng every admi nistrati on of general anesthesi a using an
anesthesia machi ne, the concentrati on of oxygen i n the pati ent breathi ng system
shal l be measured by an oxygen anal yzer wi th a l ow oxygen concentrati on l imit
al arm in use.*
2. Bl ood oxygenation: Duri ng al l anestheti cs, a quanti tati ve method of assessi ng
oxygenati on such as pulse oxi metry shal l be empl oyed.* Adequate i l lumi nation and
exposure of the patient are necessary to assess col or.*
VENTILATION
Objective
To ensure adequate venti lation of the pati ent duri ng al l anestheti cs.
Methods
1. Every pati ent recei vi ng general anesthesi a shal l have the adequacy of venti lati on
conti nual ly evaluated. Qual itati ve cl i ni cal si gns such as chest excursi on,
observation of the reservoi r breathing bag, and auscul tation of breath sounds are
useful . Conti nual monitori ng for the presence of expired carbon di oxi de shal l be
performed unless i nval idated by the nature of the pati ent, procedure, or
equipment. Quanti tati ve moni tori ng of the volume of expired gas i s strongl y
encouraged.*
2. When an endotracheal tube or l aryngeal mask is i nserted, i ts correct positi oning
must be verified by cli nical assessment and by identi fi cati on of carbon di oxide i n
the expired gas. Continual end-ti dal carbon di oxi de anal ysi s, in use from the ti me
of endotracheal tube/l aryngeal mask pl acement, unti l extubati on/removal or
initi ati ng transfer to a postoperati ve care l ocati on, shal l be performed usi ng a
quantitati ve method such as capnography, capnometry, or mass spectroscopy.*
3. When ventil ati on i s control l ed by a mechanical ventil ator, there shal l be i n
conti nuous use a device that is capabl e of detecti ng disconnecti on of components
of the breathi ng system. The devi ce must gi ve an audi bl e si gnal when i ts al arm
threshold is exceeded.
4. During regi onal anesthesi a and moni tored anesthesi a care, the adequacy of
ventil ati on shal l be evaluated, at least, by conti nual observati on of qual itati ve
cl i ni cal signs.
CIRCULATION
Objective
Thi s document i ncludes cl ear speci fi cati ons for the presence of personnel duri ng an anestheti c
epi sode and for continual evaluati on of oxygenati on, ventil ati on, ci rcul ati on, and temperature. The
rati onale for these moni toring standards i s simple; i t was felt that functi onall y mandati ng certai n
behaviors oriented toward providi ng the earl iest, maxi mum possi bl e warning of threateni ng
developments duri ng an anestheti c should hel p mi ni mize intraoperati ve catastrophi c pati ent
i njury. These ASA moni tori ng standards very qui ckl y became part of the accepted standard of care
in anesthesi a practi ce. Thi s means they are i mportant to practice management because they have
profound medi col egal i mpl i cati ons: a catastrophi c accident occurri ng whi le the standards are bei ng
acti vel y ignored i s very diffi cult to defend i n the consequent malpracti ce suit, whereas an acci dent
To ensure the adequacy of the pati ent's ci rcul atory functi on duri ng al l anestheti cs.
Methods
1. Every pati ent recei vi ng anesthesi a shal l have the electrocardi ogram continuousl y
di spl ayed from the begi nni ng of anesthesi a unti l prepari ng to l eave the
anesthetizing l ocati on.*
2. Every pati ent recei vi ng anesthesi a shal l have arteri al blood pressure and heart rate
determi ned and eval uated at l east every 5 mi nutes.*
3. Every pati ent recei vi ng general anesthesi a shal l have, in addi tion to the above,
ci rculatory function conti nual ly evaluated by at least one of the foll owi ng:
pal pati on of a pul se, auscultati on of heart sounds, moni toring of a traci ng of intra-
arterial pressure, ul trasound peripheral pul se monitori ng, or pulse
pl ethysmography or oxi metry.
BODY TEMPERATURE
Objective
To ai d i n the mai ntenance of appropri ate body temperature duri ng al l anestheti cs.
Methods
Every pati ent recei vi ng anesthesi a shal l have temperature moni tored when cl i ni cal l y
si gni fi cant changes in body temperature are intended, antici pated, or suspected.
a
Note that conti nual i s defi ned as repeated regul arly and frequentl y i n steady rapi d
successi on, whereas conti nuous means prolonged without any i nterruption at any
ti me.
Approved by House of Del egates on October 21, 1986, and l ast affi rmed on October 15,
2003.
Repri nted wi th permi ssion of the American Society of Anesthesi ol ogi sts, Park Ri dge,
Il l inoi s 60068-5586.
that occurs duri ng wel l -documented ful l compl i ance wi th the standards wi ll automati cal ly have a
strong defense because the standard of care was bei ng met. Several states in the Uni ted States
have made compl i ance wi th these ASA standards mandatory under state regulations or even
statutes. Vari ous mal practi ce insurance compani es offer di scounts on malpracti ce i nsurance poli cy
premi ums for compl iance with these standards, somethi ng qui te natural to i nsurers because they
are fami li ar wi th the i dea of managi ng known ri sks to hel p minimi ze fi nanci al loss to the company.
The ASA moni toring standards have been widel y emul ated i n other medi cal speci alti es and even in
fiel ds outsi de of medi cine. Al though there are defini te paral lel s i n these other efforts (such as in
obstetri cs and gynecol ogy), no other group has pursued the same degree of definiti on.
Many of the same management questi ons that led to the intraoperati ve moni tori ng standards have
cl ose paral lel s i n the i mmedi ate preoperati ve and postoperative periods in the PACU. With many of
the same elements of thi nki ng, the ASA adopted Basi c Standards for Preanesthesi a Care (Tabl e 2-
2). Thi s was suppl emented si gni fi cantl y by another type of document, the ASA Practi ce Advisory
for Preanesthesia Evaluati on (http://www.asahq.org, Publ icati ons and Servi ces, Practice
Parameters), a 40-page meta-anal ysi s of cl i ni cal aspects of preoperati ve eval uati on. Al so, the
ASA adopted Standards for Postanesthesi a Care (Tabl e 2-3) i n which there was consi derati on of
and col laborati on with the very detai l ed standards of practi ce for PACU care publ i shed by the
Ameri can Soci ety of Post Anesthesi a Nurses (another good exampl e of the sources of standards of
care). This al so was l ater suppl emented by an extensi ve Practi ce Gui del i ne.
9

TABLE 2-2 American Society of Anesthesiologists Basic Standards for Preanesthesia
Care
These Standards appl y to al l pati ents who recei ve anesthesi a or moni tored anesthesi a
care. Under unusual ci rcumstances, for exampl e, extreme emergenci es, these standards
may be modi fied. When this i s the case, the ci rcumstances shall be documented i n the
patient' s record.
Standard I: An anesthesi ol ogi st shal l be responsi bl e for determi ni ng the medi cal status
of the pati ent, devel opi ng a plan of anesthesi a care, and acquai nti ng the pati ent or the
responsi bl e adult with the proposed plan.
The devel opment of an appropriate plan of anesthesi a care is based upon:
1. Revi ewi ng the medi cal record.
2. Intervi ewing and examining the patient to:
a. Discuss the medi cal history, previ ous anesthetic experi ences, and drug
therapy.
b. Assess those aspects of the physi cal conditi on that might affect deci si ons
regardi ng peri operati ve risk and management.
3. Obtai ni ng and/or reviewi ng tests and consultati ons necessary to the conduct of
anesthesia.
4. Determi ni ng the appropri ate prescri ption of preoperati ve medi cati ons as necessary
to the conduct of anesthesi a.
The responsibl e anesthesi ologist shall veri fy that the above has been properl y performed
and documented i n the patient' s record.
Approved by House of Del egates on October 14, 1987, and affi rmed on October 18,
1998.
Repri nted wi th permi ssion of the Ameri can Soci ety of Anesthesi ol ogi sts, Park Ri dge,
Il l inoi s 60068-5586.
TABLE 2-3 American Society of Anesthesiologists Standards for Postanesthesia Care
These Standards appl y to postanesthesia care i n al l locati ons. These Standards may be
exceeded based on the judgment of the responsibl e anesthesi ologi st. They are i ntended
to encourage qual i ty patient care, but cannot guarantee any specific pati ent outcome.
They are subject to revi si on from ti me to ti me as warranted by the evol uti on of
technol ogy and practi ce. Under extenuati ng ci rcumstances, the responsi ble
anesthesiol ogi st may wai ve the requirements marked wi th an asteri sk (*); i t is
recommended that when thi s i s done, it shoul d be so stated (i ncl udi ng the reasons) i n a
note i n the pati ent' s medical record.
STANDARD I
All pati ents who have recei ved general anesthesia, regi onal anesthesia, or moni tored
anesthesia care shal l receive appropri ate postanesthesi a management.
a

1. A Postanesthesi a Care Unit (PACU) or an area that provi des equi valent
postanesthesia care shal l be avai labl e to recei ve pati ents after anesthesi a care. All
patients who recei ve anesthesi a care shal l be admi tted to the PACU or i ts
equival ent except by speci fi c order of the anesthesi ol ogi st responsi bl e for the
patient' s care.
2. The medi cal aspects of care i n the PACU shal l be governed by pol i ci es and
procedures that have been revi ewed and approved by the Department of
Anesthesi ol ogy.
3. The desi gn, equi pment, and staffi ng of the PACU shal l meet requirements of the
faci li ty' s accredi ti ng and l icensi ng bodi es.
STANDARD II
A pati ent transported to the PACU shal l be accompanied by a member of the anesthesi a
care team who i s knowl edgeabl e about the pati ent' s condi ti on. The pati ent shal l be
conti nual ly evaluated and treated duri ng transport wi th moni tori ng and support
appropriate to the patient' s conditi on.
STANDARD III
Upon arrival i n the PACU, the pati ent shal l be reeval uated and a verbal report provided
to the responsi ble PACU nurse by the member of the anesthesia care team who
accompani es the pati ent.
1. The pati ent' s status on arrival i n the PACU shal l be documented.
2. Information concerning the preoperati ve conditi on and the surgi cal /anestheti c
course shal l be transmi tted to the PACU nurse.
3. The member of the Anesthesi a Care Team shal l remai n i n the PACU unti l the PACU
nurse accepts responsi bil i ty for the nursing care of the pati ent.
STANDARD IV
A sl i ghtl y di fferent situation exists wi th regard to the standards for conduct of anesthesi a i n
obstetri cs. These standards were ori gi nal l y passed by the ASA i n 1988, i n the same manner as the
other ASA standards, but the ASA membershi p eventual l y questi oned whether they refl ected a
real i sti c and desi rabl e standard of care. Accordi ngl y, the obstetri c anesthesia standards were
downgraded i n 1990 to gui deli nes (Tabl e 2-4), specificall y to remove the mandatory nature of the
document. Because there was no agreement as to what shoul d be prescri bed as the standard of
care, the medi col egal i mperati ve of publ i shed standards has been temporaril y set asi de. From a
management perspecti ve, thi s makes the gui deli nes no l ess valuabl e, because the intent of
optimizing care through the avoi dance of compl i cations i s no l ess operati ve. However, i n the event
of the need to defend against a mal practi ce cl aim i n thi s area, i t i s cl ear from thi s sequence of
events that the exact standard of care is debatabl e and not yet fi nal ly establ i shed. A di fferent ASA
document, Practi ce Guidel i nes for Obstetri cal Anesthesi a, wi th more detai l and speci fi ci ty as wel l
as an emphasi s on the meta-anal yti c approach has been generated.
10

The pati ent' s condi tion shal l be eval uated conti nual l y i n the PACU.
1. The pati ent shal l be observed and moni tored by methods appropri ate to the
patient' s medi cal condi ti on. Parti cul ar attention should be given to moni toring
oxygenati on, ventil ati on, ci rculation, and temperature. Duri ng recovery from al l
anesthetics, a quanti tative method of assessi ng oxygenati on such as pulse
oxi metry shall be empl oyed in the i ni tial phase of recovery.* Thi s is not i ntended
for appl i cati on duri ng the recovery of the obstetri cal pati ent i n whom regional
anesthesia was used for l abor and vagi nal del i very.
2. An accurate wri tten report of the PACU peri od shal l be maintai ned. Use of an
appropri ate PACU scori ng system i s encouraged for each patient on admi ssi on, at
appropri ate i nterval s pri or to di scharge, and at the ti me of di scharge.
3. General medi cal supervi si on and coordinati on of pati ent care i n the PACU shoul d be
the responsi bi l ity of an anesthesi ol ogist.
4. There shal l be a pol i cy to assure the avai l abi l ity i n the faci l ity of a physi ci an
capabl e of managi ng compl i cations and provi ding cardi opulmonary resusci tati on for
patients i n the PACU.
STANDARD V
A physi cian is responsi ble for the di scharge of the pati ent from the PACU.
1. When di scharge cri teri a are used, they must be approved by the Department of
Anesthesi ol ogy and the medi cal staff. They may vary dependi ng upon whether the
patient is di scharged to a hospi tal room, to the Intensive Care Uni t, to a short stay
uni t, or home.
2. In the absence of the physi cian responsibl e for the di scharge, the PACU nurse shal l
determi ne that the pati ent meets the discharge criteri a. The name of the physi ci an
accepti ng responsibi l ity for di scharge shal l be noted on the record.
a
Refer to Standards of Post Anesthesi a Nursi ng Practi ce 1992, publ i shed by Ameri can
Society of Post Anesthesia Nurses (ASPAN), for i ssues of nursi ng care.
Approved by House of Del egates on October 12, 1988, and last amended on October 19,
1994.
Repri nted wi th permi ssion of the Ameri can Soci ety of Anesthesi ol ogi sts, Park Ri dge,
Il l inoi s 60068-5586.
TABLE 2-4 American Society of Anesthesiologists Guidelines for Regional Anesthesia
In Obstetrics
These gui deli nes apply to the use of regi onal anesthesi a or analgesi a i n whi ch local
anesthetics are admi ni stered to the parturi ent duri ng l abor and del i very. They are
intended to encourage qual ity pati ent care but cannot guarantee any specific pati ent
outcome. Because the avail abil i ty of anesthesi a resources may vary, members are
responsi bl e for i nterpreting and establ ishing the gui del ines for their own i nstituti ons and
practi ces. These gui deli nes are subject to revision from time to time as warranted by the
evol uti on of technol ogy and practi ce.
GUIDELINE I
Regi onal anesthesia shoul d be i niti ated and maintai ned onl y in l ocati ons i n whi ch
appropriate resuscitati on equi pment and drugs are i mmediatel y avail able to manage
procedurall y rel ated probl ems.
Resuscitati on equi pment shoul d i nclude, but i s not li mited to: sources of oxygen and
sucti on, equi pment to mai ntai n an ai rway and perform endotracheal i ntubati on, a means
to provi de posi ti ve-pressure ventil ati on, and drugs and equi pment for cardiopul monary
resusci tati on.
GUIDELINE II
Regi onal anesthesia shoul d be i ni ti ated by a physi ci an wi th appropri ate privil eges and
mai ntai ned by or under the medi cal di recti on
a
of such an indi vi dual.
Physi ci ans shoul d be approved through the insti tutional credenti al i ng process to i ni ti ate
and direct the maintenance of obstetric anesthesia and to manage procedural l y rel ated
compl i cati ons.
GUIDELINE III
Regi onal anesthesia shoul d not be admi ni stered until : (1) the patient has been exami ned
by a qual i fi ed i ndi vi dual
b
and (2) a physi ci an wi th obstetri cal pri vi l eges to perform
operative vaginal or cesarean del i very, who has knowl edge of the maternal and fetal
status and the progress of l abor and who approves the i ni tiation of labor anesthesia, i s
readil y avai labl e to supervi se the labor and manage any obstetri c compl i cations that may
arise.
Under ci rcumstances defi ned by department protocol , quali fi ed personnel may perform
the ini ti al pel vi c exami nati on. The physi cian responsi bl e for the pati ent' s obstetri cal care
should be informed of her status so that a deci si on can be made regardi ng present ri sk
and further management.
b
GUIDELINE IV
An i ntravenous infusi on shoul d be establ i shed before the i ni ti ati on of regional anesthesi a
and mai ntai ned throughout the durati on of the regional anestheti c.
GUIDELINE V
Regi onal anesthesia for l abor and/or vagi nal del i very requires that the parturi ent' s vi tal
si gns and the fetal heart rate be moni tored and documented by a qual i fi ed i ndi vi dual .
Additi onal moni toring appropri ate to the cli ni cal condi ti on of the parturi ent and the fetus
shoul d be empl oyed when i ndicated. When extensive regi onal bl ockade i s admi ni stered
for compl i cated vagi nal del i very, the standards for basi c anestheti c moni toring
c
shoul d
be appl i ed.
GUIDELINE VI
Regi onal anesthesia for cesarean del i very requires that the standards for basi c
anesthetic monitori ng
c
be appl i ed and that a physi ci an with pri vi l eges i n obstetrics be
i mmedi atel y avai l abl e.
GUIDELINE VII
Qual i fied personnel , other than the anesthesi ol ogist attendi ng the mother, shoul d be
immedi ately avai l abl e to assume responsibi l ity for resusci tati on of the newborn.
b
The pri mary responsi bi l i ty of the anesthesiol ogi st i s to provide care to the mother. If the
anesthesiol ogi st i s also requested to provi de bri ef assi stance i n the care of the newborn,
the benefi t to the chil d must be compared to the ri sk to the mother.
GUIDELINE VIII
A physi ci an wi th appropri ate privil eges shoul d remai n readi l y avai l abl e duri ng the
regi onal anestheti c to manage anestheti c compl i cations until the patient' s postanesthesi a
condi ti on i s sati sfactory and stabl e.
GUIDELINE IX
Al l pati ents recoveri ng from regi onal anesthesia shoul d receive appropri ate
postanesthesia care. Fol l owing cesarean deli very and/or extensi ve regi onal bl ockade, the
standards for postanesthesi a care
d
shoul d be appl i ed.
1. A postanesthesi a care uni t (PACU) shoul d be avail able to receive pati ents. The
desi gn, equi pment, and staffi ng shoul d meet requirements of the faci li ty' s
Practice Guidelines
The newest type of rel ated ASA document i s the Practi ce Gui del i ne (formerl y Practi ce
Parameter). Thi s has some of the same el ements as a standard of practi ce but i s more i ntended
to gui de judgment, l argel y through al gori thms with some el ement of gui deli nes, i n addi tion to
di recti ng the detail s of speci fi c procedures as woul d a formal standard. A good exampl e of a set

of practi ce parameters came some years ago from the cardi ol ogi sts and addressed the i ndi cati ons
for cardi ac catheteri zati on. Beyond the detai l s of the mi nimum standards for carrying out the
procedure, these practice parameters set forth al gori thms and gui del ines for hel ping to determi ne
under what ci rcumstances and wi th what ti mi ng to perform it. Understandably, purchasers of
heal th care (government, i nsurance compani es, and MCOs) with a strong desi re to l imi t the costs
of medi cal care have great interest i n practi ce parameters as potenti al vehi cles for hel ping to
el i mi nate unnecessary procedures and l i mi t even the necessary ones.
The ASA has been very acti ve i n creati ng and publ i shi ng practi ce gui del i nes. The fi rst publ i shed
parameter (si nce revi sed) concerned the use of pul monary artery (PA) catheters.
11
It consi dered
the cl i ni cal effectiveness of PA catheters, publi c pol i cy i ssues (costs and concerns of pati ents and
accredi ti ng and l i censi ng bodi es.
2. When a si te other than the PACU i s used, equi val ent postanesthesi a care should be
provi ded.
GUIDELINE X
There should be a pol icy to assure the avai labi li ty in the faci li ty of a physici an to
manage compl i cati ons and to provi de cardiopul monary resusci tation for pati ents
recei vi ng postanesthesi a care.
a
The Anesthesi a Care Team (approved by ASA House of Del egates October 6, 1982, and
last amended October 17, 2001).
b
Gui del i nes for Peri natal Care (Ameri can Academy of Pedi atrics and Ameri can Coll ege of
Obstetri cians and Gynecol ogists, 1988).
c
Standards for Basi c Anestheti c Moni tori ng (approved by ASA House of Del egates
October 21, 1986, and last amended October 21, 1998).
d
Standards for Postanesthesi a Care (approved by ASA House of Del egates October 12,
1988, and last amended October 19, 1994).
Approved by House of Del egates on October 12, 1988, and l ast amended on October 18,
2000.
Repri nted wi th permi ssion of the American Society of Anesthesi ol ogi sts, Park Ri dge,
Il l inoi s 60068-5586.
P.33
P.34
provi ders), and recommendati ons (i ndi cati ons and practi ce setti ngs). The next month, the ASA
Di ffi cul t Ai rway Al gori thm was publ i shed (al so si nce revised).
12
Thi s thoughtful document
synthesized a strategy summari zed i n a deci si on tree di agram for deal i ng acutel y wi th ai rway
problems. It has great cli nical val ue, and i t is reasonabl e to anti ci pate that i t wi ll be used to hel p
many patients. However, al l these documents are readi ly noticed by plai ntiffs' lawyers, the
di ffi cul t ai rway parameter from the ASA bei ng an excel l ent exampl e. An important and so-far
undeci ded questi on i s whether guidel i nes and practi ce parameters from recogni zed enti ti es such as
the ASA define the standard of care. There is no si mpl e answer. Thi s wi l l be deci ded over ti me by
practi ti oners' acti ons, debates in the l i terature, mandates from malpracti ce insurers, and, of
course, court deci sions. Some gui deli nes, such as the FDA preanestheti c apparatus checkout, are
accepted as the standard of care. There wi ll be debate among experts, but the practi tioner must
make the deci si on as to how to appl y practi ce parameters such as those from the ASA.
Practi ti oners have incorrectl y assumed that they must do everything speci fi ed. Thi s i s cl earl y not
true, yet there i s a val i d concern that these wi ll someday be hel d up as defi ni ng the standard of
care. Accordi ngl y, prudent attention wi thin the bounds of reason to the principl es outl i ned i n
gui del i nes and parameters wi l l put the practiti oner i n at l east a reasonabl y defensibl e posi ti on,
whereas radi cal devi ati on from them shoul d be based on obvious exi gencies of the si tuati on at
that moment or clear, defensi ble al ternati ve beli efs (wi th documentati on).
The ASA has many other task forces charged wi th the devel opment of practi ce parameters. Several
aspects of pai n management, transesophageal echocardi ography, pol i ci es for sedati on by
nonanesthesi a personnel , preoperative fasti ng, avoi dance of peri pheral neuropathies, and others
have been publ i shed and wi l l l i kel y have at l east the same i mpact as those noted above.
On the other hand, practice protocols, such as those for the fast-track management of coronary
artery bypass graft patients, that are handed down by MCOs or heal th i nsurance compani es are a
di fferent matter. Even though the desi red i mpl i cati on i s that practi ti oners must observe (or at
least strongl y consi der) them, they do not have the same impli cati ons in defi ni ng the standard of
care as the other documents. Practi ti oners must avoi d getti ng trapped. It may wel l not be a val i d
legal defense to justi fy action or the l ack of action because of a company protocol . Di ffi cul t as i t
may be to reconci l e wi th the payer, the practi ti oner sti ll i s subject to the cl assic defi niti ons of
standard of care.
The other type of standards associ ated wi th medical care are those of the JCAHO, the best-known
medical care quali ty regul atory agency. As noted earli er, these standards were for many years
concerned l argely wi th structure (e.g., gas tanks chai ned down) and process (e.g., documentati on
compl ete), but in recent years they have been expanded to i nclude reviews of the outcome of
care. JCAHO standards also focus on credenti al i ng and pri vi l eges, veri fi cation that anesthesia
servi ces are of uni form qual ity throughout an i nsti tution, the quali fi cati ons of the di rector of the
servi ce, continui ng educati on, and basic gui deli nes for anesthesi a care (need for preoperati ve and
postoperative evaluati ons, documentati on, and so forth). Ful l JCAHO accredi tati on of a heal th care
faci li ty i s usual ly for 3 years. Even the best hospitals and faci li ties receive some ci tati ons of
problems or defi ci enci es that are expected to be corrected, and an i nteri m report of efforts to do
so i s requi red. If there are enough probl ems, accredi tation can be conditi onal for 1 year, with a
compl ete rei nspecti on at that ti me. Preparing for JCAHO inspections starts with veri fi cati on that
essenti al group/department structure i s in pl ace; excell ent exampl es exist.
3
The process ul ti mately
invol ves a great deal of work, but because the standards usual ly do promote hi gh-qual i ty care, the
majority of thi s work i s hi ghly constructi ve and of benefi t to the i nsti tuti on and its medi cal staff.
Review Implications
Another type of regul atory agency i s the peer revi ew organi zation. Professi onal standards review
organizati ons (PSROs) were establ ished i n 1972 as uti li zati on revi ew/QA overseers of the care of
federal l y subsi di zed pati ents (Medi care and Medi cai d). Despi te their efforts to deal wi th qual i ty of
care, these groups were seen by al l involved as pri mari l y i nterested in cost containment. Various
negati ve factors l ed to the PSROs' bei ng replaced in 1984 wi th the peer review organizati on
(PRO).
13
There is a PRO i n each state, many being associ ated with a state medical associ ati on. The
objecti ves of a PRO include 14 goal s rel ated to hospi tal admissions (e.g., to shi ft care to an
outpati ent basis as much as possi bl e) and 5 rel ated to qual ity

of care (e.g., to reduce avoi dabl e deaths and avoi dabl e compl i cati ons). The PROs comprise ful l -
ti me support staff and physi cian revi ewers pai d as consul tants or directors. Ideal l y, PRO
moni toring will discover subopti mal care, and thi s wi l l l ead to specific recommendati ons for
improvement in qual ity. There is a percepti on that qual i ty of care efforts are hampered by the lack
of reali sti c objectives and also that these PRO groups, l i ke others before them, wi ll l argel y or
enti rely functi on to li mi t the cost of health care servi ces.
The practi ce management i mpl i cati ons have become cl ear. Asi de from the as-yet unreal i zed
potential for quali ty i mprovement efforts and the occasi onal denial of payment for a procedure,
the most l i kel y i nteracti on between the l ocal PRO and anesthesi ol ogy personnel wil l i nvol ve a
request for peri operati ve admi ssi on of a pati ent whose care i s mandated to be outpati ent surgery
(thi s could al so occur deal ing wi th a managed care organi zation). If the anesthesi ol ogi st feels, for
example, that ei ther (1) preoperative admission for treatment to opti mi ze cardi ac, pul monary,
di abeti c, or other medi cal status or (2) postoperati ve admi ssi on for moni tori ng of l abil e situations
such as uncontrol led hypertensi on wil l reduce cl ear anestheti c risks for the pati ent, an appl i cati on
to the PRO for approval

of admission must be made and vi gorousl y supported. Al l too often, however, such i ssues surface
a day or so before the schedul ed procedure i n a preanesthesi a screeni ng cl ini c or even in a
preoperati ve hol di ng area outsi de the OR on the day of surgery. Thi s wi ll conti nue to occur unti l
anesthesia providers educate their consti tuent surgeon community as to what types of associ ated
medical condi tions may di squal i fy a proposed pati ent from the outpati ent (ambul atory) surgi cal
schedule. If adequate noti ce i s given by the surgeon, such as at the ti me an electi ve case is
booked for the OR, the patient can be seen far enough in advance by an anesthesi ol ogi st to al low
appropri ate pl anni ng.
In the circumstance in whi ch the fi rst knowledge of a questi onabl e pati ent comes 1 or 2 days
before surgery, the anesthesi ol ogist can try to have the procedure postponed, i f possi bl e, or can
undertake the ti me-consuming task of multi ple tel ephone cal l s to get the surgeon' s agreement,
get PRO approval , and make the necessary arrangements. Because neither al ternati ve i s
parti cul arl y attracti ve, especi all y from administrati ve and rei mbursement perspecti ves, there may
be a strong temptati on to let i t sl i de and try to deal with the pati ent as an outpati ent even
though thi s may be questi onable. In al most al l cases, i t i s li kel y that there woul d be no adverse
resul t (the get away with it phenomenon). However, the pati ent mi ght wel l be exposed to an
avoi dabl e ri sk. Both because of the worki ngs of probabi l ity and because of the i nevitable tendency
to l et si cker and si cker pati ents sl i p by as l ax practi ti oners repeatedl y get away with it and are
lull ed i nto a fal se sense of securi ty, sooner or l ater there wil l be an unfortunate outcome or some
preventable major morbi di ty or even mortali ty.
The situation is worsened when the first contact wi th a questi onable ambul atory patient is
preoperati vel y (possibl y even al ready i n the OR) on the day of surgery. There may be i ntense
pressure from the pati ent, the surgeon, or the OR admi ni strator and staff to proceed with a case
for whi ch the anesthesi a practi ti oner beli eves the pati ent i s poorl y prepared. The arguments made
regarding patient inconveni ence and anxi ety are val i d. However, they should not outwei gh the
best medi cal i nterests of the pati ent. Al though this i s a poi nt in favor of screeni ng al l outpati ents
before the day of surgery, the anesthesi ol ogi st faci ng this si tuati on on the day of operati on shoul d
state cl earl y to al l concerned the reasons for postponing the surgery, stressi ng the issue of
avoi dabl e ri sk and standards of care, and then help wi th al ternati ve arrangements (i ncl udi ng, if
necessary, deal i ng wi th the PRO or MCO).
Potential l iabi li ty exposure is the other si de of the standard of care issue. Parti cul arl y regarding
questi ons of postoperati ve admi ssi on of ambul atory pati ents who have been unstabl e in some
worri some manner, it i s an extremel y poor defense agai nst a mal practice clai m to state that the
patient was discharged home, onl y l ater to suffer a compl i cation because the PRO/MCO deemed
that operati ve procedure outpati ent and not i npati ent surgery. As bureaucrati cal ly annoyi ng as i t
P.35
P.36
P.37
may be, i t i s a prudent management strategy to admit the patient if there is any legi timate
questi on, thus mi ni mi zi ng the chance for compl icati ons, and l ater haggl e wi th the PRO or di rectly
with the involved thi rd-party payer (MCO).
P ol i cy and P r ocedur e
Management of an anesthesi ology practice i nvol ves busi ness, organi zati onal , and cl i ni cal i ssues.
One important organizati onal point that i s often overl ooked i s the need for a complete poli cy and
procedure manual. Such a compi l ati on of documents i s necessary for al l practi ces, from the l argest
departments coveri ng multi ple hospi tal s to a single-room outpatient faci l ity wi th one anesthesi a
provi der. Contempl ati on of this compil ati on of documents may evoke a col lective groan from
anesthesiol ogy personnel , and maintai ni ng this manual may be mi sperceived as a bureaucratic
chore. Qui te the contrary, such a manual can be extraordi naril y valuabl e, as, for example, when i t
provi des cruci al i nformati on duri ng an emergency. Some suggesti ons for the content of thi s
compendi um exi st,
14
but, at minimum, organi zational and procedural elements must be i ncl uded.

The organi zati onal elements that shoul d be present incl ude a chart of organi zati on and
responsi bi li ties that is not just a call schedul e but a cl ear explanation of who i s responsibl e for
what functi ons of the department and when, wi th attendant detail s such as expectations for the
practi ti oner' s presence wi thi n the insti tuti on at desi gnated hours, tel ephone avai l abi l i ty, pager
avai labi li ty, the maxi mum permi ssibl e di stance from the insti tuti on, and so forth. Experi ence
suggests it i s especi al l y i mportant for there to be an absolutel y cl ear speci fi cati on of the
avai labi li ty of qual i fi ed anesthesi ol ogy personnel for emergency cesarean secti on, parti cul arl y i n
practi ce arrangements in whi ch there are several peopl e on cal l coveri ng mul tipl e l ocati ons. Sadly,
these i ssues often are onl y consi dered after a disaster has occurred that involved
miscommunicati on and the mistaken bel i ef by one or more peopl e that someone el se woul d take
care of an acute probl em.
The organi zati onal component of the pol i cy and procedure manual shoul d al so incl ude a cl ear
explanation of the ori entati on and checkout procedure for new personnel , continui ng medi cal
educati on requi rements and opportuni ti es, the mechanisms for evaluati ng personnel and for
communi cati ng thi s eval uation to them, disaster plans (or reference to a separate di saster manual
or protocol ), QA acti vi ti es of the department, and the format for stati sti cal record keeping
(number of procedures, types of anestheti cs gi ven, types of patients anesthetized, number and
types of i nvasi ve monitori ng procedures, number and type of responses to emergency cal l s,
compl i cati ons, or whatever the group/department deci des).
The procedural component of the pol i cy and procedure manual shoul d gi ve both handy practi ce
ti ps and speci fi c outl i nes of proposed courses of action for parti cul ar circumstances; i t al so shoul d
store l ittle-used but valuabl e i nformati on. Reference shoul d be made to the statements,
gui del i nes, practi ce parameters, and standards appeari ng on the ASA websi te. Al so i ncl uded
should be references to or specific protocols for the areas menti oned i n the JCAHO standards:
preanestheti c evaluati on, i mmedi ate preinduction reeval uati on, safety of the pati ent during the
anesthetic period, release of the pati ent from any PACU, recording of all perti nent events during
anesthesia, recording of postanesthesi a visi ts, gui del i nes defi ni ng the rol e of anesthesi a servi ces
in hospi tal i nfecti on control , and gui deli nes for safe use of general anestheti c agents. Other
appropri ate topi cs i ncl ude the fol l owing:
1. Recommendati ons for preanesthesia apparatus checkout, such as from the U.S. Food and
Drug Admi ni strati on (FDA)
15
(see Chapter 21)

2. Guidelines for minimal monitoring and duration of stay of an i nfant, chi l d, or adul t i n the
PACU
3. Procedures for transporti ng patients to/from the OR, PACU, or ICU
4. Pol icy on ambul atory surgical patientsfor exampl e, screeni ng, use of regi onal anesthesi a,
di scharge home cri teria
5. Pol icy on evaluati on and processi ng of same-day admissions
6. Pol icy on recovery room admi ssi on and di scharge
7. Pol icy on ICU admi ssi on and discharge
8. Pol icy on physi cians responsi ble for wri ti ng orders i n recovery room and ICU
9. Pol icy on i nformed consent and i ts documentati on
10. Pol icy on the use of patients i n cl i ni cal research

11. Gui del i nes for the support of cadaver organ donors and its termi nation
12. Guidel i nes on envi ronmental safety, including pol l uti on wi th trace gases and el ectri cal
equipment i nspecti on, mai ntenance, and hazard preventi on
13. Procedure for change of personnel during an anestheti c
14. Procedure for the i ntroduction of new equi pment, drugs, or cl i ni cal practices
15. Procedure for epidural and spi nal narcoti c admi ni strati on and subsequent pati ent monitori ng
(e.g., type, mi ni mum time, nursing units)
16. Procedure for i ni ti al treatment of cardi ac or respi ratory arrest
17. Pol icy for handli ng pati ent's refusal of bl ood or bl ood products, i ncluding the mechanism to
obtai n a court order to transfuse
18. Procedure for the management of mali gnant hyperthermia
19. Procedure for the i nducti on and mai ntenance of barbi turate coma
20. Procedure for the eval uati on of suspected pseudochol i nesterase defi ci ency
21. Protocol for responding to an adverse anestheti c event
22. Pol icy on resuscitati on of DNR patients i n the OR.
Individual departments wi l l add to the suggestions l i sted here as dictated by their speci fi c needs.
A thorough, careful l y concei ved pol icy and procedure manual i s a val uabl e tool. The manual shoul d
be revi ewed and updated as needed but at l east annuall y, wi th a particul arl y thorough revi ew
precedi ng each JCAHO inspection. Each member of a group or department shoul d revi ew the
manual at l east annuall y and sign off i n a log i ndi cati ng famil i arity wi th current poli cies and
procedures.
Meet i ngs and Case Di scussi on
There must be regul arly schedul ed departmental or group meeti ngs. Al though di dacti c l ectures and
conti nui ng educati on meetings are val uable and necessary, there also must be regul ar
opportuniti es for open cl inical discussi on about i nteresting cases and probl em cases. Al so, the
JCAHO requi res that there be at l east monthly meetings at whi ch risk management and QA
acti vi ties are documented and reported. Whether these meeti ngs are call ed case conferences,
morbi dity and mortali ty conferences, or deaths and compl i cations, the enti re department or group
should gather for an i nterchange of i deas. More recentl y these gatherings have been cal led QA
meeti ngs. An open revi ew of departmental stati sti cs should be done, i ncludi ng al l compl i cati ons,
even those that may appear trivial . Unusual patterns of smal l events may poi nt toward a l arger or
systemati c probl em, especi all y if they are more frequentl y associ ated wi th one indi vi dual
practi ti oner.
A probl em case presented at the departmental meeti ng mi ght be an overt acci dent, a near
acci dent (cri tical i nci dent), or an untoward outcome of unknown ori gin. Honest but constructi ve
di scussi on, even of an anesthesi ol ogi st' s techni cal defi cienci es or l ack of knowl edge, shoul d take
P.38
pl ace in the spi ri t of constructive peer revi ew. The classi c question What woul d you do di fferentl y
next time? is a good way to start the discussion. There may be si tuati ons in whi ch i nvi ting the
surgeon or the i nterni st involved in a speci fi c case woul d be advantageous. The opportuni ty for
each type of provi der to hear the perspecti ve of another discipl i ne not onl y i s i nherentl y
educational , but al so can promote communi cation and cooperati on i n future potenti al probl em
cases.
Records of these meetings must be kept for accredi tation purposes, but the enshri ni ng of overl y
detail ed minutes (potenti all y subject to discovery by a pl ai nti ff' s attorney at a l ater date) may
inhi bit true educati onal and correcti ve i nterchanges about untoward events. In the ci rcumstance of
di scussi on of a case that seems l i kely to provoke li tigation, it i s appropri ate to be certai n that the
meeti ng is cl assified as offi ci al peer review and possi bl y even i nvi te the hospi tal attorney or
legal counsel from the rel evant malpracti ce insurance carrier (to guarantee the pri vacy of the
di scussi on and mi nutes).
Suppor t St af f
There i s a fundamental need for support staff i n every anesthesi a practi ce. Even i ndependent
practi ti oners rely i n some measure on facil i ti es, equi pment, and servi ces provi ded by the
organizati on mai ntai ni ng the anestheti zi ng l ocation. In l arge, wel l -organized departments, rel i ance
on support staff i s often very great. The need for adequate staff and the inadvisabil i ty of
scri mpi ng on cri tical support personnel to cut costs i s obvious. What i s often overl ooked, however,
is a process anal ogous to that of credential ing and pri vi leges for anesthesi ol ogi sts, al though at a
sl i ghtly different level . The peopl e expected to provi de cl inical anesthesi a practi ce support must
be qual i fi ed and must at al l ti mes understand what they are expected to do and how to do i t. It i s
si ngularly unfortunate to real i ze onl y after an anesthesi a catastrophe has occurred that basi c
detail s of simple work assignments, such as the changing of carbon di oxide absorbent, were
routinely ignored. This i ndi cates the need for supervi si on and moni tori ng of the support staff by
the involved practi tioners. Further, such support personnel are favori te targets of cost-cutti ng
administrators who do not understand the functi on of anesthesi a techni ci ans or thei r equi val ent.
In the modern era, many admini strators seem dri ven almost exclusi vel y by the bottom li ne and
cannot appreci ate the connection between val uabl e workers such as these and the revenue
stream. Even though it i s obvious to al l who work i n an OR that the anesthesi a support personnel
make i t possi bl e for there to be pati ents fl owi ng through the OR, i t is thei r responsi bi li ty to
convi nce the faci l ity' s fi scal admini strator that eli mi nation of such posi tions i s genuinely fal se
economy because of the attendant loss i n effi ciency, particul arl y in turni ng over the room between
surgeries. Further, it i s also false economy to reduce the number of personnel bel ow that are
genui nel y needed to retri eve, clean, sort, disassembl e, steri li ze, reassembl e, store, and di stri bute
the tool s of dail y anesthesi a practi ce. Inadequate attention to al l these steps trul y creates the
envi ronment of an accident waiti ng to happen. When there i s threatened l oss of budget fundi ng
from a health care facility for the sal ari es of needed anesthesi a support personnel , the
practi ti oners i nvol ved must not si mpl y stand by and see the necessary functi ons thrown i nto a
hi t-or-mi ss status by a few remai ni ng heavi ly overburdened workers. Vi gorous defense (or
initi ati on of and agitati on for new posi tions i f the staff is i nadequate) by the anesthesi a
practi ti oners shoul d be undertaken, al ways wi th the real i zati on that i t may be necessary i n some
ci rcumstances for them to supplement the budget from the faci li ty wi th some of their practice
income to guarantee an adequate complement of competent workers.
Busi ness and organi zati onal issues i n the management of an anesthesi a practi ce are al so criti cal ly
dependent on the existence of a suffi cient number of appropri ately trained support staff. One
frequently overl ooked i ssue that contri butes to the negati ve i mpressi on generated by some
anesthesiol ogy practi ces centers on being certai n there i s someone avai labl e to answer the
tel ephone at al l times duri ng the hours surgeons, other physi cians, and OR schedul ing desks are
li kel y to tel ephone. Thi s seemi ngl y tri vi al component of practi ce management i s very i mportant to
the success of an anesthesi ol ogy practi ce as a busi ness whose principal customers are the
surgeons.
P.39
Certai nly there i s a commerci al servercl i ent rel ati onshi p both wi th the pati ent and the purchaser
of health care; however, the uni quel y symbi oti c nature of the relati onshi p between surgeons and
anesthesiol ogi sts i s such that avai l abi l ity even for simple just wanted to l et you know tel ephone
call s i s genui nel y important. The person who answers the tel ephone i s the representati ve of the
practi ce to the worl d and must take that responsibi l ity seriousl y. From a management standpoi nt,
si gni fi cant impact on the success of the practice as a business often hinges on such detail s.
Further, anesthesi ol ogi sts should al ways have permanent personal el ectroni c pagers and rel i abl e
mobi l e tel ephones (or the radio equi val ent) to facil i tate communicati ons from other members of
the department or group and from support personnel . Thi s may sound i ntrusive, but the unusual
positi on of anesthesi ol ogi sts i n the spectrum of physi ci ans mandates this feature of managi ng an
anesthesiol ogy practi ce. Anesthesi ology personnel shoul d have no hesitati on about spending thei r
own practi ce i ncome to do so. The symbol i sm al one i s obvious.
Anest hesi a Equi pment and Equi pment Mai nt enance
Problems with anesthesi a equi pment have been di scussed for some ti me.
16, 17
However, compared
to human error, overt equi pment fail ure very rarel y causes i ntraoperative cri ti cal i nci dents
18
or
deaths resul ti ng from anesthesi a care.
19
Asi de from the obvi ous human errors involving mi suse of
or unfamiliarity with the equi pment, when the rare equi pment fai l ure does occur, i t appears often
that correct mai ntenance and servici ng of the apparatus has not been done. These issues become
the focus of anesthesi a practi ce management efforts, whi ch coul d have si gni fi cant l i abi l ity
impli cati ons, because there can often be confusi on or even di sputes about preci sel y who i s
responsi bl e for arrangi ng maintenance of the anesthesi a equi pmentthe faci l ity or the
practi ti oners who use i t and col l ect practi ce income from that acti vi ty. In many cases, the faci l ity
assumes the responsibi l ity. In situations i n whi ch that i s not true, however, it i s necessary for the
practi ti oners to recogni ze that responsi bi li ty and seek hel p securi ng a service arrangement,
because thi s is l i kely an unfamil i ar obli gati on for cl ini ci ans.
Programs for anesthesi a equipment mai ntenance and service have been outl i ned.
3, 20
A di sti ncti on
i s made between fai l ure as a resul t of progressive deterioration of equi pment, whi ch shoul d be
preventable because it i s observabl e and shoul d provoke appropri ate remedi al acti on, and
catastrophi c fai l ure, which, real isticall y, often cannot be predi cted. Preventi ve maintenance for
mechani cal parts is cri tical and i nvol ves peri odi c performance checks every 4 to 6 months. Al so,
an annual safety i nspecti on of each anestheti zi ng l ocati on and the equi pment i tsel f is necessary.
For equi pment servi ce, an excell ent mechani sm i s a relatively elaborate cross-reference system
(possi bl y kept handwri tten i n a notebook but ideal for maintenance on an electroni c spreadsheet
program) to i denti fy both the devi ce needing servi ce and al so the mechani sm to secure the needed
maintenance or repai r.
Equi pment handl ing princi pl es are strai ghtforward. Before purchase, i t must be veri fied that a
proposed pi ece of equipment meets al l appli cabl e standards, whi ch wi l l usual ly be true when
deal i ng wi th recogni zed major manufacturers. (The recent renewed efforts of some faci l i ty
administrators to save money by attempting to find refurbi shed anesthesia machi nes and
moni tori ng systems shoul d provoke thorough revi ew by the i nvol ved practiti oners of any proposed
purchases of used equi pment. Unl i ke refurbi shed computers, used anesthesi a equi pment has many
moving mechanical parts that are subject to wear and eventual mechanical fai l ure.) On arrival ,
el ectrical equi pment must be checked for absence of hazard (especi all y leakage current) and
compl i ance with appl i cabl e electri cal standards. Complex equi pment such as anesthesia machi nes
and venti lators shoul d be assembl ed and checked out by a representati ve from the manufacturer
or manufacturer' s agent. There are potenti al adverse medi col egal impl icati ons when rel ati vel y
untrai ned personnel certify a particul ar piece of new equi pment as functi oni ng withi n speci fi cati on,
even if they do it perfectly. It i s also very i mportant to i nvol ve the manufacturer' s representati ve
i n pre- and i n-servi ce trai ni ng for those who wil l use the new equipment. On arri val, a sheet or
secti on i n the departmental master equipment l og must be created wi th the make, model , serial
number, and i n-house i denti fi cati on for each pi ece of capi tal equi pment. Thi s not only al l ows
immedi ate i dentificati on of any equi pment i nvol ved i n a future recal l or product alert, but also
serves as the permanent reposi tory of the record of every probl em, probl em resolution,
maintenance, and servi cing occurri ng unti l that parti cul ar equi pment i s scrapped. Thi s l og must be
kept up to date at al l ti mes. There have been rare but fri ghteni ng examples of potenti all y l ethal
problems with anesthesi a machines leadi ng to product al ert noti ces requi ri ng immedi ate
identi fi cation of certai n equipment and i ts servi ce status.
Service
Beyond the administrati ve li abil i ty impl icati ons, preci sel y what type of support personnel shoul d
maintai n and servi ce major anesthesi a equi pment has been wi del y debated. There are si gni fi cant
management i mpl i cati ons. Equipment setup and checkout have been menti oned. After that, some
groups or departments rel y on factory servi ce representati ves from the equi pment manufacturers
for all attenti on to equi pment, others engage i ndependent servi ce contractors, and sti l l other
(often l arger) departments have access to personnel (ei ther engi neers and/or technici ans)
permanentl y wi thin thei r faci li ty. Needs and resources di ffer. The si ngl e underl yi ng pri nci pl e i s
cl ear: the person(s) doi ng preventi ve mai ntenance and servi ce on anesthesi a equi pment must be
quali fi ed. Anesthesia practiti oners may wonder how they can assess these quali fi cati ons. The best
way i s to unhesi tati ngly ask pertinent questions about the educati on, traini ng, and experi ence of
those i nvol ved, i ncl udi ng aski ng for references and speaki ng to supervi sors and managers
responsi bl e for those doi ng the work. Whether an engineeri ng techni cian who spent a week at a
course at a factory can perform the most compl ex repairs depends on a vari ety of factors, whi ch
can be i nvesti gated by the practi tioners ul timately usi ng the equi pment i n the care of pati ents.
Fai lure to be i nvol ved i n thi s oversi ght function exposes the practi ce to i ncreased l iabi li ty i n the
event of an untoward outcome associ ated wi th i mproperl y mai ntained or serviced equi pment.
Determi ni ng when anesthesi a equi pment becomes obsol ete and shoul d be repl aced i s another
questi on that i s di ffi cul t to answer. Replacement of obsolete anesthesi a machi nes and monitori ng
equipment i s a key el ement of a ri sk modification program. Ten years i s often ci ted as an
esti mated useful l i fe for an anesthesi a machi ne, but although an ASA statement repeats that i dea,
i t al so notes that the ASA promul gated a Pol i cy for Assessi ng Obsol escence i n 1989 that does not
subscri be to any specific time i nterval . Anesthesi a machines consi derably more than 15 years ol d
li kel y do not meet certai n of the safety standards now in force for new machi nes (such as
vapori zer l ockout, fresh gas rati o protecti on, and automati c enabli ng of the oxygen analyzer) and,
unl ess extensivel y retrofi tted, do not i ncorporate the new technol ogy that advanced very rapi dl y
duri ng the 1980s, much of i t directl y related to the effort to prevent untoward i nci dents. Further,
it appears that thi s technology wil l conti nue to advance, parti cularly because of the adopti on of
anesthesia workstati on standards by the European

Economic Uni on that are affecti ng anesthesia machi ne desi gn worl dwi de. Note that some
anesthesia equipment manufacturers, anxi ous to minimi ze thei r own potenti al l i abi l ity, have
refused to support (wi th parts and servi ce) some of the ol dest of thei r pieces (parti cul arly gas
machines) stil l i n use. Thi s disowni ng of equi pment by i ts own manufacturer i s a very strong
message to practiti oners that such equipment must be repl aced as soon as possi bl e.
Shoul d a piece of equipment fail , i t must be removed from servi ce and a repl acement substi tuted.
Groups, departments, and faci l i ti es are obli gated to have suffi cient backup equi pment to cover any
reasonable inci dence of fail ure. The equi pment removed from service must be cl earl y marked with
a promi nent label (so i t i s not returned into service by a well -meani ng techni cian or practiti oner)
contai ning the date, ti me, person di scoveri ng, and the detai l s of the probl em. The responsibl e
personnel must be noti fi ed so they can remove the equi pment, make an entry in the log, and
initi ate the repai r. As i ndi cated in the protocol for response to an adverse event, a piece of
equipment i nvol ved or suspected i n an anesthesi a accident must be i mmedi atel y sequestered and
not touched by anybodyparti cul arl y not by any equi pment servi ce personnel . If a severe acci dent
occurred, i t may be necessary for the equipment in questi on to be i nspected at a l ater time by a
group consisting of qual ified representati ves of the manufacturer, the service personnel , the
pl aintiff' s attorney, the insurance compani es involved, and the practiti oner' s defense attorney. The
equipment shoul d thus be i mpounded fol l owi ng an adverse event and treated similarly to any
object in a forensi c chai n of evi dence, with careful documentati on of parti es i n contact with and
P.40
responsi bl e for securing the equi pment i n questi on fol l owi ng such an event. Al so, major equi pment
problems may, i n some ci rcumstances, reflect a pattern of fail ure as a resul t of a desi gn or
manufacturing faul t. These probl ems shoul d be reported to the FDA' s Medical Devi ce Problem
Reporti ng system
21
vi a MedWatch on Form 3500 (at http://0-
www.fda.gov.i nnopac.up.ac.za:80/medwatch/i ndex.html, or telephone 800-FDA-1088). Thi s
system accepts voluntary reports from users and requires reports from manufacturers when there
is knowledge of a medical device being i nvol ved i n a seri ous i nci dent. Whether or not fi l ing such a
report wi l l have a posi tive impact i n subsequent li tigation is i mpossi bl e to know, but i t i s a
worthwhil e practice management poi nt that needs to be consi dered i n the unli kel y but important
instance of a rel evant event i nvol vi ng equi pment fail ure.
Mal pr act i ce I nsur ance
All practiti oners need l i abi l ity insurance coverage speci fi c for the speci al ty and role in which they
are practi ci ng. Premi um rates depend on speci al ty, subspecial ty, and whether the insured
performs procedures that the insurance company' s experience suggests may be more l i kely to
resul t in a malpracti ce l awsui t. It i s absolutel y cri ti cal that appl i cants for medi cal li abil i ty
insurance be compl etel y honest i n informi ng the i nsurer what duti es and procedures they perform.
Fai lure to do so, ei ther from carel essness or from a fool ishly mi sgui ded desi re to reduce the
resul ti ng premium, may wel l resul t i n retrospective deni al of insurance coverage i n the event of an
untoward outcome from an acti vi ty the i nsurer di d not know the i nsured engaged i n.
Proof of adequate i nsurance coverage i s usual l y requi red to secure or renew pri vi leges to practi ce
at a health care faci l ity. The facil i ty may speci fy certain minimum poli cy l i mi ts i n an attempt to
li mi t i ts own li abil i ty exposure. It i s difficult to suggest speci fi c dol l ar amounts for pol i cy l imits
because the detai l s of practi ce vary so much among si tuati ons and l ocati ons. The malpracti ce
crisi s of the 1980s eased si gnifi cantly in the early 1990s for anesthesi ol ogi sts, l argel y because of
the decrease i n number and severi ty of malpracti ce cl ai ms resul ti ng from anesthesi a catastrophes
as anesthesi a care in the United States became safer.
22, 23, 24
The exact analysi s of thi s
phenomenon can be debated,
25, 26
but it i s a si mple fact that mal practice i nsurance ri sk rati ngs
have been decreased and premi ums for anesthesi ol ogists have not been i ncreased at the same
rate as for other speci al ties over the past decade and, in many cases, have actual l y decreased.
Thi s does not mi tigate the need for adequate coverage, however. In the earl y 2000s, coverage
limits of $1 million to $3 million would seem the bare minimum advi sabl e. This pol icy specificati on
usuall y means that the insurer wi l l cover up to $1 mil l ion li abil i ty per cl ai m and up to $3 mil l ion
total per year, but thi s termi nol ogy is not necessarily universal. Therefore, anesthesiol ogy
personnel must be absol utel y certai n what they are buying when they appl y for malpracti ce
insurance. In parts of the Uni ted States known for a pattern of exorbi tant settl ements and jury
verdi cts, l i abi l ity coverage l imi ts of $2 mi l li on to $5 mi ll i on may be prudent and wel l worth the
moderate addi ti onal cost. An addi ti onal feature i n thi s regard i s the potenti al to empl oy umbrell a
li abi l i ty coverage above the l i mi ts of the base pol i cy, as noted l ater.
Background
The fundamental mechani sm of medical malpractice i nsurance changed si gnifi cantly in the l ast two
decades because of the need for i nsurance compani es to have better ways to predict what thei r
losses (amounts pai d i n settlements and judgments) might be. Tradi ti onall y, medi cal l iabil i ty
insurance was sol d on an occurrence basis, meani ng that if the i nsurance pol i cy was i n force at
the ti me of the occurrence of an i ncident resul ti ng in a clai m, whenever that cl ai m mi ght be fi l ed,
the practi ti oner woul d be covered. Occurrence i nsurance was somewhat more expensi ve than the
al ternative cl ai ms made pol ici es, but was seen as worth i t by some (many) practi ti oners. These
pol ici es created some open-ended exposure for the i nsurer that someti mes l ed to unexpected l arge
losses, even some large enough to threaten the existence of the insurance company. As a resul t,
medical malpracti ce i nsurers have converted al most excl usi vel y to cl aims-made insurance, whi ch
covers cl ai ms that are fil ed whi l e the i nsurance i s i n force. Premi um rates for the fi rst year a
physi ci an i s in practice are relatively l ow because there is l ess l i kel ihood of a clai m comi ng in (a
majority of malpracti ce suits are fi l ed 1 to 3 years after the event i n questi on). The premi ums
usuall y increase yearly for the fi rst 5 years and then the pol i cy i s consi dered mature. The i ssue
comes when the physi ci an later, for whatever reason, must change insurance compani es (e.g.,
because of rel ocati on to another state). If the physi cian si mpl y disconti nues the poli cy and a clai m
is fi l ed the next year, there wi l l be no i nsurance coverage. Therefore, the physici an must secure
tail coverage, sometimes for a minimum number of years (e.g., 5) or someti mes i ndefinitel y to
guarantee li abil i ty insurance protecti on for clai ms fi l ed after the physi ci an i s no longer primari ly
covered by the i nsurance poli cy. It may be possi bl e i n some circumstances to purchase tail
coverage from a di fferent i nsurer than was involved wi th the pri mary pol i cy, but by far the most
common thi ng done i s to si mpl y extend the exi sti ng i nsurance coverage for the peri od of the tai l.
Thi s very often yi elds a bil l for the enti re tai l coverage premi um, whi ch can be qui te si zabl e,
potential ly staggeri ng a physici an who si mpl y wants to move to another state where hi s exi sti ng
insurance company i s not l icensed to or refuses to do busi ness. The i ssue of how to pay thi s
premi um i s appropri ately the subject of management attenti on and effort wi thi n the anesthesia
practi ce. Individual si tuati ons wi l l vary wi del y, but i t i s reasonable for anesthesi ol ogi sts organi zed
into a fi scal entity to consi der thi s i ssue at the ti me of the incepti on of the group and record their
pol icy deci sions i n wri ting, rather than faci ng the potenti al l y di ffi cul t questi on of how to treat one
individual l ater. Other strategi es have occasi onall y been empl oyed when

insuri ng the tai l peri od, including converting the previ ous pol i cy to part-ti me status for a peri od of
years, and purchasi ng nose coverage from the new i nsurerthat i s, paying an i ni ti al hi gher
yearly premium with the new insurer, who then wi ll cover cl aims that may occur duri ng the tail
peri od. Whatever strategy i s adopted, i t is cri tical that the i ndi vi dual practi ti oner be absol utel y
certai n through personal veri fi cati on that he or she is thoroughly covered at the ti me of any
transi tion. The potenti al stakes are much too great to l eave such i mportant i ssues sol el y to an
office clerk. Further, a practi tioner arriving i n a new l ocati on i s often fi ll i ng a need or voi d and i s
urged to begi n cl i ni cal work as soon as humanly possi bl e by others who have been shoul deri ng an
increased l oad. It i s essential that the new arri val veri fy wi th confi rmati on i n wri ti ng (often call ed
a bi nder) that mal practi ce li abil i ty i nsurance coverage i s i n force before any pati ent contact.
Another component to the l iabi li ty i nsurance si tuati on i s consi derati on of the advisabil i ty of
purchasi ng yet another type of insurance cal led umbrell a coverage, whi ch i s acti vated at the
ti me of the need to pay a cl aim that exceeds the l i mi ts of coverage on the standard mal practice
li abi l i ty insurance pol icy. Because such an enormous clai m i s extremely unli kel y, many
practi ti oners are tempted to forgo the comparati vel y modest cost of such insurance coverage i n
the name of economy. As before, i t is easy to see that thi s i s potenti all y a very fal se economyif
there i s a huge cl aim. Practiti oners shoul d consult wi th thei r fi nanci al managers, but i t is l i kel y
that i t woul d be consi dered wise management to purchase umbrell a li abi l i ty insurance coverage.
Medi cal mal practi ce i nsurers are becomi ng i ncreasingl y acti ve i n tryi ng to prevent i ncidents that
wil l l ead to i nsurance cl aims. They often sponsor ri sk-management semi nars to teach practices
and techni ques to l essen the chances of li abi l i ty cl aims and, i n some cases, suggest (or even
mandate) speci fi c practi ces, such as stri ct documented compl i ance with the ASA Standards for
Basi c Anestheti c Moni tori ng. In return for attendance at such events and/or the signing of
contracts stating that the practi tioner wi l l fol l ow certai n gui deli nes or standards, the i nsurer often
gi ves a di scount on the l iabi li ty insurance premi um. Cl earl y, i t i s sound practi ce management
strategy for practi ti oners to partici pate maxi mal ly i n such programs. Li kewise, some i nsurers make
coverage condi ti onal on the consi stent i mplementation of certai n strategi es such as mi ni mal
moni tori ng, even sti pul ati ng that the practiti oner wi l l not be covered i f i t is found that the
gui del i nes were being consci ously i gnored at the ti me of an untoward event. Agai n, i t i s obvi ousl y
wise from a practice management standpoi nt to cooperate ful ly wi th such sti pul ati ons.
Response t o an Adver se Event
In spite of the decreased inci dence of anesthesia catastrophes, even wi th the very best of
practi ce, it i s stati sti cal l y l i kely that each anesthesi ologi st at least once i n hi s or her
professi onal l i fe wi l l be involved i n a major anesthesi a acci dent. (See Chapter 5.) Preci sel y
because such an event i s rare, very few are prepared for i t. It i s probabl e that the i nvol ved
P.41
personnel wi l l have no relevant past experi ence regardi ng what to do. Al though an obvi ous
resource i s another anestheti st who has had some exposure or experi ence, one of these may not
be avai l abl e either. Vari ous authors have di scussed what to do in that event.
27, 28, 29
Cooper et al .
have thoughtful l y presented the appropri ate i mmediate response to an acci dent i n a
strai ghtforward, l ogi cal , compact format
30
that shoul d periodi cal l y be revi ewed by al l
anesthesi ol ogy practi ti oners and shoul d be i ncl uded i n al l anesthesi a pol icy and procedure
manual s. Thi s adverse events protocol is also always i mmediately avai l abl e at
http://www.apsf.org, Resources: Clinical Safety. Unfortunately, however, the pri nci pal personnel
invol ved in a significant untoward event may react wi th such surpri se or shock as to temporari ly
lose si ght of logic. At the moment of recogni tion that a major anestheti c compl i cation has
occurred or i s occurri ng, hel p must be cal led. A suffici ent number of peopl e to deal wi th the
si tuati on must be assembl ed on site as qui ckly as possi bl e. For exampl e, i n the unl i kel y but sti ll
possi bl e event that an esophageal i ntubation goes unrecogni zed l ong enough to cause a cardi ac
arrest, the i mmedi ate need i s for enough ski ll ed personnel to conduct the resusci tati ve efforts,
incl udi ng maki ng the correct di agnosi s and repl aci ng the tube i nto the trachea. Whether the
anesthesi ol ogi st apparentl y responsi bl e for the compl i cation should di rect the i mmedi ate remedi al
efforts wi ll depend on the person and the si tuati on. In such a circumstance, it would seem wi se for
a senior or supervi si ng anesthesi ol ogi st qui ckly to eval uate the scenario and make a deci si on. Thi s
person becomes the inci dent supervi sor and has responsibi l ity for helpi ng prevent conti nuation
or recurrence of the i ncident, for investi gati ng the i ncident, and for ensuring documentati on whi le
the ori gi nal and hel pi ng anesthesiol ogi sts focus on cari ng for the pati ent. As noted, involved
equi pment must be sequestered and not touched unti l such time as it i s certai n that i t was not
invol ved in the i nci dent.
If the acci dent is not fatal , continui ng care of the pati ent i s cri ti cal . Measures may be i nsti tuted to
hel p l i mi t damage from brai n hypoxi a. Consul tants may be hel pful and shoul d be cal l ed wi thout
hesitati on. If not al ready involved, the chi ef of anesthesiology must be notified as wel l as the
faci li ty admi ni strator, ri sk manager, and the anesthesiol ogi st' s i nsurance company. These l atter
are cri ti cal to al l ow consi derati on of immedi ate efforts to l i mi t later fi nanci al loss. (Li kewi se, there
are often provi sions i n medi cal malpracti ce i nsurance poli cies that mi ght l i mi t or even deny
insurance coverage if the company i s not notified of any reportable event i mmedi atel y.) If there i s
an i nvolved surgeon of record, he or she probabl y wil l fi rst notify the famil y, but the
anesthesiol ogi st and others (ri sk manager, insurance l oss control offi cer, or even l egal counsel )
mi ght appropri atel y be i ncl uded at the outset. Ful l disclosure of facts as they are best known
with no confessi ons, opinions, specul ati on, or placi ng of bl amei s currentl y sti ll bel ieved to be the
best presentati on. Any attempt to conceal or shade the truth wi ll l ater onl y confound an already
di fficul t situation. Obviousl y, comfort and support should be offered, i ncl udi ng, i f appropri ate, the
servi ces of facil i ty personnel such as cl ergy, soci al workers, and counsel ors. There i s a new
movement i n medi cal ri sk management and insurance advocating i mmedi ate ful l di scl osure to the
victim or survivors, i ncluding confessions of medi cal judgment and performance errors wi th
attendant si ncere apol ogi es. If i ndi cated, early offers of reasonabl e compensation may be
incl uded. There have been instances when thi s overal l strategy has prevented the fi l i ng of a
malpractice l awsui t and has been appl auded by al l i nvol ved as an exampl e of a shi ft from the
culture of bl ame with punishment to a just culture with restituti on. Laudable as thi s approach
may sound, i t woul d be mandatory for an indi vi dual practi ti oner to check with the i nvol ved l iabi li ty
insurance carrier, the practice group, and the faci li ty admini stration before attempting i t.
The primary anesthesia provider and any others involved must document rel evant i nformati on.
Never, ever change any exi sti ng entri es i n the medi cal record. Wri te an amendment note i f needed
with careful expl anati on of why amendment i s necessary, parti cul arl y stressi ng expl anati ons of
professi onal judgments involved. State onl y facts as they are known. Make no judgments about
causes or responsi bil i ty and do not poi nt fi ngers. The same gui del ines hold true for the fil i ng of
the incident report in the faci li ty, whi ch shoul d be done as soon as i s practi cal . Further, all
di scussi ons wi th the patient or fami l y shoul d be careful l y documented i n the medi cal record.
Recogni zi ng that detai l ed memories of the events may fade i n the 1 to

3 years before the practi ti oner may face deposi ti on questi ons about exactl y what happened, i t i s
P.42
possi bl e that i t wi l l be recommended, immedi atel y after the inci dent, that the i nvol ved cl inical
personnel sit down as soon as practical and write out thei r own personal notes, whi ch wi ll i ncl ude
opi ni ons and i mpressi ons as wel l as maximall y detail ed accounts of the events as they unfol ded.
These personal notes are not part of the medi cal record or the facil i ty fi l es. These notes shoul d be
wri tten i n the physi cal presence of an involved attorney representi ng the practi ti oner, even if thi s
is not yet the specifi c defense attorney secured by the mal practi ce insurance company, and then
that attorney shoul d take possession of and keep those notes as case materi al. Thi s strategy i s
intended to make the personal notes attorneycl i ent work product, and thus not subject to
forced di scovery (revel ati on) by other parti es to the case.
Foll ow-up after the immedi ate handli ng of the i ncident wi ll i nvol ve the pri mary anesthesiologi st
but shoul d agai n be directed by a senior supervisor, who may or may not be the same person as
the incident supervi sor. The fol l ow-up supervi sor veri fi es the adequacy and coordi nation of
ongoi ng care of the pati ent and faci li tates communicati on among al l involved, especi al l y wi th the
ri sk manager. Lastly, i t is necessary to veri fy that adequate postevent documentati on i s taki ng
pl ace.
Of course, it i s expected that such an adverse event wil l be discussed in the appl icable morbi dity
and mortali ty meeti ng. This i s good and appropri ate. It is necessary, however, to coordi nate thi s
acti vi ty with the involved ri sk manager and attorney so as to be compl etely certai n that the
contents and concl usi ons of the di scussi on are clearly consi dered peer review activity, and thus
are shi el ded from di scovery by the pl ai nti ffs' attorney.
Unpleasant as this is to contempl ate, i t is better to have a clear plan and execute i t in the event
of an acci dent causi ng i njury to a pati ent. Vi gorous immedi ate i nterventi on may i mprove the
outcome for al l concerned.
PRACTICE ESSENTIALS
The J ob Mar ket f or Anest hesi ol ogi st s
Whil e i t i s true that i n the mi d 1990s, for the fi rst ti me, uncertai nty faced resi dents fi ni shi ng
anesthesiol ogy training because of a percepti on that there were not enough jobs avai l abl e, that
concept faded rel ati vel y quickly. Somewhat of a manageable bal ance between suppl y and demand
devel oped, but wi th a si gni fi cant ongoi ng component of the idea that there i s an overall shortage
of anesthesi a providers. It i s l ikely that this fundamental paradigm wi ll persist in the next decade.
Factors governi ng the i ssues of suppl y of and demand for anesthesi ol ogi sts are compl ex and
evol vi ng. Before about 1993, wi th the excepti on of a very few of the most popular citi es, fini shing
resi dents coul d fi rst deci de where they wanted to l i ve and then seek an anesthesiol ogy practi ce
there to joi n or simpl y start one themsel ves. Al though a maldi stri bution of anesthesi ol ogi sts i n the
Uni ted States existed (and sti ll exi sts, with underserved rural and i nner-ci ty areas that may have
few or no physi cian anesthesi a servi ces), there were enough finishing resi dents comi ng into the
system to populate practi ces across the country in a manner that created a more normal
marketpl ace system in whi ch candidates for anesthesi ology jobs faced most of the same
consi derati ons as al l other professi onals. Another factor of hi stori cal si gni fi cance (but also wi th
potential appl i cation in the future) was the proposal i n 1993 by the U.S. federal admini stration to
restructure radicall y American heal th care del ivery. Al though thi s proposal was abandoned as too
radical, it i ntroduced an element of uncertai nty that persi sted l ong after the idea had been
di smi ssed. Thi s el ement of uncertai nty l ed many anesthesi ologists and facil i ti es to adopt a wai t
and see atti tude about hi ri ng new anesthesi ol ogi sts at that ti me.
Later, there was an el ement of pent up demand that opened many anesthesi ol ogi st posi ti ons
later i n the decade of the 1990s. Another factor i s the marketpl ace forces that have been and
conti nue to i nduce si gni fi cant changes in the U.S. heal th care system i ndependent of any
government proposal for change. Put as simply as possi bl e, the busi ness communi ty, empl oyers
who provi de health care insurance for thei r empl oyees, and government entiti es that fund
programs such as Medi care and Medicaid have suggested that i t may be i mpossi bl e for them to
conti nue to fund the rapidl y increasi ng expendi tures necessary to provi de heal th care coverage. As
a resul t, an enti re new i ndustry, managed health care, appeared. The managed care concept i s
bui lt on the idea that traditi onal fee-for-servi ce heal th care has no incenti ve for heal th care
provi ders, princi pall y physi ci ans, to l i mi t expendi tures. In fact, physi ci ans, health care workers,
and health care faci l iti es were financi all y rewarded the more heal th care was consumed or
rendered to patients. Accordingl y, MCOs came into bei ng, decl ari ng to busi ness and government
that a new admi ni strative l ayer was needed to control (reduce) what physi cians and health care
faci l i ti es spend. Thi s management of care by outsi de, i ndependent revi ewers and deci sion makers
who determi ne what care can and shoul d be rendered to the patient was i ntended to replace the
tradi tional fee-for-servi ce i ndemni ty system (bil l s submi tted by physi ci ans based on what they
deci de i s necessary that are then paid after the fact by a health plan or i nsurance company) and
thereby si gni fi cantl y reduce the cost for heal th care to empl oyers and governments. One of the
mai n themes of managed care pl ans was that there woul d be much l ess surgery. Thi s i dea led
logicall y to questions about how many anesthesiol ogi sts real ly were needed i n thi s country.
Discussi ons occurred both outside and wi thi n organi zed anesthesi ol ogy about such
questi ons,
31, 32, 33, 34
but, predi ctabl y, no defi ni ti ve answers were or are possi bl e.

By 2001, the si tuati on had l argel y reversed with the marketpl ace decl ari ng a shortage of
anesthesia providers and mul ti pl e attracti ve job offers for most resi dents bei ng graduated. Seni or
medical students very qui ckly reali zed this and the number of hi ghl y quali fi ed Ameri can graduates
appl yi ng to anesthesi ol ogy resi dencies i ncreased dramaticall y in the fi rst years of the twenty-first
century.
35
The si tuati on i s evol vi ng and fl uid,
36
and i t is i mportant to remember that there wi ll
al ways be surgery, no matter what heal th system changes take pl ace. Even i n the face of new
potential heal th system reforms and also conti nued cl i ni cal i nnovati on wi th nonoperati ve
procedures repl aci ng some traditi onal surgical operati ons, it seems l ikel y that, again, any
predi cti ons of less need for OR anesthesi a si mpl y wil l not come true and there may wel l be, i n
fact, ongoing i ncreases i n demand. Moreover, anesthesi ol ogists do more than just OR anesthesia
(and l i kel y i ncreasingl y so in the future). Accordi ngl y, at the ti me of this wri ti ng, prospects for
fini shing anesthesi ology resi dents are extremel y bri ght and they must be armed wi th knowl edge
about the practice worl d.
Types of P r acti ce
Wi th the al phabet soup of new practi ce arrangements for physi ci ans (IPA, PPO, PHO, MCO, MSO,
HMO) and the rapi dl y evol vi ng forces of the health care marketpl ace, as wel l as the i ntermi ttent
appearance of major governmental i niti atives to i nsti tute radi cal reform of the health care system,
it i s diffi cult to outl i ne the detail s of all the possi bl e types of opportuni ti es for anesthesiol ogi sts.
Rather, it i s reasonabl e to provi de basi c background information and also suggesti ons of sources
of further informati on.

At l east through the fi rst decade of the twenty-first century, resi dents finishing anesthesi ol ogy
trai ni ng wi ll stil l need to choose among three fundamental possi bil i ti es: academic practice i n a
teaching hospital envi ronment; a practi ce exclusi vel y of patient care in the private practice
marketpl ace; and a practi ce exclusi vel y of patient care as an employee of a health care system,
organizati on, or faci li ty.
Teachi ng hospi tal s wi th anesthesi ol ogy resi dency programs constitute onl y a very smal l fraction of
the total number of facil i ti es requiri ng anesthesi a servi ces. These academi c departments tend to
be among the largest, but the aggregate fraction of the enti re anesthesiologi st popul ati on i s smal l .
It i s interesti ng, however, that by the nature of the system, most resi dents finishing thei r trai ni ng
have almost exclusi vel y been exposed only to academi c anesthesiol ogy. Accordi ngly, fi ni shi ng
residents i n the past often were comparatively unprepared to evaluate and enter the
anesthesiol ogy job market. As noted, the Anesthesiology Resi dency Revi ew Commi ttee now
requi res teaching of job acqui siti on ski ll s and practi ce management as part of the resi dency
di dacti c curri culum.
Speci al ty certi fi cation by the Ameri can Board of Anesthesi ol ogy (ABA) shoul d be the goal of al l
anesthesia resi dency graduates. Some graduati ng resi dents who know they are eventuall y headed
P.43
for private practi ce have started their attendi ng careers as juni or facul ty. This al lows them to
obtai n some cl i ni cal practice and supervi sory experience and offers them the opportuni ty to
prepare for the ABA exami nati ons i n the nurturing, protected academi c envi ronment with whi ch
they are famil i ar. Most resi dents, however, do not become junior faculty; they accept practi ce
positi ons immedi atel y. But such newl y trained resi dents should take i nto account the need to
become ABA-certi fi ed and bui l d into thei r new practi ce arrangements the sti pul ati on that there wil l
be ti me and consi derati on gi ven toward thi s goal . The hecti c and unsettli ng ti me of embarki ng on
a new career, possibl y moving one' s home and fami l y, and getti ng accli mated to a new
professi onal and fi nancial environment may i nhibit opti mum performance on the examinati ons. The
possi bi li ties to avoi d thi s disruption may be comparati vely l imited, but awareness of the probl em
can hel p. At the very least, it may lead to the forgi ng of initi al practice arrangements that wi ll
maxi mi ze the probabi li ty of success.
Academi c P r act i ce
For those who choose to stay in academi c practice, the fi rst questi on i s whether to consi der
staying at one' s trai ni ng insti tuti on. On the one hand, the devi l you know i s better than the devi l
you don' t know. On the other hand, however, fear of the unknown shoul d not i nhibi t i nvestigati on
of al l possibi l iti es. Asi de from obvi ous personal preferences such as area of the country, si ze of
ci ty, and cl imate, a number of specifi c characteristics of academi c anesthesia departments can be
used as screeni ng questi ons.
How bi g i s the department? Juni or facul ty someti mes can get lost i n very bi g departments and be
treated as l i ttl e better than gl ori fi ed senior resi dents. On the other hand, the avai labi li ty of
subspecial ty servi ce opportuni ti es and signi fi cant research and educati onal resources can make
large departments extremel y attracti ve. In small er academi c departments, there may be fewer
resources, but the l i keli hood of bei ng qui ckl y accepted as a val ued, contri buting member of the
teaching facul ty (and research team, if appropriate) may be hi gher. In very smal l departments,
the number of expectati ons, projects, and involvements could potenti al l y be overwhel mi ng.
Addi ti onal l y, a smal l department may l ack a dedi cated research infrastructure, so i t may be
necessary for the facul ty i n this si tuati on to coll aborate wi th other, l arger departments to
accompl i sh meaningful academi c work.
What exactl y i s expected of juni or faculty? If teachi ng one resident cl ass every other week i s
standard, the candi date must enthusi asti cal ly accept that assi gnment and the attendant
preparati on work and ti me up front. Li kewi se, if it i s expected that juni or faculty wi ll , by
definiti on, be acti vel y i nvol ved i n publ i shabl e research, speci fi c plans for projects to whi ch the
candi date i s amenabl e must be made. In such si tuati ons, cl ear stipulations about startup research
funding and noncl inical ti me to carry out the projects shoul d be obtai ned as much as possibl e.
Parti cul arl y i mportant i s determi ni ng what the expectati on i s concerni ng outside fundingit can be
a rude shock to real ize that projects wi ll suddenl y hal t after, for exampl e, 2 years i f extramural
fundi ng has not been secured.
What are the prospects for advancement? Many new juni or facul ty di rectly out of resi dency start
with medi cal school appoi ntments as instructors unl ess there i s somethi ng el se i n thei r
background that i mmediately qual ifi es them as assi stant professors. It i s wi se to understand from
the beginning what it takes in that department and medi cal school to facil i tate academi c
advancement. There may be more than one academic track; the tenure track, for example, is
usuall y dependent on publi shed research whereas the cli nical or teacher track rel i es more heavi l y
on one's value i n patient care and as a cli nical educator. The cri teria for promotion may be clearl y
spel led out by the i nstituti onnumber of papers needed, i nvol vement and recogni ti on at vari ous
l evel s, grants submi tted and funded, and so onor the system may be l ess ri gi d and depend more
heavil y on the department chai rman' s and other facul ty eval uati ons and recommendati ons. In
ei ther case, careful inqui ry before accepti ng the positi on can avert l ater surpri se and
di sappoi ntment.
How much does i t pay? Tradi ti onal l y, academi c anesthesiol ogi sts have not earned quite as much as
those i n pri vate practi cein return for the advantage of more predi ctabl e (and maybe less
strenuous) schedules, continued i ntel lectual sti mul ati on, and the i ntangibl e rewards of academic
success. There is now great acti vity and attenti on concerni ng reimbursement of anesthesi ologi sts,
and i t i s di ffi cul t to predi ct future i ncome for any anesthesiol ogy practi ce si tuati on. However, al l
of the forces infl uenci ng payment for anesthesi a care may significantly di mi ni sh the traditi onal
income di fferenti al between academic and pri vate practi ce. Thi s is not a smal l i ssue.
Anesthesi ol ogists justifi ably can expect to l ive reasonabl y wel l. Income is also a vali d
consi derati on both because anesthesiol ogi sts are frequentl y at least 30 years ol d when they fi ni sh
trai ni ng and are thus starti ng wel l behi nd their age-mates i n l i fetime earni ngs and because most
physi ci ans have substanti al educati onal l oans to repay when fi ni shi ng resi dency. The compensation
arrangements i n academi c practi ce vary wi del y in structure. In some cases, a facul ty member is
excl usi vel y an empl oyee of the insti tution, whi ch bil l s and col l ects or negotiates group contracts
for the patient care rendered by the faculty member, and then pays a negoti ated amount (ei ther
an absol ute dol l ar fi gure or a floati ng amount based on vol ume and/or col l ecti onsor a
combi nation of the two) that constitutes the facul ty person' s entire i ncome. Under other l ess
common arrangements, facul ty members themselves may be abl e to bi l l and col l ect or negoti ate
contracts for their cl inical work. Some insti tutions have a (comparati vel y smal l) academic sal ary
from the medi cal school for bei ng on the facul ty, but many do not; some channel vari able amounts
of money (from so-call ed Part A cl i ni cal revenue) i nto the academi c practi ce i n recogni ti on of
teaching and admi nistrati on or si mpl y as a subsi dy for needed servi ce. A sal ary from the medi cal
school , i f extant, is then suppl emented si gnifi cantly by the practi ce i ncome. Usuall y, the faculty
will be members of some type of group or practi ce pl an (ei ther for the anesthesia department
al one or the enti re faculty as a whol e) that bi l ls and coll ects or negoti ates contracts and then
di stri butes the practi ce income to the facul ty under an arrangement that must be

examined by the candi date. In most academic insti tutions, practice expenses such as al l overhead
and mal practi ce i nsurance as wel l as reasonabl e benefi ts, incl udi ng di screti onary funds for
meeti ngs, subscripti ons, books, dues, and so on, are automati cal ly part of the compensation
package, which often may not be true i n pri vate practi ce and must be counted in maki ng any
compari son. An important corol lary i ssue is that of the source of the sal ari es of the department' s
pri mary anesthesi a provi dersresidents and, in some cases, nurse anestheti sts. Al though the
hospi tal usual l y pays for at l east some of these, arrangements vary, and i t i s important to
ascertai n whether the facul ty practi ce i ncome i s al so expected to cover the cost of the primary
provi ders. Overal l, it i s reasonabl e to sound out faculty, both anesthesi ol ogy and others, regardi ng
the past and l i kely future commi tment of the i nstituti on to the establ i shment and maintenance of
reasonable compensation for the expected i nvol vement.
P r i vat e P r act i ce i n t he Mar ket pl ace
As noted, some resi dents fi ni sh thei r anesthesi a trai ni ng never havi ng seen a pri vate practice
anesthesia setti ng or even tal ked to an anesthesi ol ogi st who has been in private practi ce. These
candi dates are i l l -equi pped to seek a posi ti on i n the private practi ce marketpl ace. Obvi ously,
rotati ons to a pri vate practice hospi tal in the final year of anesthesi a resi dency could hel p greatly
in thi s regard, but not al l resi dency programs offer such opportuni ti es. In that case, the fini shing
resident who i s certai n about going i nto pri vate practi ce must seek i nformati on on career
devel opment and mentors from the pri vate sector.
Armed wi th as much informati on as possi bl e, one fundamental ini ti al choi ce i s between
i ndependent i ndi vi dual practi ce and a posi ti on with a group (ei ther a sol e propri etorship,
partnershi p, or corporation) that functi ons as a si ngle financi al entity. Independent practice may
become i ncreasingly l ess vi abl e i n many locations because of the need to be able to bi d for
contracts wi th managed care enti ti es. However, where i ndependent practi ce i s possi bl e, i t usual ly
first involves attempti ng to secure cl inical pri vi l eges at a number of hospi tal s or faci li ties i n the
area i n which one chooses to l ive. Thi s may not al ways be easy, and thi s i ssue has been the
subject of many (frequentl y unsuccessful ) anti trust sui ts over recent years (see Antitrust
Consi derations). Then the anesthesi ol ogi st makes it known to the respecti ve surgeon communi ti es
that he or she i s avai l abl e to render anesthesi a servi ces and waits unti l there is a request for hi s
or her servi ces. The anesthesi ol ogi st obtains the requisi te financial i nformati on from the pati ent
P.44
and then ei ther indi vi duall y bil l s and col lects for services rendered or employs a servi ce to do
bi l l ing and col l ecti on for a percentage fee (whi ch wi l l vary dependi ng on the ci rcumstances,
especi al l y the vol ume of busi ness; for bil l ing [without schedul i ng servi ces] it would be unli kel y to
be more than 7% or, at the most, 8% of actual coll ecti ons). How much of the needed equi pment
and suppl i es wi l l be provi ded by the hospi tal or faci li ty and how much by the i ndependent
anesthesiol ogi st vari es widel y. If an anesthesi ologist spends consi derabl e ti me in one operating
suite, he or she may purchase an anesthesi a machine excl usively for hi s or her own use and move
i t from room to room as needed. It is l i kel y to be i mpracti cal to move a full y equi pped anesthesi a
machine from hospital to hospi tal on a day-to-day basi s. Among the features of thi s styl e of
practi ce are the col l egi ali ty and rel ati onships of a genui ne pri vate practi ce based on referral s and
al so the abi li ty to deci de i ndependentl y how much ti me one wants to be avai labl e to work. The
downsi de i s the potenti al unpredictabi l ity of the demand for servi ce and the ti me needed to
establ i sh referral patterns and obtai n booki ngs suffi ci ent to generate a li vable income.
Acknowl edgi ng that the issues presented earl ier may at some times render components of these
suggestions moot, i t is reasonabl e for the graduati ng resi dent to know that when seeking a
positi on wi th a private group, the appl i cant shoul d search for potenti al practi ce opportuniti es
through word of mouth, recruiti ng l etters sent to the trai ni ng program supervi sor, journal
adverti sements, and pl acement servi ces (ei ther commercial or professional , such as that provi ded
at the ASA annual meeti ng). Some of the screeni ng questi ons are the same as for an academi c
positi on, but there must be even more emphasi s on the exact detai l s of cl i ni cal expectations and
financial arrangements. Some resi dents finish resi dency (or fel l owship trai ni ng to an even greater
extent) very hi ghly skil l ed i n compl ex, di ffi cul t anesthesi a procedures. They can be surpri sed to
find that in some pri vate practi ce group si tuati ons, the junior-most anesthesi ologist must wai t
some ti me, perhaps even years, before bei ng el i gi bl e to do, for exampl e, cardiac anesthesi a and i n
the meantime wi l l mostl y be assi gned more routi ne or l ess chal lenging anestheti cs. Of course, thi s
is not always the ci rcumstance, but the appl i cant needs to i nvestigate thoroughl y to be certain
that the opportuni ty sati sfi es the desi re for professi onal chal l enge.
Fi nanci al arrangements i n pri vate group practices vary wi dely. Some groups are l oose
organizati onal all i ances of i ndependent practi tioners who bi l l and col l ect separatel y and rotate
cl i ni cal assi gnments and cal l for mutual conveni ence. Many groups act also as a fiscal enti ty, and
there are many possibl e variations on thi s theme. In many circumstances i n the past, new juni or
members started out as functional empl oyees of the group for a probati onary i nterval before bei ng
consi dered for ful l membershi p or partnershi p. This i s not a cl assi c empl oyment situation because
it i s intended to be temporary as a prel ude to full fi nanci al parti cipation in the group. However,
there have been enough instances of establi shed groups abusi ng thi s arrangement that the ASA
incl udes i n its fundamental Statement of Poli cy the provi so: Expl oi tati on of anesthesi ol ogi sts by
other anesthesi ol ogists i s i mproper.
3
Thi s goes on to say that after a reasonable trial peri od,
income should refl ect services rendered. Unfortunatel y, these statements may have l ittl e meaning
or i mpact on groups i n the marketpl ace. Some groups have a hi story of demandi ng excessivel y
long trial peri ods duri ng whi ch the junior anesthesi ol ogi st' s i ncome i s artifi ci al l y l ow and then
denyi ng partnershi p and termi nati ng the relationshi p to go on to empl oy a new probati oner and
start the cycl e over agai n. Accordi ngl y, new juni or staff attempti ng to joi n groups shoul d try to
have such an arrangement spell ed out careful l y i n the agreement drafted by an expert
representi ng the anesthesiol ogi st. Another vari ation of thi s, in an attempt to di sgui se the
fundamental l y unethi cal nature of the practi ce, i s to empl oy anesthesi ol ogists on a fi xed sal ary
with the fal se i ncenti ve of no ni ght or weekend cal l . Thi s i s disi ngenuous, as the vast majori ty of
income i s usual l y generated duri ng routi ne scheduled day work, for whi ch the anesthesi ol ogi st-
empl oyee i s poorl y compensated. Yet another usuri ous scheme i s for a group to employ an
anesthesiol ogi st for a peri od of years at a low salary and then require a further cash outl ay to
purchase partnership in the corporati on. As the cash outl ay can be qui te substanti al, it i s
frequently borrowed from the corporation, leadi ng to a sophi sti cated form of i ndentured servi tude.
Sadl y, when the job market condi ti ons are poor as they were some years ago, the tendency is for
there to be less l ikel i hood of securi ng a prospective commi tment of partnershi p at a speci fi ed
future time. Thi s i s especi al l y true i n the more desirabl e areas of the Uni ted States where stories
of abuse of junior partners have been more common. Whether this shoul d substanti al l y affect an
appl icant' s interest i n or wi l li ngness to accept a posi ti on i s a hi ghl y i ndi vi dual matter that must be
eval uated by each appl i cant. As the market turned and the demand often exceeded the suppl y of
new anesthesi ol ogi sts, such abuses appeared l ess

li kel y. In al l cases, the appli cant must uti li ze resources
4
that al low them to enter the negoti ati ng
process armed with maxi mum i nformati on and reasonabl e expectati ons.
P r i vat e P r act i ce as an Empl oyee
There has been some trend toward anesthesiologi sts becomi ng permanent empl oyees of any one of
vari ous fi scal enti ties. The key difference i s that there i s no i ntention or hope of achi eving an
equity posi ti on (share of ownership, usuall y of a partnershi p, thus becomi ng a ful l partner).
Hospi tal s, outpatient surgery centers, mul ti di sci pli nary cl inics, other faci li ties ti ed to a speci fic
location where surgery is performed, physi ci an groups that have umbrel la fiscal enti ti es
specificall y created to serve as the empl oyer of physi cians, and even surgeons may seek to hi re
anesthesiol ogi sts as permanent empl oyees. The common thread in thi s system is that these fiscal
enti ties see the anesthesi ol ogists as additi onal ways of generati ng profi ts. Agai n, in many cases it
woul d appear that empl oyees are not pai d a salary that is commensurate wi th thei r producti on of
recei vabl es. That is, the fiscal enti ty wi l l pay a sal ary substantial ly below coll ecti ons generated
pl us appropriate overhead. These arrangements are parti cularl y favored by some l arge managed
care organi zati ons in certain citi es that vi ew anesthesiol ogi sts simply as expensive necessi ti es
that prevent hospitals from real i zi ng maximum profi t (al though someti mes there i s a promi se of a
li ghter or more manageabl e schedul e i n these posi ti ons compared to marketplace pri vate
practi ce). At the height of the managed care mani a of the mid to l ate 1990s, there were
predi cti ons that thi s trend would conti nue to grow, and that eventual ly most physi ci ans i n the
support speci al ties of anesthesi ol ogy, radi ol ogy, pathol ogy, and emergency medi ci ne woul d be
outri ght permanent empl oyees of an organi zed enti ty of some type. Whi l e cl earl y thi s di d not
happen and the managed care bubbl e has defl ated somewhat, it i s i mpossi ble to speculate on the
future i n thi s regard. Many anesthesi ol ogi sts bel i eve that the future i s extraordi nari l y bright and
that anesthesi ol ogy wi l l expand i ts rol e, predicting that anesthesi ol ogi sts wil l increasi ngl y assume
positi ons of central authority in managed care and other practi ce entiti es, maki ng decisi ons about
the hiring and firing of physi cians of other speci alti es.
Negoti ati ng for a posi ti on as a permanent empl oyee i s somewhat si mpler and more strai ghtforward
than i t i s i n marketpl ace pri vate practi ce. It parall els the usual understandi ngs that apply to most
regul ar employeremployee si tuations: job descri pti on, rol e expectati ons, working conditi ons,
hours, pay, and benefits. The i dea of anesthesi ol ogists functi onal l y becoming shi ft workers
di sturbs many i n the profession because i t contradi cts the tradi ti onal professi onal model . On the
other hand, major upheaval i n the heal th care deli very system has someti mes l ed to
reorgani zati on that, unti l very recentl y, was unheard of. Agai n, the compl ex nature and mul tipl e
level s of such consi derati ons make it a personal issue that must be carefull y evaluated by each
individual with ful l awareness and consi deration of the i ssues outl ined here.
Bi l l i ng and Col l ect i ng
In practi ces i n which anesthesi ol ogi sts are directl y i nvol ved with the fi nanci al management, they
need to understand as much as possi bl e about the compl ex worl d of heal th care rei mbursement.
This significant task has been made easi er by the ASA, whi ch some ti me ago added a si gni fi cant
component to i ts Washi ngton, D.C., offi ce by addi ng a practi ce management coordi nator to the
staff. One of the associ ated assi gnments i s hel pi ng ASA members understand and work wi th the
sometimes confusing and convol uted issues of effective bi ll i ng for anesthesi ol ogi sts' services.
There are often updates with the latest i nformati on and codes i n the monthl y ASA Newsl etter.
There continue to be proposal s for si gni fi cant changes i n bil l ing for anesthesiol ogy care. However,
the basi cs have changed onl y sl i ghtl y in recent years. It i s important to understand that many of
the most contentious issues, such as the requi rement for physi ci an supervi sion of nurse
anesthetists and the i mpl i cations of that for rei mbursement, appl y i n many ci rcumstances mostl y
to Medicare and, in some states, Medi cai d. Thus, the fracti on of the pati ent popul ation covered by
P.45
these government payers i s i mportant i n any consi derati on. Different practi ce si tuati ons have
di fferent arrangements regardi ng the fi nanci al relationshi ps between anesthesi ologi sts and nurse
anesthetists, and thi s can affect the compl ex si tuati on of who bi l l s for what. The nurses may be
employees of a hospital, of the anesthesi ol ogists who medi cal ly di rect them, or of no one i n that
they are i ndependent contractors bil l ing separatel y (even in cases in whi ch physi cian supervisi on
not medical directi onis requi red but where those physici ans do not bi l l for that component). In
1998, Medi care mandated that an anesthesia care team of a nurse anestheti st medi cal l y di rected
by an anesthesiol ogi st coul d bi ll as a team no more than 100% of the fee that woul d appl y i f the
anesthesi ol ogi st di d the case al one. The i mpl icati ons of thi s change are compl ex and variabl e
among anesthesi ol ogy practi ces, particul arl y because there i s another trendfor heal th care
faci li ties that traditi onal l y had employed nurse anestheti sts to seek to shi ft total fi nanci al
responsi bi li ty for them to the anesthesi ologi st practice group. Al so, compl ex rel ated i ssues pl ayed
out i n the earl y 2000 years. The federal government i ssued a new regul ati on al lowi ng i ndividual
states to opt out of the requirement that nurse anestheti sts be supervi sed by physi ci ans and
several states di d so. Thi s was opposed by the ASA. Because peri operati ve patient care, one
component of whi ch i s admi ni steri ng anesthesi a, is traditi onal l y consi dered the practi ce of
medici ne, the impli cati ons of thi s change as far as the rol e of surgeons supervi sing nurse
anesthetists and the malpracti ce l i abi l ity status of nurse anestheti sts practi cing i ndependentl y
were uncl ear. Further, the i mpl i cations of al l this for bil l i ng i nsurers other than Medicare and
Medi cai d are exceedi ngl y compl ex. Obvi ously, careful considerati on of these issues and seeki ng
out advi ce from knowl edgeabl e resources (such as the ASA Washi ngton offi ce) i s cri ti cal to fi scal
stabi l ity in modern anesthesi ology practi ce.
There has been significant consi deration of the mechani sm of bil l ing for anesthesi ol ogy. There
have been some suggestions that so-call ed schedul e fees (a si ngl e predetermi ned fee for an
anesthetic, i ndependent of i ts length or compl exi ty) wil l become more common. Further, there i s
pressure from some quarters to bundl e together all the physi ci ans' fees for one procedure i nto a
si ngl e gl obal professi onal fee that woul d pay the surgeon, anesthesi ologist, radi ol ogi st,
pathologi st, and so on for one case, such as a l aparoscopi c chol ecystectomy. However, all of this
concern about bi l l ing for specific procedures coul d become i rrel evant i n systems wi th prospecti ve
capitated payments for large popul ati ons of pati ents, i n whi ch each group of i nvol ved physi cians i n
a system woul d recei ve a fixed amount per enrol l ed member per month (PMPM) and agree, except
in the most unusual ci rcumstances, to provi de whatever care is needed by that popul ati on for that
prospecti ve payment. These are i ntended to be l arge-scal e operati ons i nvol vi ng at l east tens of
thousands of peopl e (covered li ves) in each organi zati on. There was a trend in thi s directi on i n
the late 1990s, but, as with so many aspects of managed care, the actual implantati on of the
ideas in real l ife did not work out smoothly or as planned and there was a resul ting retrenchment
i nto more bl ended model s of faci l ity rei mbursement based on DRG (di agnosi s rel ated group) codes
and professi onal rei mbursement based on a

negoti ated mul ti pl e (or fracti on) of the correspondi ng Medi care payment for that service.
Classic Methodology
Because there i s sti ll wi despread appl i cation of the traditi onal method of bi ll i ng for anesthesi ology
servi ces, understanding i t is very important for anesthesi ologi sts starti ng practice. In this system,
each anestheti c generates a val ue of so many uni ts, whi ch represent effort and ti me. A
conversion factor (dol l ars per uni t) that can vary wi del y mul ti pl ied by the number of uni ts
generates an amount to be bi l l ed. Each anestheti c has a base value number of uni ts (e.g., 8 for a
chol ecystectomy) and then the ti me taken for the anestheti c i s di vi ded i nto uni ts, usuall y 15
mi nutes per uni t. Thus, a chol ecystectomy wi th anesthesia time of 1 hour and 50 mi nutes would
have 8 base units and 7.33 ti me uni ts for a total of 15.33 uni ts. In some practi ce setti ngs, it may
be al l owed to add modi fiers, such as extra uni ts for complex pati ents wi th mul ti pl e problems as
refl ected by an ASA physi cal status cl assi fi cati on of 3 to 5 and/or E (emergency) or for i nserti on
of an arteri al or pul monary artery catheter. The sum i s the total bil l ing uni t value. Determi ni ng
the base value for an anesthetic i n uni ts depends on ful l and correct understanding of what
operation was done. Although thi s sounds easy, it i s the most diffi cult component of tradi tional
P.46
anesthesia bi l li ng. The process of determi ni ng the procedure done is known as codi ng because the
procedure name l isted on the anesthesi a record i s assigned an i denti fyi ng code number from the
uni versal l y used CPT-4 codi ng book. Thi s code i s then transl ated through the ASA Rel ati ve Val ue
Guide, whi ch assi gns a base unit val ue to the type of procedure i dentified by the CPT-4 code. In
the past, some anesthesi ol ogi sts fai l ed to understand the importance of correct coding to the
success of the bil l ing process. Pl aci ng thi s task i n the hands of someone unfami l iar wi th the
system and wi th surgical termi nol ogy can easi ly lead to incorrect coding. This can fai l to capture
charges and the resulti ng i ncome to whi ch the anesthesi ol ogi st is enti tled or, worse, can
systemati cal l y overcharge the payers, whi ch wi l l bri ng sanctions, penalti es and, i n certain cases,
crimi nal prosecuti on. In recent years a prevai li ng offi ci al atti tude has been that there are no
si mpl e, i nnocent codi ng errors. Al l upcodi ng (chargi ng for more expensi ve services than were
actual l y deli vered) i s consi dered to be prima faci e evi dence of fraud and subject to severe
di scipl i nary and l egal acti on. Al l practi ces should have detai led compl i ance programs i n place to
ensure correct coding for servi ces rendered.
37
Outsi de expert help (such as from a health care law
firm that speci ali zes i n compl i ance programs) is hi ghl y desi rabl e for the process of formul ati ng
and i mpl ementi ng a compl i ance pl an.
Assembl y and transfer of the i nformati on necessary to generate bil l s must be effici ent and
compl ete. Traditi onal l y, thi s i nvol ved deposi ti ng i n a secure central locati on a paper extra copy of
the anesthesi a record and often a bi l l ing sheet with it, on whi ch was i nscri bed the names of al l
the involved personnel and any additi onal i nformati on about other potenti all y bi l l abl e servi ces,
such as invasi ve monitors. Any practice i nvol ved with a comprehensi ve electroni c peri operati ve
information management system i n the faci l ity should be usi ng that to assembl e thi s front end
bi l l ing i nformati on. Short of that, some practi ces coll ect el ectronic i nformation specificall y
generated by the anesthesi a provi ders for that purpose. They have equi pped each staff member
with a hand-hel d organi zer into whi ch data are entered and then the devi ce is synched wi th a
departmental computer at the end of the day. If the OR suite has wi -fi (wirel ess el ectroni c
connecti on), the same functi on could be accompli shed i n real ti me wi th the providers enteri ng the
requi site i nformati on i nto a mi ni program on a l aptop computer affi xed to each anesthesi a machine
(or one carri ed by each staff member). Of course, the uni versal use of hand-hel ds or laptops coul d
have significant other benefits to the members of the group/department. Overal l , whil e achi eving
ful l compl i ance wi th such a protocol of bi ll i ng data entry by the group's staff may take significant
in-servi ce educati on and trai ni ng, it wi l l only take one reduced or, better, mi ssed paycheck to
achi eve ful l compl i ance by any given member. Once the informati on has been secured, a
mechanism must be employed to generate the actual bi l l and communicate it to the payer (on
paper, on di sk, or, usuall y, directl y computer-to-computer: el ectronic cl ai ms submi ssi on). The
possi bl e preci se arrangements for doi ng thi s vary wi dely. Ul timatel y, the enti ty actual l y submi tti ng
the bil l wi l l veri fy that i t has been pai d (posti ng of recei pts) and may or may not actual l y handle
the incoming money. Very often, anesthesi a practi ces or indi vi duals who use a bi ll i ng service wi l l
arrange that the payments go directl y to a bank l ockbox, whi ch is a post office box (better
individual than shared, even i f more expensi ve) to whi ch the payments come and then go di rectly
into a bank account. Thi s system avoi ds the situation of havi ng the peopl e who generate the bi ll
actual l y handl e the i ncoming recei pts, a practi ce that has l ed to theft and fraud i n a few cases.
Eventual decisi ons about how hard to try to coll ect from payers who deny coverage and then from
patients di rectly wi l l depend on the ci rcumstances, including l ocal customs.
Detail ed summary stati sti cs of the work done by an anesthesi ol ogy practi ce group are cri ti cal for
l ogi sti c management of personnel , scheduli ng, and fi nanci al anal ysi s. Spreadsheet and database
computer programs customi zed for an individual practi ce' s characteri sti cs wi ll be i nvaluabl e. A
summary of the types of data an anesthesi a practi ce shoul d track i s shown i n Tabl e 2-5. Once al l
the data are assembl ed and revi ewed, at least monthl y anal ysis by a business manager or
equival ent as wel l as offi cers/l eaders of the practi ce group can spot trends very earl y i n thei r
devel opment and al l ow appropri ate correction or pl anni ng. Often the responsibl e members of an
anesthesiol ogy group questi on how effecti ve thei r fi nanci al servi ces operation i s, parti cularly
regardi ng net col lecti ons. This i s a compl ex issue
38
that, again, often requi res outsi de hel p.
Routi ne i nternal audi ts can be useful but coul d be sel f-servi ng. No bi l l i ng offi ce or company that i s
honest and compl etel y above board shoul d ever object to a cl ient, in thi s case the anesthesi ol ogy
practi ce group, engagi ng an i ndependent outside audi tor to come i n and thoroughly exami ne both
the effi ciency of the operati on and al so the books concerning correctness and compl eteness of
coll ecti ons.
TABLE 2-5 Types of Data an Anesthesiology Group Should Track and Maintain
Concerning Its Own Practice
Types of Data the Anesthesiol ogy Group' s Computer System Shoul d Track
1. Transaction-based system (track each case and charge as separate record)
Track i ndi vi dual charges by CPT-4 code
Track i ndi vi dual payments by payer
2. Track al l data el ements on an interrel ated basi s
By place of service
By charge, broken down
by number of uni ts (ti me and base)
by ASA modi fi ers
by number of l ines
By CPT-4 code
By payer
By payment code (ful l payment, di scount, wri te-off, or refund)
By di agnosi s (ICD-9 code)
By surgeon
By anesthesiol ogi st
By anesthesia care team provi der
By start and stop times
By age
By gender
By employer
By ZIP code
Type of Information to Generate from These Data
1. Aggregate number of cases per year for the group
2. Total number of cases per year for each provi der within the group
Number of cases performed by anesthesi ol ogi sts
Number of cases performed by the anesthesi a care team
3. Average number of uni ts per case (as one measure of i ntensi ty per case)
4. Average number of uni ts per CPT-4 code
5. Average time units per case and per CPT-4 code
Group shoul d be abl e to cal cul ate ti me uni ts per i ndi vi dual surgeon
6. Average l ine charge per case
7. Charges per case by CPT-4 code
8. Payments per case by payer
9. Patient mi x
Percent traditi onal i ndemni ty
Percent managed care (broken down by each MCO for whi ch servi ces are
provi ded)
Percent sel f-pay
Percent Medicare
Percent Medicaid
10. Col l ecti on rate for each popul ati on served
Anesthesi a bil l ing and coll ecti ng are among the most complex chal l enges i n the medi cal
rei mbursement fi el d. Tradi ti onal anesthesi a rei mbursement i s uni que i n al l of medi cine. The
experi ence of many peopl e over the years has suggested that i t often is well advi sed to deal with
an entity that is not only very experienced in anesthesi a bi l l i ng, but al so does anesthesi a bil l ing
excl usi vel y or as a l arge fraction of its efforts. It is very diffi cult for an anesthesiologi st or a
famil y member to do bi l li ng and col lecting as a si de activity to a normal l i fe. This has l ed to
ineffi ci ent and inadequate efforts i n many cases, il l ustrati ng the value of payi ng a reasonabl e fee
to a professi onal who wi l l devote great ti me and energy to thi s chall engi ng endeavor.
Ant i t r ust Consi der at i ons
Although i t is true that there are many potential antitrust impl icati ons of busi ness arrangements
invol vi ng anesthesi ol ogistsparti cul arl y wi th all the reali gnments, consoli dati ons, mergers, and
contracts associ ated wi th the advent of managed careit i s al so true that the appli cabl e statutes
and regul ati ons are poorl y understood. Contrary to popul ar bel ief, the antitrust laws do not
invol ve the ri ghts of i ndi vi dual s to engage i n busi ness. Rather, the laws are concerned sol ely wi th
the preservation of competi ti on withi n a defi ned marketpl ace and the

ri ghts of the consumer, i ndependent of whether any one vendor or provider of servi ce i s involved.
Thi s mi sunderstandi ng has been the source of confusion. When an anesthesi ol ogist has been
excluded from a particular hospital 's staff or anesthesia group and then sues based on an al l eged
anti trust vi olation, the anesthesi ol ogist loses virtuall y automaticall y. Thi s is because there i s sti l l
si gni fi cant competiti on i n the rel evant marketpl ace and competiti on i n that market is not
threatened by the excl usi on of one physician from one staff.
In essence, i f there are several hospi tal s offeri ng rel ati vel y si mi lar servi ces to an i mmediate
communi ty (the market), deni al of pri vi l eges to one physi cian by one hospi tal i s not
anti competi ti ve. If, on the other hand, there i s only one hospi tal i n a smal l er market, then the
same act, the same set of circumstances, coul d be seen very differentl y. In that case, there woul d
be a l i mi tati on of competi ti on because the hospital domi nates and, i n fact, may control the market
for hospital servi ces. Exclusi on of one physi ci an, then, would li mit access by the consumers to
al ternative competing services and hence would l i kel y be judged an anti trust vi olation.
The Sherman Anti trust Act i s a federal l aw more than 100 years old. Secti on 1 deals wi th
contracts, combi nati ons, conspi racy, and restraint of trade. By defini ti on, two or more separate
economi c entiti es must be i nvol ved i n an agreement that i s chall enged as i ll egal for thi s section to
appl y. Secti on 2 prohi bi ts monopoli es or conspiracy to create a monopoly, and it i s possi bl e that
this coul d appl y to a single economi c entity that has i l legall y gai ned dominati on of a market.
Consi deration of possibl e monopoli sti c domi nati on of a market i nvol ves a situation in which a
si ngl e enti ty control s at l east 50% of the busi ness in that market. The stakes are high i n that the
anti trust legi slation provi des for tri pl e damages i f a l awsui t i s successful . The U.S. Department of
11. Overal l col l ecti on rate
12. Costs per uni t (total costs, excl udi ng compensati on total units) (costs incl ude
li abi l i ty insurance, rent, coll ecti on costs, and l egal and accounting fees)
13. Compensati on costs per uni t (total compensati on total units) for MCO
popul ati ons, uti l izati on patterns by age, gender, and di agnosi s
Repri nted wi th permi ssi on from Ameri can Soci ety of Anesthesi ologi sts. Managed Care
Rei mbursement Mechanisms: A Gui de for Anesthesi ol ogi sts. Park Ri dge, IL: ASA; 1994.
P.47
Justi ce and the Federal Trade Commi ssi on are keenl y i nterested i n the current rapid evol uti on i n
the health care industry, and thus are actively involved i n eval uati ng si tuati ons of possi ble
anti trust vi olations. There are two ways to judge vi ol ati ons. Under the per se rul e, whi ch i s
appl ied rel ati vely rarel y, conduct that i s obvi ously l imiti ng competiti on i n a market is
automati cal l y i l legal . The other type of vi ol ati on i s based on the rule of reason, which involves a
careful analysi s of the market and the state of competi ti on. The majori ty of complai nts agai nst
physi ci ans are judged by thi s rule. The more competi tors there are i n a market, the l ess li kel y
that any one act i s anti competi ti ve. In a communi ty wi th two hospi tal s, one smal ler than the
other, wi th an anesthesiol ogy group practi ce excl usi vel y at each, if the l arger anesthesi ol ogy
practi ce group buys out and absorbs the smal l er, l eavi ng onl y one group for the onl y two hospi tal s
in the communi ty, that may be anti competi ti ve, particul arl y i f a new anesthesiol ogi st seeks to
practi ce solo at those hospi tal s.
Legal Implications
In the current era of rapi dly evolving managed care arrangements, the antitrust laws are
important. If physi ci ans (individual s or groups) who normal l y woul d be competi tors because they
are separate economi c enti ti es meet and agree on the pri ces they wi l l charge or the terms they
wil l seek i n a managed care contract, that can be anti competi tive, monopol i sti c, and hence
possi bl y i l legal . Note that sharing a common offi ce and common bil l ing servi ce al one i s not enough
to consti tute a true group. If, on the other hand, the same physi cians joi n i n a true economi c
partnershi p to form a new group (total integrati on) that i s a single economi c entity (and meets
certai n other criteri a) that wil l set pri ces and negoti ate contracts, that i s perfectly l egal . The other
criteri a are criti cal. There must be capital i nvestment and also ri sk sharing (i f there i s a profi t or
l oss, i t i s di stri buted among the group members)that is, total i ntegrati on i nto a genui ne
partnershi p. This i ssue i s very important

in consi deri ng the dri ve for new organi zati ons to put together networks of physi cians that then
seek contracts wi th major empl oyers to provide medical care. Someti mes, hospi tal s or cli ni cs
attempt to form a network compri si ng al l the members of the medi cal staff so that the resul ti ng
enti ty can bi d gl obal ly for total care contracts. Any network is a joi nt venture of i ndependent
practi ti oners. If the partici pati ng physici ans of one speci al ty i n a network are separate economi c
enti ties and the network advertises one price for their servi ces, thi s would seem to suggest an
anti trust vi ol ati on (hori zontal pri ce fi xi ng). In the past, if a network involved fewer than 20% of
one type of medi cal speci al i st i n a market, that was cal led a safe harbor, meani ng that i t was
permi ssi bl e for nonpartners to get together and negoti ate pri ces. The federal government has
tried to encourage formati on of such networks to help reduce heal th care costs and, as a resul t,
made some rel evant excepti ons to the appl i cati on of these rul es. As l ong as the network i s
nonexclusive (other nonnetwork physi cians of a gi ven speci al ty are free to practi ce in the same
faci li ties and compete for the same patients), the network can compri se up to 30% of the
physi ci ans of one speci alty in a market. Note speci fi cal ly that thi s does not al low a l ocal speci al ty
soci ety i n a bi g ci ty to serve as a bargai ning agent on fees for its members, because i t i s very
l i kel y that more than 30% of the speci al i sts i n an area wil l be members of the soci ety. The onl y
real excepti on to thi s provi sion is i n thinl y popul ated rural areas where there may be just one
physi ci an network. In such cases (whi ch are, so far, rare because the major managed care and
network acti vi ty has occurred mainl y i n heavi ly popul ated urban areas), there i s no l imi t on how
many of one speci al ty can become network members and have the network negotiate fees, as l ong
as the network is nonexclusive.
Clearl y, these issues are very compl ex. Rel evant legi slation, regulations, and court actions al l
happen rapi dl y and often. Mergers among anesthesi ol ogy groups i n a market area for the purposes
of both effi ci ency and strength i n negoti ati ng fees have been very popul ar as a response to the
rapi dl y changi ng marketpl ace. A l i st of questions must be answered to determi ne if such a merger
would have anti competiti ve i mpl i cations. Al though compendia of relevant informati on are avail able
to anesthesi ol ogists,
39, 40, 41
they cannot substi tute for expert advice and hel p.

Obvi ously, anesthesi ologists contempl ati ng a merger or faci ng any one of a great number of other
P.48
si tuati ons in the modern heal th care arena must secure assi stance from professional advisors,
usuall y attorneys, whose job i t i s to be aware of the most recent devel opments, how they appl y,
and how best to forge agreements i n formal contracts. Anesthesi ol ogi sts hopi ng to fi nd reputabl e
advi sors can start thei r search wi th word-of-mouth referrals from col l eagues who have used such
servi ces. Local or state medi cal soci eti es frequentl y know of attorneys who speci al i ze i n this area.
Fi nal l y, the ASA Washi ngton, D.C., offi ce has compi l ed a state-by-state l i st of advi sors who have
worked successfull y wi th anesthesi ol ogi sts i n the past.
Excl usi ve Ser vi ce Cont r act s
Often, one of the l arger issues faced by anesthesi ol ogi sts seeki ng to defi ne practi ce arrangements
concerns the desi rabi l ity of consi deri ng an exclusi ve contract wi th a health care faci l ity to provi de
anesthesia services. An excl usi ve contract states that anesthesiologi sts seeking to practi ce at a
gi ven faci l i ty must be members of the group hol di ng the exclusi ve contract and, usual ly, that
members of the group wi ll practice nowhere el se. A hospi tal may want to gi ve an excl usi ve
contract in return for a guarantee of coverage as part of the contract. Al so, the hospi tal may
bel i eve that such a contract can hel p ensure the qual i ty of the practi tioner because the contract
can contai n credential ing and performance criteri a. It is i mportant to understand that the hospi tal
li kel y wil l exerci se a degree of control over the anesthesi ologi sts wi th such a contract i n force,
such as requi ring them to parti ci pate as provi ders i n any contracts the hospital makes wi th thi rd-
party payers and al so tyi ng hospi tal pri vi leges to the exi stence of the contract (the so-call ed
cl ean sweep provi si on that bypasses any due process of the medi cal staff shoul d the hospi tal
termi nate the contract). Certai n of these types of provisi ons constitute economi c credential ing,
whi ch i s defi ned as the use of economi c criteri a unrel ated to the qual ity of care or professional
competency of physici ans in granti ng or renewi ng hospi tal privi l eges (such as the acceptance of
bel ow-market fees associ ated with a hospi tal -negoti ated care contract or even requiri ng financi al
contri buti ons i n some form to the hospi tal ). The ASA i n 1993 i ssued a statement condemni ng
economi c credential ing.
3
The anesthesiologi sts i nvol ved may accept such an exclusive servi ces
contract to guarantee that they al one wi ll get the busi ness from the surgeons on staff at that
hospi tal , and hence the resul ting i ncome. There may be other consi derati ons on both si des, and
these have been outl i ned i n extensi ve rel evant ASA publ i cati ons that al so i ncl ude a sampl e
contract for i nformati on purposes onl y.
37, 40
Al though many excl usi ve contracts wi th anesthesi ology
groups are i n force, the senti ment, parti cul arl y from the ASA, i s agai nst them. As has been stated,
it i s cri ti cal that anesthesi ol ogists faced wi th i mportant practice management deci sions such as
whether to enter i nto an exclusive contract must seek outsi de advice and counsel . There are a
great many nuances to these i ssues,
40, 41, 42, 43
and anesthesi ol ogi sts are at risk attempti ng to
negoti ate such compl ex matters al one, just as pati ents woul d be at ri sk i f a contract attorney
attempted to i nduce general anesthesi a.
Deni al of hospi tal pri vi l eges as a resul t of the exi stence of an exclusi ve contract wi th the
anesthesiol ogi sts i n place at the faci li ty has been the source of many l awsui ts, i ncl udi ng the wel l -
known Loui si ana case of Hyde v. Jefferson Pari sh. In that case, the court found for the defendant
anesthesiol ogi sts and the hospi tal , sayi ng that there was no anti trust viol ation because there was
no real adverse effect on competi ti on as far as pati ents were concerned because there were
several other hospi tal s wi thi n the market to whi ch they coul d go, and therefore they coul d
exercise thei r ri ghts to take advantage of competiti on i n the rel evant market. Thus, existence of
an exclusi ve contract only i n the rare setti ng where anti competi tive effects on pati ents can be
proved mi ght l ead to a l egiti mate anti trust clai m by a physi ci an deni ed pri vi l eges. This was proven
true i n the more recent Kessel v. Monongal ia County General Hospi tal case i n West Vi rgi ni a in
whi ch an excl usi ve anesthesiol ogy contract was hel d il l egal . Therefore, agai n, these arrangements
are by defi ni ti on compl ex and fraught wi th hazard. Accordi ngl y, outsi de advice and counsel are
al ways necessary.
Hospi t al Subsi di es
Modern economic real i ti es have forced a si gni fi cant number of anesthesi ol ogy practi ce groups (i n
both pri vate and academic setti ngs) to recogni ze that their pati ent care revenue, after overhead i s
pai d, does not provi de suffici ent compensation to attract and retain the number and quali ty of
staff necessary to provi de the expected cl ini cal servi ce (and ful fi l l any other group/department
mi ssi ons). Attempting to do the same (or more) work with fewer staff may temporari l y provide
increased fi nanci al compensati on. Cutti ng benefi ts (di screti onary personal professi onal expenses,
retirement contri buti ons, or even insurance coverage) may al so be a component of a response to
inadequate practi ce revenue. However, the resul ti ng decrements i n personal securi ty, i n
convenience, and i n qual i ty of l i fe as far as acute and chroni c fati gue, decreased fami l y and
recreati on ti me, and tensi on among coll eagues fearful someone el se i s getti ng a better deal wi l l
qui ckly overcome any bri ef advantage of a somewhat higher income. Therefore, many practice
groups i n such situations are requesti ng their hospi tal

(or other health care faci l ity where they practi ce) to pay them a di rect cash subsidy that is used
to augment practi ce revenue to mai ntai n benefi ts and ameni ti es whil e i ncreasing the pay of staff
members, hopeful l y to a market-competiti ve l evel that wil l promote recrui tment and retenti on of
group members.
Obvi ousl y, requests by a practi ce group for a di rect subsi dy must be thoroughl y justi fi ed to the
faci li ty admi ni strati on recei vi ng the peti tion. The group' s busi ness operati on should al ready have
been exami ned careful ly for any possi bl e defects or means to enhance revenue generati on.
Expl anati on of the general trend of decl i ni ng rei mbursements for anesthesia services shoul d be
careful ly documented. Facts and figures on that and al so the shortage of anesthesi a provi ders can
be obtai ned from journal arti cles and ASA publ i cations, particul arl y the Newsl etter. Demand for
anesthesia coverage for the surgi cal schedul e is a key component of thi s proposal . Schedul i ng and
util i zati on, parti cul arly i f earl y-morni ng staffi ng is requi red for many operating rooms that are
routinely unused l ater during the tradi ti onal work day, i s a major i ssue to be understood and
presented. Any other OR ineffi cienci es created by hospi tal support staff and previ ous efforts to
deal wi th them shoul d al so be hi ghl i ghted. Unfavorabl e payer mi x impact of contracts and
programs i ni tiated by the hospi tal al so often is a major factor i n si tuati ons of i nadequate practi ce
revenue. Al ways, the group' s good wi l l wi th the surgeons and the communi ty in general should be
emphasized, as wel l as of the i ndi rect or behind the scenes servi ces and benefits the
anesthesi ol ogy group provi des to the hospital.
Clearly, any request for a subsidy must be reasonabl e. An overl y aggressi ve effort beyond the
bounds of l ogi c coul d provoke the facil i ty to consi der al ternati ve arrangements, even up to the
poi nt of putti ng out a request for proposal from other anesthesi ol ogy practi ce groups. Therefore,
thoughtful cal cul ations are requi red and a careful bal ance must be sought, seeki ng enough
financial support to suppl ement practi ce revenues so that members' compensation is competiti ve
but not so much as to be excessi ve. Supporti ng statements about offers and potenti al earni ngs
el sewhere must be compl etel y honest and not exaggerated or credibi l ity and good fai th wi l l be
lost. Further, part of any agreement wil l be the ful l shari ng of the group' s detai led financi al
information wi th the faci li ty admi ni strati on, both at the ti me of the request and on an ongoi ng
basis i f the payment i s more than a one-ti me bai l out. Pl ans for revi ew and renewal should be
made once a subsi dy i s pai d.
Any subsi dy wi ll l i kely require a formal contract. There may be concern about malpracti ce l i abi l ity
impli cati ons for the hospi tal even though the practi ce group stays an i ndependent enti ty as
before. There may be inurement or pri vate benefi t concerns that coul d be percei ved as a
threat to the tax-exempt status of a nonprofit hospital. Lack of understandi ng of the appl i cabl e
laws may lead to fears that a subsi dy coul d be an i l legal kickback or a vi ol ati on of the Stark II
sel f-referral prohi bi ti on. As i s al most al ways the case, expert outsi de professi onal consul tant
advi ce, usual l y from an attorney who speci ali zes excl usi vely i n heal th care finance contracti ng, is
mandatory i n such ci rcumstances. The ASA Washi ngton, D.C., office maintains l i sts of consul tants
who have hel ped other anesthesi ol ogists or groups i n the past on various subjects and, also, the
ASA has some basi c i nformati on on subsidies to anesthesi ol ogy practi ce groups.
44, 45

Managed Car e and New P r act i ce Ar r angement s
As noted, managed care systems for health care deli very fundamental ly exi st as a mechani sm
P.49
to control and then reduce heal th care costs by havi ng i ndependent reviewers and decisi on makers
who are not the physi cians renderi ng the care l imit the health care servi ces del ivered to large
groups of pati ents. These i deas represent a huge change for American physici ans. For a ti me,
these changes appeared i nescapable, not necessaril y because of government i ni tiati ves, but
because of marketpl ace forces that resul t from the busi ness communi ty and government enti ti es
si mpl y refusi ng to conti nue to pay ever-increasi ng sums for heal th care. However, there was a
dramati c publ i c backl ash agai nst the l imi tati ons on medical care servi ces, so much so that several
states passed l aws outl ini ng for certai n ci rcumstances what MCOs must pay for. Thi s led to
decreased expansion of managed care and to some easing of the restri cti ons on services in many
pl ans. The overall i mpact was to slow (but not stop) the adopti on of ri gidl y managed health care
and to rekindle anew many of the concerns about how to structure and fund the heal th care
system i n this country. Some MCOs were forced to retool thei r operati ons and some went out of
business enti rel y. However, many conti nued operati ons, al beit more qui etl y. The degree of
penetrati on of managed care i nto market areas around the country has been highly vari able. Areas
such as Mi nneapol is, San Di ego, San Franci sco, eastern Massachusetts, and several other northern
ci ti es were the fi rst to become mature managed care markets wi th a significant majori ty of the
popul ati on enrol l ed in one or another managed care heal th pl an. Other parts of the country wi th
very sparsel y popul ated areas such as secti ons of the Deep South and the West were not much
affected because the populati on densi ty was i nsuffi ci ent to support MCO requirements. An MCO
attempts to secure heal th care provi sion contracts with empl oyers who provi de health plan
coverage for their workers and wi th government agenci es (e.g., Medi cai d) responsibl e for the
heal th care of large populations. Each worker or covered head of a household may have
dependents covered by the pl an. Each person covered i n the pl an i s referred to as a covered l i fe.
An MCO probabl y needs contracts for at l east 10,000 covered l ives and preferabl y many more to
make a l egi timate entry into the marketpl ace. The MCO then enrol ls physici ans or physi cian
groups and hospitals as provi ders and contracts to send i ts enroll ed pati ents (the covered l ives) to
the health care provi ders under contract. The central i ssue is fi nances. The MCO seeks to enrol l
covered li ves by offeri ng the lowest pri ces possibl e. In turn, i t seeks to contract wi th provi ders
(i ndi vi dual s and faci l iti es) for the l owest possi ble fees for medi cal care i n return for sending large
vol umes of pati ent busi ness to those provi ders.
In the i ni tial stages of the evoluti on of a

managed care marketpl ace, the MCOs usual l y seek contracts with provi ders based on di scounted
fee-for-servi ce arrangements. Thi s preserves the basi c tradi tional i dea of producti on-based
physi ci an rei mbursement (do more, bil l more) but the pri ce of each act of servi ces is lower (the
provi ders are i nduced to gi ve deep di scounts wi th the promi se of si gnifi cant volumes of pati ents)
and, also, the MCO gatekeeper pri mary care physi ci ans and the MCO revi ewers are strongly
encouraged to l i mi t compl ex and costl y servi ces as much as possi bl e. There are other features
intermi ttentl y al ong the way, such as gl obal fees and negoti ated fee schedul es (agreed-upon
si ngl e pri ces for i ndi vidual procedures, i ndependent of l ength or complexi ty). Further, another
el ement is i ntroduced to encourage the providers, both gatekeepers and special ists, to reduce
costs. In an appl i cation of the concept of ri sk-sharing (spend too much for pati ent care and l ose
income), thi s usual ly is i niti al l y manifest i n the form of withholds, the practi ce of the MCO
hol di ng back a fracti on of the agreed-upon payment to the providers (e.g., 10 or 15%) and
keeping thi s money unti l the end of the fi scal year. At that ti me, if there i s any money left in the
ri sk pool or withhol d account after al l the (parti al) provi der fees and MCO expenses are pai d, i t is
di stri buted to the provi ders i n proporti on to their degree of parti ci pati on during the year. Thi s is a
cl ever and powerful i ncentive to providers to reduce health care expenses. It i s not as powerful as
the stage of full risk sharing, however. As the managed care marketpl ace matures and MCOs grow
and succeed, the existing organi zations and, especi al l y, any new ones, shi ft to prospecti ve
capi tated payments for provi ders.
Prospective Payments
Thi s eventual rei mbursement arrangement constitutes an enti rel y new worl d to the provi ders,
i nvol vi ng prospecti ve capi tated payments for l arge popul ati ons of patients, i n whi ch each group of
P.50
provi ders i n the MCO receives a fi xed amount per enroll ed covered l i fe per month (PMPM) and
agrees, except i n the most unusual ci rcumstances, to provide whatever care i s needed by that
popul ati on for that prospecti ve payment. The most unusual ci rcumstances involve carve-out
arrangements i n which specific very costl y and unusual condi tions or procedures (such as the bi rth
of a chil d wi th di sastrous mul ti pl e congeni tal anomal i es) are covered separatel y on a discounted
fee-for-servi ce basis. Wi th ful l capi tati on, the enti re financial underpi nning of Ameri can medi cal
care does a compl ete about-face from the tradi ti onal rewards for gi vi ng more care and doi ng more
procedures to new rewards for givi ng and doi ng l ess. Some managed care contracts contai n other
features intended to protect the provi ders against unexpected overuti l i zati on by pati ents that
would stretch the provi ders beyond the bounds of the origi nal contract wi th the MCO. The
provi si ons setting the boundari es are cal l ed ri sk corri dors, and the stop-loss cl auses add some
di scounted fee-for-servi ce payment for the excess care beyond the ri sk corri dor (capitated
contract li mi t). Provi ders who were used to getti ng pai d more for doi ng more suddenl y fi nd
themsel ves getti ng pai d a fi xed amount no matter how much or how l ittle they do wi th regard to a
speci fi ed popul ati onhence the percei ved i ncenti ve to do, and consequentl y spend, less. If the
provi ders render too much care wi thi n the defined boundary of the contract, they essenti all y wil l
be worki ng for free, the ul ti mate in risk-sharing. There are cl earl y potenti al internal confl icts i n
such a system,
46
and how pati ents reacted i ni ti all y to thi s radi cal change i n attitude on the part of
physi ci ans demonstrated that thi s overall mechanism is unl i kely to be readil y embraced by the
general publ i c. Thi s has forced some return to the drawi ng board thinki ng and it i s not cl ear how
ful l y managed care as i t was ori gi nall y constituted wil l evolve. What is cl ear i s that nothi ng is
settl ed and there wi l l be ongoi ng debate about and experi mentation in the Ameri can health care
system.
Heal th care providers (physici ans, health care workers, and faci l iti es), i n turn, all i ed themselves in
a wide vari ety of organi zati ons to create strength and desi rabl e resources to present to the MCOs
in contract negoti ati ons. Some of these all i ances were formed very qui ckl y, al most i n a panic,
because of fears by provi ders that they might get l eft out of the managed care marketpl ace and
thus depri ved of major sources of i ncome or, someday, any income at all . Management servi ce
organizati ons (MSOs) are joi nt venture network arrangements that do not i nvol ve true economi c
i ntegrati on among the practi tioners, but merely offer common servi ces to physi cians who may, as
a loosel y organized informal group, el ect to seek MCO contracts. Preferred provi der organizations
(PPOs) are network arrangements of otherwise economi call y independent physi ci ans who form a
new corporate entity to seek managed care contracts i n which there are si gni fi cant fi nancial
incenti ves to patients to use the network provi ders and fi nancial penal ti es for goi ng to out-of-
network provi ders. This has proved a rel ati vel y popul ar model and appears to be gai ni ng wi de
acceptance. Physi cianhospi tal organi zati ons (PHOs) are si mi l ar enti ti es but i nvol ve
understandi ngs between groups of physi cians and a hospi tal so that a large package or bundl e of
servi ces can be constructed as essenti all y one-stop poi nts of care. Independent practi ce
associations (IPAs) are l i ke PPOs but are speci fi cal ly ori ented toward capitated contracts for
covered li ves wi th si gnifi cant ri sk-sharing by the provi ders. Groups (or cl i ni cs) wi thout wal ls are
coll ecti ons of practi tioners who ful ly i ntegrate economi cal ly i nto a si ngl e fi scal entity (true
partnershi p) and then compete for MCO contracts on the basi s of ri sk-sharing i ncenti ves among
the partners. Full y i ntegrated groups or heal th maintenance organi zati ons (HMOs) house the group
of partner provi der physici ans and associ ated support staff at a si ngl e l ocati on for the conveni ence
of pati ents, a bi g sel li ng poi nt when they seek MCO contracts.
Changing Paradigm
The questions anesthesiologi sts face when addressi ng thi s al phabet soup of organi zati ons are
many and complex, even more complex than those faced by offi ce-based pri mary care or special ty
physi ci ans, because of the interdependent relationshi ps wi th heal th care faci li ties as practi ce
locations and wi th surgeons. The era of sol o i ndependent practi tioners may be endi ng i n some
locations where MCOs domi nate. Smal l groups of anesthesi ol ogi sts may find themselves at a
competi ti ve di sadvantage unless they become part of a verti cal l y integrated (multi speci al ty) or
hori zontal l y i ntegrated (with other anesthesi ol ogi sts) organi zati on. An extensi ve compendi um of
rel evant i nformati on has been prepared by the ASA.
39
Because it appears l i kel y that many
anesthesiol ogi sts i n the United States wi ll be affected by managed care, the informati on i n thi s
and rel ated publ i cati ons
47
is very important. Negoti ati ons wi th MCOs require expert advi ce,
probabl y even more so than even the tradi tional excl usive contracts with hospi tal s noted earli er.
Before any negoti ati on can even be consi dered, the MCO must provi de si gni fi cant amounts of
information about the covered pati ent popul ati on. The projected heal th care uti li zation pattern of
a l arge group of whi te-col l ar workers (and thei r fami l i es) from major upscale empl oyers i n an
urban area wi l l be qui te di fferent from that of a rural Medicaid popul ati on. Speci fi c demographi cs
and past uti li zation hi stori es are absolutel y mandatory for each proposed popul ati on to be
covered, and thi s i nformati on shoul d go directl y to the advisi ng experts for eval uati on, whether
the proposed negoti ati on i s for di scounted fee-for-servi ce, a fee schedule, global bundl ed fees, or
ful l capi tation.
A component of the shi fting thi nking i n the 1990s was consi deration of val ue-based anesthesi a
practi ce,
2
an attempt to bal ance reasonably the relationshi p of the cost of care and ul ti mate
patient outcomes (with a very strong emphasi s on control l ing costs). Elaborate modeli ng was
employed to attempt to calcul ate appl i cable cost-benefi t rati os and thus defi ne the poi nt on a
hypotheti cal curve of care at which the l east resource i nvestment woul d yi el d the hi ghest quality.
A systems approach was careful l y appli ed to attempt to defi ne and track the component elements
of both cost and outcome, whi ch woul d l ead to model s of the l arger concepts of val ue and quali ty.
Understandi ng effecti veness and effi ciency of the i nvol ved processes was essential . Quanti fiabl e
outcomes and costs were compared to nati onal benchmarks found i n the li terature or from
surveys. The ulti mate goal was appl i cation of outcome data to the management (reducti on) of
costs. Medi cati on choi ce and uti l izati on by anesthesiol ogi sts was a frequentl y cited exampl e of the
potential benefi cial appli cation of the tenets of val ue-based anesthesi a practi ce. Attempts to appl y
this type of anal ysis to overall anesthesi a morbi di ty and mortal ity were compl icated by the
(fortunate) extreme rarity of si gnifi cant adverse outcomes and the difficulty of calculating the
associated actual incremental ly i ncreased costs, as well as of defi ni tivel y identi fying remedi able
causes that coul d be prevented through system change. Attempts to assess the rel ative value of
di fferent anesthetic techni ques (e.g., regi onal vs. general ) for specifi c surgical procedures were
compl i cated by probl ems discoveri ng the true cost of di fferent scenari os. Anal ysi s of the cost of

moni tori ng reveal ed the di ffi cul ty of determi ni ng the total costs saved or incurred by, for example,
the insertion of a TEE in a speci fi c pati ent, and, further, the belief that pulse oximetry has never
been stati sti cal ly proven to i nfl uence anesthesi a outcome provoked questi ons about i ts cost and
value in direct conflict with the fact that it is a universal standard of care. Overal l, because
hard number data readil y amenable to rigorous statistical anal ysi s for both the actual costs and
the outcomes of anesthesi a care have been very difficult, if not i mpossi bl e, to generate, the
widespread appl icabi l i ty of thi s approach i n everyday anesthesi a practi ce remai ns to be devel oped.
Significant questions were rai sed about the reimbursement impl icati ons for anesthesiol ogi sts of
the putati ve managed care revol uti on. Agai n, the ASA assembl ed a great deal of rel evant
information, the understanding of which is essenti al to successful negoti ati ons.
39
Tabl e 2-5 has a
li st of informati on an anesthesi a practi ce shoul d have about i ts acti vi ti es. Ini ti al consi derati on of a
capitated contract should involve an attempt to take all the data about the existing practice and
the proposed MCO-covered popul ati on from a capitati on checkl i st
39
and translate back from the
proposed capi tated rate to i ncome fi gures that would correl ate wi th the exi sti ng practice structure,
to all ow a comparison and an understanding of the rel ati onshi p of the projected work in the
contract to the projected income from it. It i s, of course, i mpossi ble to suggest dol lar values for
capi tated rates for anesthesi ol ogy care because detai l s and condi tions vary so wi dely. One ASA
publ icati on
39
used exampl es, purely for il l ustrati ve purposes, involving $2.50 or $4.00 PMPM, but
there were unconfirmed reports at the peak of the managed care acti vi ti es of capi tated rates as
low as $0.75 PMPM for anesthesiol ogy. Di scounted fee-for-servi ce arrangements are easi er for
anesthesiol ogi sts to understand because these are di rectl y referable to exi sti ng fee structures.
Reports of groups i nsti tuti ng 10 to 50% di scounts off the starti ng poi nt of 80% of usual and
customary rei mbursement i n vari ous practi ce ci rcumstances were ci rcul ated at nati onal meeti ngs
of anesthesi ol ogi sts. Were ri gi dly control l ed full y mature managed care to domi nate the practi ce
communi ty, i t woul d be l i kel y that the average i ncome for anesthesi ol ogi sts would decrease from
P.51
past level s. However, i t li kel y al so would be true that anesthesi ologi sts woul d conti nue to have
incomes sti l l above average among all physici ans in that market.
Heal t h I nsur ance P or t abi l i t y and Account abi l i t y Act ( HI P AA)
All heal th care professional s in acti ve practi ce were aware of the Apri l 2003 impl ementati on of the
Pri vacy Rul e of the Heal th Insurance Portabi li ty and Accountabil i ty Act of 1996 (HIPAA), because
of the required si gnifi cant changes i n how medi cal records and patient i nformation are handl ed in
the day-to-day deli very of heal th care. The impact on and requi rements for anesthesi ol ogi sts are
summarized in a comprehensive publ icati on from the ASA
48
that fol l owed two educati onal
summaries.
49, 50

Attention is focused on protected heal th i nformation (identi fi abl e as from a speci fic patient by
name). Pati ents must be noti fied of their privacy ri ghts. Usual ly thi s wil l be covered by the heal th
care faci li ty in whi ch anesthesi ol ogists work, but i f separate private records are maintai ned,
separate noti fi cation may be necessary. Pri vacy pol i ci es must be created, adopted, and
promul gated to all practiti oners, all of whom then must be trai ned in appli cati on of those pol ici es.
Often, anesthesi ol ogy groups can combi ne with the facil i ti es in whi ch they practi ce as an
organized health care arrangement so that the anesthesi a practi ti oners can be covered i n part
by the HIPAA compl i ance activiti es of the faci l ity. A pri vacy offi cer must be appoi nted for the
practi ce group. Fi nal l y, and most importantl y, medical records containi ng protected health
information must be secured so they are not readil y avai l abl e to those who do not need them to
render care.
One of the most obvi ous appli cati ons for many anesthesi ologi sts is concern about the assembl ed
preoperati ve i nformati on and charts for tomorrow' s cases that frequently were pl aced promi nentl y
in the OR holdi ng area at the end of one work day i n readi ness for the next day' s cases. HIPAA
provi si ons require that al l that pati ent i nformati on be locked away overnight. Another cl assi c
example is what many ORs refer to as the board. Often, a l arge whi te marker board occupi es a
promi nent wal l near the front desk of an operati ng room sui te and the rooms, cases, and
personnel assi gnments are inscribed thereon at the beginni ng of the day and modi fi ed or crossed
off as the day progresses. Under HIPAA, pati ents' names may not be used on such a board i f there
is any chance that anyone not directl y i nvol ved i n their care coul d see them. The same is true for
si mi l ar boards i n hol di ng areas and PACUs. Many anesthesi ol ogy practi ces al so must apply HIPAA
provi si ons to thei r bil l ing operati ons; the detai ls wil l vary dependi ng on the mechani sms used and
a great deal wi l l depend on which type of electronic claims submi ssi on software i s bei ng used by
the bil l ing enti ty actuall y submi tti ng the cl aims.
51
Tel ephone cal l s and faxes into offices must be
handl ed speci al l y i f contai ni ng identi fi able patient information. Presentati on of pati ent i nformati on
for quali ty assurance or teaching purposes must be free of al l i denti fi ers unl ess speci fi c individual
permi ssi on has been obtained on prescri bed printed forms. Requests for patient information from a
wide vari ety of outsi de enti ti es, including i nsurance compani es and col l ecti on agencies, must be
processed i n HIPAA-compl i ant ways. HIPAA pol i cy and acti ons, as well as enforcement activiti es,
are bei ng devel oped over ti me and as si tuati ons devel op. Parti cul arl y because thi s system depends
on pati ent complai nts for both enforcement and pol i cy evol ution, it i s l ikel y that i t wi ll be at l east
several years until a wel l -accepted smoothl y functi oning system i s establi shed.
Expansi on i nt o P er i oper at i ve Medi ci ne, Hospi t al Car e, and
Hyper bar i c Medi ci ne
As the rol e of the anesthesi ol ogist changes, new opportuni ti es shoul d be expl ored. One set of
ideas that has been ci rculating for some ti me l ed to seri ous suggesti ons that the name of the
professi on of anesthesi ology be changed to peri operati ve medi cine and pai n management. Thi s
suggestion il l ustrates that one prospecti ve si gni fi cant anesthesi ol ogy practice management
strategy can be more formal organi zation of responsi bi li ties for pati ents in the pre- and
postoperative peri ods.
Some anesthesi ol ogi sts now functi on at least some of the ti me in preoperati ve screening cli ni cs
because of the great fracti on care of OR patients who do not spend the ni ght before surgery i n the
hospi tal or who do not come to a hospi tal at al l . In such settings, these anesthesi ol ogi sts
frequently assume a rol e anal ogous to that of a pri mary care physi cian, planni ng and executi ng a
workup of one or more signi fi cant medi cal or surgi cal probl ems before the pati ent can reasonabl y
be expected to undergo surgery. More formal ized arrangements of thi s type would involve the
creati on of desi gnated peri operati ve cl i ni cs operated and staffed by anesthesiologi sts.
Ophthal mol ogi sts and orthopedi sts, for exampl e, woul d no longer need to try to manage thei r
surgi cal pati ents' medi cal probl ems themsel ves or send thei r patients proposed for surgery to an
interni st or other primary care provider for preop cl earance that often has l ittle val ue in a
compl ex pati ent faci ng specifi c anesthesi a chal l enges that only an experienced anesthesiol ogi st
woul d, by defi ni ti on, understand. The anesthesiologi st would

assume that rol e at the same ti me the pati ent is undergoi ng preoperati ve eval uati on for
anesthesia care.
Likewise, thi s concept woul d be excel lent for the postoperative peri od. An anesthesi ol ogi st,
compl etel y free of OR or other duties, coul d not only make at l east twice-dai ly rounds on pati ents
after surgery and provi de exceedi ngl y comprehensi ve pai n management servi ce, but also could
fol l ow the surgi cal progress and make vi rtual l y continuous reports (l ikel y vi a an electroni c medi cal
record or e-mail ) to the surgeon' s offi ce or al phanumeric pocket communi cator. Surgeons woul d
have a much better handl e on thei r pati ents' progress whil e havi ng more ti me to tend to other
new patients i n the offi ce or the OR. The uti l izati on review and fast-track protocol administrators
would have a contact person who is not tied up i n an OR or office continuousl y avai l abl e. Pati ents
would receive much more physi ci an attenti on and perceive thi s as actual ly a si gnificant
improvement in thei r care. Equi valent outpatient or recuperati ve center servi ces coul d easi ly be
establ i shed. In thi s regard, some anesthesiol ogi sts function as hospi tali sts for the care of both
surgi cal and medi cal pati ents. A fundamental aspect of the practice of anesthesi ology i s the
management of acute problems in the hospi tal setting. It is l ogi cal that anesthesi ol ogi sts would be
among the physi ci ans best sui ted to provi de primary care for patients i n the hospi tal setti ng.
Although the comfort l evel of anesthesi ol ogi sts vari es i n the fi elds of i nternal medi ci ne and
pedi atrics, i t is l i kel y that thi s trend wi l l conti nue among those anesthesiol ogi sts i nterested and
competent i n hospi tal care.
Fi nal ly, anesthesi ol ogists have become increasi ngl y involved in the practi ce of hyperbari c medi ci ne
and wound care. Thi s i s l i kel y related to the fami li ari ty of anesthesi ologi sts wi th concepts of gas
l aws and physi cs, al ong wi th thei r constant presence in the hospi tal . The treatment of vari ous
medical condi tions by the appli cati on of oxygen under i ncreased pressure, usual ly 2 to 3
atmospheres absol ute, at one ti me was one of the most rapi dl y growi ng hospi tal servi ces.
Anesthesi ol ogists are among the l eaders of thi s fi eld, with unli mited opportuni ti es for cl ini cal care,
teaching, and research. Even a brief discussion of thi s fiel d i s outsi de the scope of thi s chapter
and interested readers are referred to the Undersea and Hyperbari c Medical Society,
http://www.uhms.org.
Creati ve exploration of new opportuniti es involving these and other ideas wi l l open new avenues
for anesthesi ology (or whatever the special ty is eventual l y cal l ed) practi ce.
OPERATING ROOM MANAGEMENT
The rol e of anesthesi ologists in OR management has changed dramati cally in the past few
years. Whi l e not that l ong ago, most anesthesi ol ogi sts avoi ded any responsi bil i ti es of
administrati ve duties (contri buti ng si gni fi cantl y to a potenti al l y negative professi onal image, as
noted earl i er), more recently many anesthesi a practi ces have pl eaded for an expanded rol e i n OR
management, both to promote effici ency and al so to protect their i nterests. Wi th the current
cl i mate of a considerabl e shortage of anesthesi a provi ders, hospitals subsi dizing many
anesthesiol ogy group practi ces, and an i ncreasi ng workl oad, parti ci pati on i n OR management is
essential ly mandatory. The professi on needs to move beyond exclusi ve attenti on to what i s and
al ways wi l l be the mai nstay of our practice, the administration of anestheti cs for surgery. The
current emphasi s on cost containment and effi ci ency wi ll force anesthesiol ogi sts to take an active
role i n eli mi nati ng many dysfuncti onal aspects of OR practi ce that were previousl y i gnored. Fi rst-
P.52
case morning start ti mes have changed from a suggesti on to a mandate. Del ays of any sort are
now careful l y scruti ni zed to el iminate waste and i neffi ciency. Whi l e a hel pful cooperati ve approach
from the anesthesi ol ogi sts may have suffi ced in the past, today' s anesthesi ol ogists should take an
extremel y acti ve rol e i n OR management. Real li fe has demonstrated and management courses
teach that strong leadershi p i s necessary for any group to achi eve thei r stated goal s.
Anesthesi ol ogists should adopt a leading rol e among the other consti tuent personnel i n the OR
team. Together, anesthesi ol ogi sts, surgeons, OR nurses and techni ci ans, and, i ncreasi ngl y,
professi onal admi ni strators/managers need to determi ne who i s best qual ified to be a l eader in the
day-to-day management of the operating room. Cl earl y, di fferent groups have di fferent
perspectives. However, anesthesi ol ogists are in the best posi ti on to see the bi g pi cture, both
overal l and on any gi ven day. Surgeons are commonl y el sewhere before and after thei r i ndi vi dual
cases; nurses and admi ni strators may lack the medi cal knowl edge to make appropri ate, ti mel y
deci si ons, often on the fl y. It i s the anesthesi ol ogi st wi th the i nsi ght, overview, and uni que
perspective who i s best quali fi ed to provi de l eadership in an OR communi ty. Anesthesiologi sts
must step forward and aggressi vel y seek involvement at the hi ghest level possi bl e in the OR at
whi ch they practi ce. The subsequent recogniti on and appreci ati on from the other groups
(especi all y hospi tal admi ni strati on) wil l clearl y establi sh the anesthesi ol ogi sts as concerned
physi ci ans genuinely i nterested i n the wel fare of the OR and the i nstituti on. Fai l ure to be i nvol ved
in any leadershi p rol e not only negates the desi red i mage of anesthesiol ogi sts as concerned
physi ci ans, but al so may result i n a loss of autonomy i n practi ce or a l oss of support from the
other groups i n the OR and the i nsti tuti on overall .
By nature, an OR i s a society unto itself wi th i ts vari ous constituent groups, i nterdepartmental
dynami cs, and uni quel y high l evels of stress all defi ni ng the ebb and fl ow of the workplace. The
essential groups: anesthesi a provi ders, surgeons, OR staff (usuall y compri si ng nursing, scrub
technici ans and other support personnel), hospi tal admi ni strators and/or professi onal managers
need to devel op a worki ng rel ati onshi p to survi ve. As diverse as the pri ori ti es of these vari ous
groups seem, i t is i mperati ve that these groups move beyond si mple cooperati on and construct a
fri endl y effi ci ent work envi ronment that provi des hi gh-quali ty pati ent care. Because the spectrum
of operating rooms varies signi fi cantl y from the l argest regi onal teaching hospi tal to the small est
freestandi ng ambul atory care center, i t is difficul t to provi de anythi ng but the broadest of
gui del i nes for OR management. However, despi te each faci l ity' s di sti nct characteri sti cs, many of
these pri nci pl es can be i mpl emented at vi rtuall y al l i nsti tutions.
Or gani zati on
Traditi onal l y (al though excepti ons may be increasi ng), i n vi rtuall y every OR setti ng, nei ther the
anesthesia providers nor the surgeons have been empl oyees of the insti tuti on housi ng the OR.
Rarel y di d ei ther group/servi ce report to a central authori ty. Even when one or both consti tuents
were empl oyees, they reported through thei r respecti ve chi efs/chai rmen to the chi ef of the
medical staff, not to a hospi tal admi ni strati on. Consequentl y, a natural divisi on exi sted between
the hospi tal (OR) staff and the physici ans practi cing there. Anesthesi a provi ders were commonl y
thrust i nto a posi ti on of bei ng the arbi trator between the surgeons and the OR staff, bal anci ng
what both those parti es consi dered reasonabl e, desi rabl e, and possi bl e.
The symbi oti c rel ati onshi p between anesthesi a provi ders and surgeons remains unchanged. Both
groups recogni ze thi s fact and al so the common goal of havi ng the operati ng room functi on i n a
safe, expedi tious manner. The age-ol d questi on Who i s i n charge of the Operating Room? stil l
confronts most hospi tal s/i nstituti ons. Because some anesthesia groups are

subsi di zed by the hospi tal , the OR organi zati on i n such cases has changed accordi ngl y. Many
hospi tal admi ni strators want to have i nput regardi ng Who' s i n charge of the OR? wi th an eye to
increasi ng effici ency and throughput whil e reducing cost. Thei r wi shes have an even added
si gni fi cance when more of thei r doll ars are i nvol ved through the anesthesi ol ogy group subsi dy.
Someti mes there can be no real answer to Who' s i n charge? because of the compl exity of the
interpersonal relationshi ps i n the OR. Some i nsti tutions have a professi onal manager (often a
former OR RN) whose sol e job i s to organi ze and run the OR. Thi s i ndi vi dual may be vested wi th
P.53
enough authori ty to be recognized by all as the person in charge. Other insti tutions ostensibl y
have a medical director of the OR. However, the impl icati ons to the surgeons that an
anesthesiol ogi st i s i n charge, or vice versa, have caused many insti tutions to abandon the ti tle or
retai n the posi ti on but assign no authori ty to i t. In such instances, i nsti tutions usual l y resol ve
di sputes through some authori ty wi th a physi cian's perspective. If there is no medical director
with authori ty to make deci sions stick, central authority usuall y resides wi th the Operati ng Room
Commi ttee, most often populated by physi ci ans, seni or nurses, and admini strators. Every
operati ng room has thi s forum for major pol i cy and fi scal deci sions. As part of committee functi on,
the standard practi ces of negoti ati on, di pl omacy, and l obbyi ng for votes are regul arl y carried out.
The i mpact of such an OR commi ttee vari es wi dely among i nstituti ons.
Despi te the constantl y changi ng dynami cs of the OR management and the frequent major
frustrati ons, anesthesiol ogi sts shoul d pursue a greater role in day-to-day management i n every
possi bl e appl i cabl e practi ce setting. An anesthesi ol ogi st who i s capable of faci l itati ng the start of
cases with mi ni mal delays and solving probl ems on the fl y as they arise wi l l be i n an excel l ent
positi on to serve hi s or her department. Succeedi ng i n thi s rol e wi l l have a dramatic posi tive
impact on all the OR consti tuents. The surgeons wi l l be less concerned about Who' s i n charge?
because thei r cases are getting done. The hospi tal admi ni strati on wi l l wel come the effort because
they want somethi ng extra i n return for any money they are now giving to the anesthesiol ogy
groups as a subsi dy. Furthermore, the OR Committee (or whatever system for di spute resol uti on i s
in pl ace) is stil l functi onal and has not been ci rcumvented (and wi ll be thankful for the absence of
di sputes needi ng resol ution).
Some insti tutions use the term cl i ni cal di rector of the OR. The person awarded thi s desi gnati on
shoul d be a seni or-l evel i ndi vi dual wi th fi rsthand knowl edge of the OR envi ronment and function.
Anesthesi ol ogists have a better understandi ng of the peri operati ve process. They possess the
medi cal knowl edge to make appropri ate decisi ons. Thei r inti mate associ ati on wi th surgeons and
thei r pati ents al l ows them to best all ocate resources. Accordi ng to a survey conducted by the
Ameri can Association of Cl inical Directors (AACD) i n 2002, 71% of the respondents reported that
an anesthesi ol ogist was desi gnated as the cli ni cal di rector of the OR.
52

Those i n li nes of authority must possess the correspondi ng responsibi l ity. Who has power over
who wi l l determi ne a great deal about the function of an individual OR. A cl assic example i nvol ves
pefusioni sts for cardiac surgery. In some ci rcumstances, they are empl oyed by the hospi tal ; in
others, by the cardi ac surgeons; i n a few, by the anesthesi a group; and some are i ndependent
contractors. The organi zati onal logi sti cs of each of the above scenarios need to ful fi l l the standard
functi ons regardi ng call , work shi fts, pol i cy and procedure for cardi ac bypass operati ons,
equi pment purchasi ng, and so forth. Each i nsti tution develops i ts own method for deal ing wi th
these i ssues. Someti mes the system uti l ized falters and one of the consti tuents out of power
offers to step i n (or just sei zes control ) to recti fy the deteriorated si tuati on. Then the process
begi ns anew, under new management. These changes are frequentl y vi ewed as healthy for the
perfusi oni sts i n that previous unresolved issues can be settl ed (i ncl udi ng often a pay rai se). The
OR that has no such cycl i cal changes because a very strong central authority prevents them is
commonly an unappeal i ng pl ace to work. Probl ems get brushed asi de or i gnored unti l they seem to
explode wi th vengeance onto the scene. The nature of surgery and working i n an operati ng room
creates si gni fi cant stress on the peopl e empl oyed there. Thi s fact remai ns underappreci ated by the
outsi de worl d but al so becomes commonpl ace for those who work there because the stress i s
constant and therefore routi ne. Until an individual steps aside and refl ects for a moment, he or
she may never reali ze the odd nature of thei r workpl ace and changes they' ve been through.
Because of thi s burnout-prone, high-stress envi ronment, those i n charge need to be
understandi ng, sympatheti c, faci l itati ve, and often somewhat parental to al l i nvol ved. The
resul ti ng col legi al and supportive work envi ronment wil l pay many di vi dends over the long run for
al l involved.
Other aspects that involve l ines of authori ty al so impact the dail y functi on of the OR. Al most
al ways, the OR staff are empl oyees of the hospi tal /faci l ity. Frequentl y, the hospi tal i s perceived as
bei ng pri maril y concerned wi th contai ni ng cost and generati ng more revenue regardl ess of the
si tuati on. From a purel y business perspecti ve, payi ng overti me i s more cost efficient than hiring
addi ti onal staff to open more operating rooms at 7 AM. Thi s fact often works agai nst the desires of
surgeons and anesthesiologi sts who want more fl exibi l ity in thei r scheduli ng abi l ity. The topi c of
adequate nursi ng and techni cal support personnel and functi on frequentl y domi nates many OR
committees. The anesthesi ol ogist, whether cl inical director or not, who has establ i shed hi s or her
reputati on as one who has the operati ng room' s best interest i n mi nd is i n a good posi ti on to hel p
resol ve these di sputes. Gone are the days when many anesthesi a groups/departments have
surpl us funds to hi re addi tional anesthesi a technici ans from thei r budget to hel p the hospi tal ,
demonstrati ng team spiri t, promoti ng effi ci ency, and thus ensuring a healthy worki ng rel ati onshi p
with admi ni stration. Someti mes, stil l , surgeons who feel constrai ned by the l ack of insti tuti onal
support may be abl e to get together and fund posi ti ons (usual l y dedi cated scrub techni cians) from
thei r practi ce i ncome. Regardless of the source of the probl em, or i ts ul ti mate sol ution, it remains
imperati ve that all members of the OR famil y, led by the responsi bl e anesthesi ol ogi sts, practi ce
a spi ri t of cooperati on.
Contact and Communication
An i mportant i ssue for the anesthesia providers in any OR setti ng is who among the group wi l l be
the contact person to i nteract with the OR and its rel ated admi nistrati ve functi ons. In situations
where everyone i s an independent contractor, there may be a ti tul ar chi ef who by desi gn i s the
contact person. The anesthesi ol ogist i n thi s rol e commonl y changes yearly to spread the duti es
among al l the members. Large groups or departments that functi on as the sol e provi di ng enti ty for
that hospital/facil i ty often i denti fy an i ndi vi dual as the contact person to act as the voice for the
department. Furthermore, these same groups del i neate someone on a dai l y basi s to be the cl i ni cal
di rector, or the person runni ng the board. Frequentl y, thi s posi ti on i s best fi l l ed by one of a
smal l dedi cated fracti on of the group (three peopl e, for example) rather than rotati ng the
responsi bi li ty among every member of the group. Experi enced board runners have an
i nsti nctual l y deri ved better perspecti ve on the nuances of managi ng the operati ng schedul e i n real
ti me. Certain procedures may requi re speci fi c trai ni ng (e.g., TEE ski l ls) that not al l members of
the group possess. Cl earl y, changes someti mes have to be made to match the abil i ty of the
anesthesia provider and the requi rements of the procedure when urgent or emergent cases are
posted. Another benefi t of a very smal l number of dail y cl i ni cal di rectors is a

rel ati ve consi stency i n the appl icati on of OR pol i ci es, particularl y in rel ati onshi p to the schedul ing
of cases, especial ly add-ons. One of the most frustrati ng aspects to both surgeons and OR
personnel is unpredictabi l ity and inconsi stency i n the deci si ons made by the anesthesi a
group/department members. A patient deemed unacceptable for surgery by anesthesi ol ogi st X on
Monday may be perfectl y acceptabl e, i n the same medi cal condi tion, for anesthesiol ogi st Y on
Tuesday. Disagreements are inevi tabl e in any l arge group. However, day-to-day OR function may
be hampered by a l arge number of these types of ci rcumstances. Havi ng one member of a very
smal l group in charge wi ll l ead to more consi stency in thi s process, especi al l y i f the board
runner/cl ini cal di rector has the authori ty to swi tch personnel to accommodate the si tuati on.
Wi thout sti fl i ng i ndi vi dual practices, phi l osophies, and comfort l evels, a certain amount of
consi stency appl ied to simil ar cl i ni cal scenarios wi ll i mprove OR functi on i mmeasurabl y. These few
dedi cated di rectors shoul d be able to accompli sh both goal s better than a l arge rotati ng group.
Another i mportant aspect of OR organizati on i s material s management. The avail abi l i ty of the
requi red suppli es for the safe admini stration of anesthesi a needs to be mai ntained at al l ti mes.
Usuall y, the insti tutional component of the anesthesi a servi ce staffs and mai ntains a locati on
contai ning the speci fi c suppl ies uni que to the practi ce of anesthesi a (the workroom). Objecti ves
necessary for effi cient material s management include the standardization of equi pment, drugs,
and suppl i es. Avoi dance of dupl i cati on, vol ume purchasi ng, and i nventory reducti on are al so
worthwhil e. There needs to be coordinati on wi th the OR staff as to who i s responsi bl e for
acqui siti on of routi ne hospi tal suppl ies such as syringes, needl es, tubing, and intravenous fl uids.
Deci sions as to whi ch brands of whi ch suppl i es to purchase ideal ly shoul d be made as a group.
Often, when several compani es compete agai nst each other i n an open market, lower pri ces are
negoti abl e. These negotiations may occur between the anesthesi a provi ders and the hospi tal
administrati on, or by the physi ci an components of the OR Commi ttee. In many cases, however,
P.54
hospi tal s belong to l arge buying groups that determi ne what brands and model s of equi pment and
suppl i es wi l l be avai l abl e, wi th no excepti ons possi bl e except at greatl y increased cost.
Someti mes, thi s is fal se economy i f the provided i tems are i nferi or (cheap) or annoying and, for
example, if it routinely takes openi ng three or four IV cannul ae i n the process of starti ng a preop
IV as opposed to the hi gher qual i ty and reli abl e si ngl e one that may cost more per cannul a but i s
less expensi ve overal l because so many fewer wil l be used. Dispassi onate presentati on of such
logic by a respected team-pl ayer senior anesthesi ol ogi st to the OR Committee or di rector of
material s management may hel p resolve such conundrums.
Schedul i ng Cases
Anesthesi ol ogists need to parti cipate in the OR schedul ing process at thei r faci l ity or i nsti tution.
In some facilities the scheduli ng offi ce and the associ ated cl eri cal personnel work under the
anesthesia group. Commonl y, schedul ing fall s under the OR staff' s responsi bi l ity. Direct control of
the schedul e usual l y resi des wi th the OR supervi sor or charge person, frequentl y a nurse.
Whatever the arrangements, the anesthesia group must have a direct l i ne of communi cati on with
the schedul ing system. The necessary number of anesthesia provi ders that must be suppl i ed often
changes on a dai l y basi s per the caseload and someti mes due to i nstituti onal poli cy deci si ons.
After-hours call s must be arranged, pol i cy changes factored i n, and additi ons/subtracti ons to the
surgi cal l oad (day to day, week to week, and l ong term as surgi cal practices come and go i n that
OR) deal t wi th as wel l. These issues are i mportant even when all the anesthesi a provi ders are
independently contracted and are not affi l i ated wi th each other. In such situations, the ti tul ar
chief of anesthesi a should be the one to act as the l i nk to the schedul i ng system. When the
anesthesia group/department functions as a si ngl e enti ty, the chai rman/chief, cl i ni cal director, or
appoi nted spokesperson wi l l be the i ndi vi dual who represents hi s or her group at meeti ngs where
scheduli ng deci sions are made in conjuncti on wi th the OR supervi sors, surgeons, and hospi tal
administrators.
There are as many di fferent ways to create schedul i ng pol ici es as there are operati ng room suites.
Most hospi tal s/facil i ti es foll ow patterns establi shed over the years. Despi te al l the efforts di rected
toward i ts creati on, the OR schedul e, both weekl y ti me al lotments and day-to-day scheduli ng of
specific cases, remains one of the most contentious subjects for the Operati ng Room Committee or
whatever body presi des over the operati ng room. Recogni zi ng the fact that it i s i mpossi ble to
sati sfy compl etel y even a moderate percentage of the surgeons i nvol ved, the anesthesi a group
should endeavor to faci l itate the process as much as possi ble. Initi al l y, anesthesiol ogi sts need to
be sympatheti c toward al l the surgeons' desi res/demands (stated or i mpl i ed) and attempt to
coordi nate these requests wi th the insti tuti on' s abi l i ty to provide rooms, equi pment, and staff.
Second, the anesthesi a group shoul d make every possible effort to provi de enough anesthesi a
servi ces and personnel to meet reali sti cal l y the goals of the insti tuti on. In l ight of the current
shortage of anesthesi a provi ders i n thi s country, these efforts need to be made wi th a great deal
of open communicati on among al l conti ngenci es of the OR Commi ttee as wel l as every member of
the anesthesi a group. Fail ure to do so wi l l resul t in hard feel i ngs, mi sunderstandi ngs, and
resignati ons among the anesthesi a provi ders. After all , they may cl aim, the hospi tal across
town will pay me more money for fewer hours!
Regardi ng schedul i ng, surgeons essenti al l y fal l i nto one of three groups. One group wants to
operate any ti me they can get their cases schedul ed. Thi s group wants the operati ng room open
24/7 and doesn' t understand why they can' t do thei r case whenever they want to. Another larger
group wants first case of the day as often as possibl e so they can get to thei r offices. A smal l er
third group wants either the first ti me sl ot or an opening foll owi ng that ti me sl ot, a several -hour
hi atus, then to return to the OR after office hours to complete additi onal cases; usual ly starti ng
after 5 PM. Cl earl y a compromi se among these di sparate consti tuenci es must be reached.
Obvi ously, none of these groups can be completel y sati sfied at the same i nsti tuti on.
Anesthesi ol ogists who approach the OR Commi ttee regardi ng thi s di l emma wi th a
nonconfrontati onal atti tude wil l greatly faci l itate agreement on a compromi se. There wi ll al ways be
a certain amount of both overt and covert pol i ti cki ng by surgeons regardi ng schedul i ng.
Types of Schedules
The majori ty of operati ng rooms uti li ze ei ther block schedul i ng (preassigned guaranteed OR time
for a surgeon or surgical servi ce to schedul e cases pri or to an agreed upon cutoff ti me, e.g., 24 or
48 hours before) or open schedul ing (fi rst come, first serve). Most l arge i nsti tutions have a
combi nation of both. Bl ock scheduli ng inherently contai ns several advantageous aspects for
creati ng a schedul e. Bl ock schedul ing all ows for more predi ctabi l i ty i n the dai l y OR functi on as
well as an easy review of uti li zati on of al l otted ti me. Hi stori c util i zati on data should be revi ewed
wi th surgeons, OR staff, and the OR Commi ttee to determi ne i ts vali di ty. Many operating sui tes
have found i t useful to assembl e rather comprehensive stati sti cs about what occurs i n each OR.
Some computeri zed schedul i ng systems (see bel ow) are part of a larger computeri zed
peri operative i nformati on management system that automati cal ly generates stati sti cs. Graphi c
examples are 13-month statisti cal control charts or

run charts that show the number of cases, number of OR mi nutes used for those cases (and
when: i n bl ock, exceedi ng bl ock, eveni ngs, ni ghts, weekends, etc.), number of cancel lati ons (and
mul ti pl e other rel ated parameters i f desi red) by servi ce, by i ndi vi dual surgeon, and total for the
current month and the 12 prior months, al ways wi th control l imits (usuall y two standard
deviati ons from the 13-month moving average) cl earl y i ndi cated. Al l these data are val uable i n
that they generate a cl ear pi cture of what is actuall y goi ng on i n the OR rather than just li stening
to surgeons cl ai m they are busi er than ever or supervi sors cl ai m they have staff who sit around
idl e hal f the day. It i s al so extremel y val uabl e in that block time all ocati on should be reviewed
peri odi cal ly and adjusted based on changes, degree of uti l i zati on, and projected needs. Infl exi ble
bl ock time schedul ing can create a major poi nt of contenti on i f the assi gned blocks are not
regul arl y reevaluated. The surgeon or surgical servi ce wi th the earl y starti ng block that habi tual l y
runs beyond hi s or her bl ock ti me wi l l create problems for the following cases. If this surgeon
were made to schedul e i nto the later bl ock on a rotati ng basi s, del ays in his or her start caused by
others may provoke i mproved accuracy of hi s or her subsequent earl y case posti ngs. Adjustments
in avai l abi l ity of block time can al so be made i n the setti ng of the rel ease time, the ti me pri or to
the operati ve date that a gi ven bl ock i s declared not ful l and becomes avai l abl e for open
scheduli ng. Surgeons prefer as l ate a rel ease ti me as possi bl e to mai ntain their access to thei r OR
bl ock time. However, unused reserved bl ock ti me wastes resources and prevents another service
from scheduli ng. Whi le a si ngl e rel ease ti me rarel y fits al l circumstances, negoti ati ng service-
specific rel ease ti mes may l ead to i mproved satisfacti on for al l . In the ideal system, enough OR
ti me and equi pment shoul d exist to provide for each surgical servi ce' s genuine needs, whil e
retai ni ng the abi l i ty to add to the schedule (via open schedul i ng) as needed. Such an environment
does not exi st. Invari abl y, surgi cal demand exceeds avail able block and open ti me, l eading
servi ces to request addi tional block ti me. When thi s ti me is not granted, servi ces perversely then
schedul e procedures i n open ti me before fi l l i ng thei r bl ock ti me. Surgeons who prefer open time
woul d then be shut out of OR ti me. Open schedul ing may reward those surgeons who run an
effi ci ent service, but i t also may be a source of problems to those surgeons who have a signi ficant
porti on of thei r servi ce arri ve unscheduled, for exampl e, orthopedi c surgeons. Some degree of
flexibi l ity wil l be necessary whichever system i s used. The anesthesia group shoul d adopt a
neutral posi tion i n these discussi ons whi le bei ng reali sti c about what can be accompli shed gi ven
the number of operati ng rooms and the l ength of the normal operati ng day.
The handli ng of the urgent/emergent case posti ng precipi tates a great deal of di scussi on i n most
OR environments. There are as many methods to handl e thi s dil emma as there are i nstituti ons
that provi de emergency servi ces. No studi es al l ow determi nati on of exactl y what rate of OR
util i zati on i s the most cost-effecti ve. However, many i nstituti ons subscribe to the fol lowi ng
parameters: adjusted uti li zation rates averagi ng bel ow 70% are not associ ated wi th full use of
avai labl e block ti me, wasti ng resources, whil e rates above 90% are frequentl y associated wi th the
need for overti me hours.
53
Di fferent OR consti tuenci es have di fferent comfort zones for degrees of
util i zati on (see Tabl e 2-6). Most insti tutions cannot afford to have one or two operating rooms
staffed and waiti ng unl ess there i s a rel iabl e steady suppl y of l ate open-schedule addi tions, that
is, urgents/emergenci es, during the regul ar work day. A previ ousl y agreed upon, clear al gori thm
P.55
for the acceptance and orderi ng of these cases wil l need to be adopted. In general , cri ti cal l i fe-
threatening emergencies and el ective add-ons are fairly straightforward and at the two ends of the
spectrum. The cri ti cal emergency goes in the next avai l abl e room whereas the elective case gets
added to the end of the schedul e. The so-call ed urgent patient requi res the most judgment.
Indi vi dual servi ces shoul d provi de gui deli nes and li mi tati ons for thei r expected urgent cases.
These add-on case pol i cy gui del i nes
54
shoul d be common knowl edge to everyone i nvol ved i n
runni ng the operati ng room. Consequentl y, these cases, such as ectopic pregnancies, open
fractures, the patient with obstructed bowels, and eye i njuries, can then be tri aged and i nserted
into the el ecti ve schedul e as needed wi th mini mal discussi on from the del ayed surgeon. The
surgeons whose urgent case is presented as one that must i mmedi atel y bump another servi ce's
patient, yet coul d wai t several hours if i t i s thei r own pati ent that wi ll be delayed, wil l have to
face thei r own previ ousl y agreed-upon standards in a future OR Committee meeti ng. A simpl e way
to express one l ogical pol icy for urgent cases (e.g., acute appendici ti s, unruptured ectopi c
pregnancy, intestinal obstruction) i s: (1) bump the same surgeon's el ecti ve schedul ed case; (2) i f
none, bump a schedul ed case on the same servi ce (GYN, General A, etc.); (3) i f none, bump a
scheduled case from an open-schedule surgi cal servi ce; and (4) i f none, bump a schedul ed case
from a bl ock-schedule service.
54
Some i nsti tutions requi re the attendi ng surgeon of the posted
urgent/emergent pati ent to speak personal ly wi th the surgeon of any bumped case, as opposed to
letti ng the anesthesi ol ogist board runner or charge nurse take the heat for del ayi ng a schedul ed
case.
Another area of burgeoni ng growth that must be accounted for i n the dai l y work schedul e i s the
nonoperating room off-si te di agnosti c test, or therapeutic i nterventi on that requi res anesthesia
care. In many i nstances these procedures replace operati ons that, i n the recent past, would have
TABLE 2-6 OR Utilization Comfort Zones of the OR Personnel Constituencies
FACILITY
ADMINISTRATION
ANESTHESIOLOGY
GROUP
OR
STAFF
SURGEONS
Block time utilization
>100% ++ -- --- ----
85
100%
++++ ++ - ---
7084% +++ ++++ + +/-
5569% + +++ +++ ++
<55% -- - ++ ++++
+ = favorable; - = unfavorable
Repri nted wi th permi ssi on from Ameri can Soci ety of Anesthesiol ogi sts: Mazzei WJ. OR
management: state of the art. 2003 conference on practi ce management. Park Ri dge, IL:
Ameri can Soci ety of Anesthesi ol ogi sts; 2003:65.
been posted on the OR schedul e as urgent/emergency cases. For exampl e, cerebral aneurysm
coi l i ng and CT gui ded abscess drai nage, among other procedures, are done in imagi ng sui tes.
However, they do require anesthesi a care from anesthesi a personnel , al bei t i n a new

l ocati on. Addi ti onal l y, dependi ng on distances i nvol ved and logi sti cs, i t may even be necessary to
assi gn two peopl e, a pri mary provi der and an attendi ng, exclusivel y to that remote l ocati on when,
had the case come to the OR, the attending may have been abl e to cover another or other cases
al so. Hospi tal admini stration or the OR Committee may try to view these cases as unrel ated to OR
function and, thus, purely a problem for the anesthesi a group to sol ve. These cases must be
treated wi th the same methodology regardi ng access and pri ori ti zati on as al l other OR procedures.
To apportion hospi tal -based anesthesi a resources reasonabl y, these off-si te procedures shoul d
be subject to the same gui del ines and processes as any other OR posting. Most i nsti tutions have
added at least one extra anestheti zi ng l ocation to thei r formal operati ng schedul e to desi gnate
these off-si te procedures (occasional ly wi th an i magi nati ve name such as road show,
outfield, or safari). For many of these off-site cases, there i s li ttl e or no rei mbursement for
anesthesia care. Most government pl ans and i nsurance carri ers wil l probabl y not pay for the
cl austrophobi c adul t to recei ve a MAC or even a general anestheti c for an obviousl y needed
di agnosti c MRI, as much as the pati ent, the surgeon, and the hospi tal benefit from the test
resul ts. The anesthesi a group, the OR Commi ttee, and the hospi tal admi ni stration need to reach
compromises regardi ng off-si te procedures, regarding schedul ing, all ocation of anesthesi a
resources that woul d otherwi se go to the OR, and even subsidi zation of the personnel costs to
conti nue this obvi ousl y benefi ci al servi ce.
Computerization
Computeri zed schedul i ng wil l l ikely benefi t every operati ng room regardl ess of si ze.
Computeri zati on al l ows for a faster more effici ent method of case posting than any handwri tten
system. Changes to the schedul e can be made qui ckl y wi thout any l oss of information.
Rearrangi ng the dai ly schedul e i s much si mpler on a computer than erasing and rewri ting on a
ledger. Furthermore, most hospi tal s have adopted a computer-determi ned time for a gi ven
surgi cal procedure for that particular surgeon. Commonl y, this ti me i s the average of the l ast 10
of the speci fi c procedure (e.g., total knee repl acement) wi th the potenti al to add a modi fi er (e.g.,
it i s a redo) that shows a materi al di fference i n the projected ti me l ength (almost always l onger)
for one parti cul ar pati ent. Suppose surgeon X has a bl ock ti me of 8 hours on a gi ven day and
wants to schedul e four procedures i n that all otted time. The computerized schedul ing program
looks at surgeon X' s past performances and determi nes a projected l ength for each of the
procedures that are identi fi ed to the computer, usual l y by CPT-4 codes or possibl y some other
code devel oped l ocal l y for frequent procedures done by surgeon X. (Note that the recorded time
length i ncludes the turnover ti me, thus maki ng the case ti me defini ti on from the ti me the patient
enters the OR unti l the time any fol l owing pati ent enters that OR [unl ess an excepti on is entered
specificall y for an unusual ci rcumstance].) The use of agreed-upon codes i nstead of just text
descri ptions helps ensure accuracy because i t el iminates any need for the scheduli ng cl erk to
guess what the surgeon intends to do. Bookings shoul d not be taken wi thout the accompanyi ng
codes. The computer then decides whether surgeon X wil l fi ni sh the four procedures i n the al l otted
bl ock time. If the computer concludes that the fourth case woul d fi ni sh si gni fi cantl y (the defi ni ti on
of whi ch can be determi ned and entered i nto the program) beyond the avai l abl e bl ock ti me, i t wi l l
not accept the fourth case into that room' s schedul e on that parti cul ar day. The surgeon wi ll
accept the computer's assi gned ti mes and adjust accordi ngl y, pl anni ng onl y three cases, or appeal
for an excepti on based on some factor not i n the booki ng that i s clai med wi l l materi al l y decrease
the ti me needed for at l east one of the four cases, which the surgeon must expl ain to the
excepti on czar (anesthesiol ogy cl i ni cal director or OR charge nurse) of the day. Note that,
routinely, surgeons general ly object to havi ng actual past turnover times counted i n the case
length average. An al ternative method has the computer si mpl y add (to each case except the l ast)
a projected turnover ti me that i s agreed upon by all i nvol ved at an (often contentious) OR
committee meeti ng. Computerizing the schedul i ng process si gni fi cantl y reduces any personal
bi ases and smoothes out the entire operati ng day. The long-standi ng ritual of l ate-afternoon
P.56
di sputes between the surgeons and the anesthesia group and/or OR staff whether to start the last
case or not may be el i mi nated or at least reduced by thi s more reali sti c prospecti ve OR schedul ing
method.
There are many vari ables to consi der i n any OR schedul ing system. The pati ent popul ati on served
and the nature of the i nstituti on di ctate the overall structure of the OR schedul e. Inner-ci ty Level
1 Trauma Centers must accommodate emergencies on a regul ar basis, 24 hours a day. These
centers are unli kel y to create a workable schedul e more than a day i n advance. An ambulatory
surgery center serving pl astic surgery pati ents may see onl y the rare emergency bri ng-back
bl eedi ng patient. Their schedul e may be accurate many days i n advance wi th a hi gh degree of
expectati on that the pati ent wi l l arri ve on ti me properl y prepared for surgery. The anesthesia
group at thi s ambul atory center may rarel y have to make changes to the schedul e, al l owing them
to proceed wi th a fai rl y predi ctable dai l y workload. At the i nner-ci ty trauma hospi tal , a great deal
of fl exi bil i ty and constant communi cation wi th the surgeons wi ll be requi red i n an attempt to get
the cases done in a reasonabl e time frame wi th the i nherent constrai nts placed on the OR staff' s
resources and the time avail able. These two extreme examples from opposi te ends of the
scheduli ng-process spectrum can provi de gui del ines for the majority of the i nsti tutions that fall
somewhere i n between. Independent of where an i ndi vi dual operati ng theater fal l s in thi s
spectrum, open communi cation and an honest di scussi on among the three pri nci pl e groups
invol ved in OR scheduli ng i s criti cal i n mai ntaini ng a smooth functi oning operati ng room. Avoidi ng
the anesthesi asurgery us versus them mental i ty hel ps keep the schedul e on track. Surgeons
are frequentl y vi ewed as havi ng total ly unreali sti c expectations of what the operati ng room is
capabl e of accompl i shing. Anesthesi ologi sts are someti mes accused of tryi ng to avoi d work when a
case is cancel ed for l egi ti mate medi cal reasons or turnover between cases is percei ved as too
sl ow. The OR staff often feel s they are bei ng pushed too hard. These confli cti ng and contenti ous
atti tudes shoul d not and need not dominate the operati ng room envi ronment. When each of the
three conti ngenci es genui nel y appreci ates the others' points of view and everyone starts worki ng
toward a l ogi cal common goal safe, effici ent, expedi ent pati ent carethen the al ready stressful
OR environment wi ll be a much better pl ace to work.
Beyond open communi cati on, how best to work toward thi s mutual understandi ng depends on the
parti cul ars of the people i nvol ved and the envi ronment, but some ORs report benefits from team-
bui ldi ng exerci ses, leadershi p retreats, and even OR-wide soci al events. ORs with a parti cul arl y
mali gnant history of finger-poi nti ng and bad feel i ngs among the personnel groups may consti tute
one of the few instances an outsi de consul tant real l y may be valuabl e i n that there are workplace
psychol ogi sts who speci al i ze i n anal yzing dysfuncti onal work envi ronments and i mpl ementi ng
changes to i mprove the si tuati on for all i nvol ved.
Anesthesia Preoperative Evaluation Clinic
An anesthesia preoperative evaluati on cli ni c (APEC) that provi des a comprehensi ve perioperative
medical eval uati on usual ly resul ts in a more effi cient runni ng of the operati ng room

schedule.
55, 56
Unanti cipated cancel lations or del ays are avoi ded when the anesthesi a group
eval uates compl ex pati ents prior to surgery. Even i f the patient arri ves to the OR on ti me the day
of surgery, i nadequate preoperati ve cl earance mandati ng the orderi ng of addi ti onal tests wi l l
consume preci ous OR ti me duri ng the delay waiti ng for resul ts. Cancell ati ons or del ays adversely
affect the effici ency of any operating room. Subsequent cases i n that room, whether for the same
or a different surgeon, may get si gnificantly delayed or forced to be squeezed into an already busy
schedule on another day. The fi nanci al i mpact of del ays or cancel lations on the insti tution is
consi derable. Revenue i s l ost wi th no offsetting absence of expenses. Worse, expenses may
actual l y i ncrease when overtime has to be pai d, or the steri l e equi pment has to be repackaged
after havi ng been opened for the cancel ed procedure. Even worse, the i nconveni enced pati ent
and/or surgeon go to another facil i ty.
Optimal ti mi ng for preoperative evaluati on shoul d be rel ated to the insti tution' s schedul i ng
preferences, patient conveni ence, and the overal l health of the pati ent. Earli er compl etion of the
preop eval uati on may not reduce the overal l cancell ati on rate when compared to a more proxi mate
P.57
eval uation. However, an earl y eval uation and cl earance may well provide a l arger pool of pati ents
avai labl e to pl ace on the OR schedule (bl ock or open), resul ting i n a more effi ci ent use of OR time.
Additi onal l y, a protocol -dri ven eval uation process can antici pate possi ble need for ti me-consuming
investi gati ons (such as a cardi ology eval uation for the patient wi th probable angi na). Early
recogniti on of a fail ed preoperative test al l ows ti me for another patient to be moved into the now-
vacant time slot. Al so, earl y i denti fi cation of certai n probl ems requiri ng speci al care on the day of
surgery (for example, preoperati ve epi dural or PA catheter pl acement) shoul d l ead to fewer
unanti ci pated del ays. Unfortunately, many i ssues preci pi tati ng delays are discovered on the day of
surgery. Some of these preventabl e del ays are unrel ated to the pati ents' health status. Seemi ngl y
si mpl e i ssues such as veri fi cation of a ri de home, or incomplete fi nanci al i nformati on al so
contri bute to unexpected del ays. A properl y functi oning APEC may be abl e to el i mi nate a majori ty
of these annoying causes of unnecessary delays.
Regardl ess of the insti tutional speci fi cs surroundi ng the service provided by the APEC, further cost
savi ngs can be obtai ned through its proper usage by the anesthesia group. Wi th onl y a basi c
protocol to go on, commonly a ful l shotgun battery of tests i s ordered by surgeons to cover al l
the bases for every pati ent from a specifi c surgeon or surgi cal servi ce in the hopes of avoi di ng
last-mi nute del ays on the day of surgery. The APEC frequently reduces dramaticall y the number of
pre-op tests performed by focusing on whi ch diagnosti c tests and medi cal consul ts are reall y
requi red for any speci fi c pati ent. In some ci rcumstances, the APEC may al so function as an
addi ti onal source of revenue for the anesthesia group when a formal preop consul t on a
compl i cated pati ent i s ordered wel l in advance by the surgeon, i n the same manner as woul d have
otherwi se been directed to a pri mary care physi cian for cl earance for surgery. Securi ng a
genui nel y rel evant medi cal evaluati on of the pati ent pri or to anesthesi a and surgery wi th i ts
subsequent reducti on of wasted OR resources and cost containment are not the only benefi ts of an
APEC. The abi l ity to central ize pertinent i nformati on i ncl udi ng admi ssion
precertificati on/cl earance, fi nanci al data, di agnosti c and l aboratory results, consult reports, and
preoperati ve recommendati ons i mproves OR functi on by decreasi ng the ti me spent searchi ng for
al l these items after changes have been made to the schedule. Pati ent and fami l y educati on
performed by the APEC frequentl y l eads to an i ncrease in pati ents' overal l sati sfaction of the
peri operative experi ence. In addi tion, pati ent anxi ety may be reduced secondary to the more i n-
depth contact possi ble inherent in the APEC process when compared to anesthesi a practi tioners
meeti ng an ambul atory outpati ent for the fi rst ti me in an OR hol di ng area i mmedi atel y pri or to
surgery. The APEC model enabl es the anesthesi a group to be more acti ve and proacti ve i n the
peri operative process, improvi ng their rel ati ons wi th the other OR constituents. By taking a
leading rol e in establ ishi ng and runni ng an APEC, the anesthesi a group enhances its reputati on as
a cooperati ve, concerned enti ty by si gnifi cantly contributi ng to hi gh-quali ty pati ent care as wel l as
the overall effici ency of the operating room function.
Anest hesi ol ogy P er sonnel I ssues
In l ight of the current and future shortage of anesthesi a care provi ders, managi ng and mai ntai ning
a stabl e suppl y of anesthesia practiti oners promi ses to domi nate the OR l andscape for years to
come. The 2002 shortfal l of anesthesi ol ogi sts was calcul ated at 100 to 3,800 and the esti mate for
2005 was 500 to 3,900, the range dependent on servi ce demand growth.
34
A survey of hospi tal
administrators revealed that nearl y 60% of them are acti vel y recruiti ng anesthesi ologi sts; over
half of them have done so for more than six months.
57
The lean resident recruiti ng years of the
mi d- to l ate 1990's continue to impact the professi on. Even though appl icati ons to anesthesiol ogy
residenci es rebounded si gnifi cantly, i t wil l take many years of rel ati vel y l arge numbers of
anesthesia resi dency graduates to reverse thi s trend. Furthermore, the suppl y of nonphysici an
anesthesia providers is al so dwi ndl i ng. Wi th the agi ng popul ati on of nurse anestheti sts and the
li mi ted number of appl i cations to schools i n that professi on, as wel l as the very li mited number of
trai ni ng faci l iti es for anesthesi ol ogy assi stants, the overall supply of anesthesi a provi ders remai ns
inadequate to meet current and, at least, short-term future demands. The need for anesthesia
groups to create a fl exi ble, attractive work envi ronment to retai n provi ders who mi ght l eave or
retire wi l l conti nue to i ncrease.
A rel ated i ssue i s consi derati on of what i s a reasonabl e work l oad for an anesthesi ol ogist and
how best to measure, if possibl e, the cl ini cal productivity of an anesthesi a group/department.
These questi ons have been the subject of consi derabl e discussion.
58, 59, 60, 61
Subjects involve
compari sons among members of the anesthesi ology group, both agai nst outsi de benchmarks and
al so against each other as wel l as the group as a whol e agai nst others, i f possi ble. Beyond the
si mpl e number of FTEs, cases, and OR mi nutes, consi deration of factors such as the nature of the
faci li ty, types of surgi cal practi ce, patient acui ty, and speed of the surgeons must be incorporated
to all ow fai r compari sons. Thoughtful fi lteri ng of resul ting data shoul d take pl ace before
di ssemi nati on of the aggregate informati on to al l members of a group because of the
understandable extreme sensi ti vi ty among stressed and fatigued anesthesi ol ogists to a suggesti on
that they are not worki ng as hard as thei r group/department peers.
Except in hi ghly unusual ci rcumstances, fl exi bl e schedul ing of anesthesi a provi ders and al so
ful fi l li ng the demands pl aced on the group by the insti tution conti nues to be a constant bal ancing
act. Thi s demand assumes added si gnifi cance because i nstituti ons now subsi dize many anesthesi a
groups. Even when a majori ty of providers in a faci l ity are i ndependent contractors where it is
requi red that a speci fi c surgeon request thei r servi ces, there are time confli cts rangi ng from no
one at all bei ng avai l abl e to unwanted downti me. When the anesthesi a group/department accepts
the responsi bi l ity of provi ding anesthesi a servi ces for an i nsti tuti on, they must schedul e enough
provi ders for that OR sui te on each given day. Ideall y, a suffi cient number of provi ders woul d be
hi red so that there woul d al ways be enough personnel to staff the mi ni mum number of

rooms scheduled on any gi ven day, as well as after-hours call duty. Thi s situation rarel y exists
because i t would be fi nanci al l y di sadvantageous to have an excess number of provi ders with no
cl i ni cal acti vity. Havi ng exactl y the ri ght number of anesthesia providers in a group for the cl i ni cal
load works wel l until one (or more) of them i s out wi th an unpl anned absence such as an extended
il l ness or a fami ly emergency. Many academi c departments have a natural buffer wi th some
cl i ni ci ans assi gned interval s of noncli ni cal ti me for research, teaching, or administrati ve duties.
However, repeated l oss of these noncl ini cal days because of i nadequate cl i ni cal staffi ng in the OR
leads to undermini ng the academic/research mission of the department. Conti nued loss of this
ti me wil l eventual l y l ead to resi gnati ons, thus el imi nati ng the ori ginal buffer. Consequentl y,
anesthesia groups/departments need to anti ci pate avai labl e cli ni cal personnel and match them to
the operati ng room demands. Ideal ly, thi s i nformati on shoul d be accurate for several months into
the future. Meeting thi s speci fi cati on has become more diffi cult i n the recent past. Wi th sudden
major real ignments of i nsurance carri ers, changes i n managed care, and the constant bi ddi ng war
for anesthesi a provi ders, predicting both personnel avail abil i ty and the correspondi ng operati ng
room case load any length of time into the future may require a crystal ball . There i s no easy
answer to this di l emma and no clear solution presents itself, except to acknowledge that the
si tuati on exi sts and is l i kely to continue for the foreseeabl e future. Hospi tal admi ni strators must
offer reasonabl e assurances to the anesthesi a group provi ding servi ce that a gi ven OR uti li zati on
rate i s l i kel y, as wel l as accurate data regardi ng rei mbursement (payer mi x and any package
contracts negotiated by the hospi tal ). Thi s data must be provi ded accuratel y and updated
frequently if a heal th care insti tution is to acqui re and retain an anesthesia group staffed wi th the
personnel to meet the expected demands.
Timing
Each operati ng envi ronment has i ts own personnel schedul i ng system and expectations for the
anesthesi a group. Dai l y coordi nati on between the anesthesi a group' s cl i ni cal di rector and the OR
supervi sor permi ts the constructi on of a reasonabl e schedul e showi ng the number of operati ng
rooms that day and when the schedul e expects each of them to fi ni sh. Invari abl y, some cases take
longer than anti ci pated, or add-ons are posted requiring the OR to run i nto the l ate afternoon or
early eveni ng. Many anesthesia provi ders accept thi s occurrence as a matter of course. Few
anesthesia providers wi ll tol erate thi s sequence of events as an essenti al l y dai ly routi ne whether
they are pai d overtime or not. These practiti oners become exhausted and resent the burdens
conti nuousl y pl aced on them. If the OR schedule i s such that add-ons frequently occur and
el ecti ve cases run wel l into the eveni ng, many anesthesia providers wi ll opt to protect thei r
P.58
personal and famil y ti me and cut back thei r worki ng hours or resi gn. Nei ther woul d be wel come i n
such a tight market. Under these ci rcumstances, hiri ng addi ti onal personnel who are scheduled to
arri ve at a later ti me, for exampl e, 11:00 AM, and then provi di ng l unch reli ef and stayi ng late
(e.g., 7:30 PM or later i f needed) to fi ni sh the schedule may wel l be a very worthwhi l e
investment.
Another possi bl e sol ution to the demands of an extended OR schedul e on an anesthesia group's
personnel may revolve around employi ng part-ti me anesthesi a provi ders. Part-ti me opportuniti es
coul d enhance a group' s abi l i ty to attract addi ti onal staff. According to a New York Times survey,
many medi cal practi ti oners (12% of mal e physi ci ans and 25% of femal e physi cians) currentl y work
fewer than 40 hours a week.
57
In the past, a di sproporti onatel y hi gh percentage of women chose
anesthesiol ogy as a career. In 1970, women represented 7.6% of the physi cian population but
were 14% of anesthesiol ogi sts; much more recently, they make up 45% of the physi ci an
popul ati on and onl y 20% of anesthesi ol ogists, proportionatel y a si gni fi cant reduction.
62
Beyond
the basi c demographi c shift among al l physici ans, one li kel y parti al expl anati on for the decreased
number of women anesthesiol ogi sts may be the l ack of part-ti me positi ons, whi ch wil l hamper an
anesthesia groups' abi l ity to attract and keep at l east some of the femal e anesthesia provi ders.
Schedul ing after-hours coverage also adds to the personnel diffi culti es faci ng the anesthesi a
group. The vari ati ons of cal l schemes are endl ess. The nature of the i nsti tution and the workl oad
determi ne the degree of late ni ght coverage. Major referral centers and Level 1 trauma centers
requi re i n-house pri mary provi ders. If these provi ders i nclude residents and/or nurse anestheti sts,
then the supervi sing attendi ng staff wi l l al so be in-house 24 hours a day. In other l ess intense
setti ngs, the pri mary provi der wi ll be i n house wi th the attending taking cal l from home (wi thi n
the boundary of a predetermined maximum arri val ti me, usuall y 30 mi nutes). The number of
provi ders required to take cal l (in-house or back-up) is always a never-endi ng topi c of ani mated
di scussi on. Shoul d the cal l team staff for a mi ni mum, average, or potenti al l y possi ble number of
cases, with a cal l -in l ist as further backup? A common sol uti on empl oyed at many insti tuti ons i s to
staff the eveni ng/ni ght cal l shi fts for an average workl oad, recogni zi ng that on some occasions
there wi l l be idl e operati ng rooms, and on other ni ghts, the surgi cal demand wil l exceed the cal l
team' s numbers, resul ti ng in a scrambl e. Obviousl y i f this occurs frequentl y, changes are needed
in the number of staff on cal l .
There are al so medi colegal i ssues surrounding the call team' s avai l abi l ity. At a smal l community
hospi tal wi th a l i mi ted number of independent attendi ng practiti oners, the practi ti oners may agree
to cover cal l on a rotati ng basi s. The i ndi vi dual s not on cal l are usual l y not obli gated to the OR
and may wel l be trul y unreachabl e. What happens then when the on-call anesthesiol ogi st is
administeri ng an anestheti c and another true emergency case arri ves i n the OR sui te and the
remai ni ng staff anesthesi ologi sts are l egiti matel y unavai lable? Does that anesthesi ol ogist leave hi s
or her current patient under the care of an operati ng room nurse and go next door to tend to a
more acutel y (possi bl y cri ti cal l y) i ll pati ent? Shoul d the pati ent be transferred from the ER to
another (hopeful ly nearby) hospi tal ? These questi ons have no easy answers. Cl early, those
practi ti oners on the scene have to assess i n real ti me the rel ati ve risks and benefi ts and make the
di fficul t decisi ons. Thi s exampl e is but one of the many issues faci ng any call scheme, whatever
the si ze of the faci l ity and the number of people i nvol ved, and the possi ble scenari os that exi st i n
staffi ng an operati ng sui te.
A rel ated schedul i ng i ssue regarding the evening and ni ght cal l assi gnments revol ves around what
to do wi th the call team that has worked the previ ous night. Shoul d they provi de anesthesi a care
the next day? As always, the answers to this questi on are as vari ed as there are heal th care
faci li ties. If the cal l duty requi res the practi ti oner(s) frequently to work much or all of the ni ght,
l eavi ng the i ndi vi dual (s) stressed and fati gued, they shoul d not be required to work the next day
duri ng normal worki ng hours. However, i f that call team normal l y works most of the ni ght, but
they have not had any cases to do and were abl e to sl eep, i t i s not unreasonabl e to expect such
individual s to remai n in the OR i n the morning and help out as l ong as needed. A more
compl i cated answer i nvol ves what to do when the call assi gnment rarel y requires a l ong ni ght' s
work and the on-call anesthesia providers routinely have rooms assigned to them the next day,
but at l east one person has just finished a difficult 24-hour shift bei ng awake worki ng al l ni ght.
Does the group wi sh the practi tioner to continue the schedul ed dayti me

assi gnment wi th the intent of being rel i eved as soon as possi bl e? Al ternativel y, shoul d the
practi ti oner go home, wi th the resul t of closing or del aying a l ineup of scheduled cases, whi ch wi l l
bri ng si gni fi cant negati ve feedback to the anesthesi ol ogy group? Common sense and reason shoul d
gui de everyone in such a ci rcumstance. Anesthesi a groups need to deci de how to handl e the
possi bl e cal l shi ft scenarios, wi th permutati ons and combi nations, and cl earl y communi cate
prospecti vel y thei r deci si ons to the OR Commi ttee before any di ffi cul t deci sion has to be made one
morni ng. As al ways, the medi col egal aspects of any deci si on such as thi s need to be taken i nto
consi derati on. Whether or not fati gue was a factor, the practi ti oner who worked throughout the
ni ght before and appeared to contribute to an anestheti c catastrophe the next morni ng woul d have
a very diffi cult defense i n court. Further, the anesthesi ol ogy group may al so be hel d l i abl e i n that
thei r practi ce/poli cy was i n pl ace, al l egedl y authori zi ng the supposedl y dangerous conduct.
Cost and Qual i t y I ssues
One of the more pervasive aspects of Ameri can medi cal care i n today' s envi ronment i s the dri ve to
mai ntai n and i mprove hi gh-quali ty heal th care whi l e reduci ng the cost of that care. Heal th care
accounts for approximatel y 14% of the Gross Domesti c Product, nearly triple the fraction a
generati on ago. Consequentl y, al l physi ci ans, i ncl udi ng anesthesiol ogi sts, are urged constantly to
incl ude cost-consciousness i n decisi ons bal ancing the natural desire to provide the hi ghest
possi bl e qual ity of care with the overal l pri ori ti es of both the heal th care system and the
individual pati ent, al l whi l e faci ng increasi ngl y li mi ted resources.
63
Anesthesi ologi sts remai n a
target for li mi ting heal th care expenditures. Anesthesi a provi ders (di rectl y and i ndi rectl y) have
represented 3 to 5% of the total heal th care costs in the country.
64
Anesthesi ologi sts are under
more and more pressure to l i mi t expenses. Compl i cated deci si ons are requi red regardi ng whi ch
patients are suitable for ambul atory surgery, what preoperati ve studi es to order, what anestheti c
drugs or techni que i s best for the pati ent, what moni tors or equipment are reasonably required to
run an OR, and the li st goes on and on. Addi ti onall y, anesthesi ol ogi sts must not lose si ght of
maintai ni ng the quali ty of care i n this ever-increasi ng cost-conscious environment in which there
is i ntense producti on pressure to cut corners that i s fuel ed by the get away with i t mental i ty i n
whi ch i t i s noted that the vast, vast majori ty of the ti me one does something inherently unsafe,
nothi ng bad happens to the pati entsetti ng up some subsequent pati ent for a potentiall y
catastrophi c adverse event when the pressured anesthesi ol ogi st does not get away with it. Wi th
this as background, anesthesi ol ogi sts l egi ti mately can include economi c consi derations i n their
deci si on processes. When presented with mul tipl e opti ons to provi de for therapeutic i nterventi on
or pati ent assessment, one shoul d not automati cal ly choose the more expensi ve approach (just to
cover al l the bases) unl ess there is compel li ng evi dence provi ng i ts value. Decisi ons that clearly
material ly increase cost shoul d onl y be pursued when the benefi t outwei ghs the ri sk. In anesthesi a
care as wel l as medici ne i n general , such deci si ons can be di ffi cul t regardi ng interventi ons that
provi de margi nal benefi t but contai n si gni fi cant cost increases.
65
To del i ver hi gh-qual i ty
anesthesia care, anesthesiol ogi sts are obl iged to consi der the goal s of the pl anned i nterventi on,
the expectati ons of all of thei r customers (pati ents, surgeons, coll eagues, hospi tal admi ni strators,
payers, etc.), and the costs of the antici pated care. Because cost containment i niti al l y requi res
accurate cost awareness, anesthesi ol ogi sts need to find out in an organi zed manner, more than
ever before, the actual costs and benefi ts of thei r anesthesi a care techniques. Detai ls wil l be
uni que to each practi ce setting. Because they wil l be exci ted that the anesthesiol ogi sts actual l y
care, usuall y it i s possibl e to get the cooperati on of the faci li ty admi ni strati on' s fi nancial
department members i n researchi ng and cal culating the actual cost of anesthesi a care so that
thoughtful eval uati ons of potenti al reductions can be i niti ated.
Anesthesi a drug expenses represent a smal l portion of the total peri operati ve costs. However, the
great number of doses actual l y admi nistered contributes substanti all y to aggregate total cost to
the insti tution in actual dol l ars. Prudent drug selection combi ned with appropri ate anestheti c
technique can resul t i n substanti al savi ngs. Reduci ng fresh gas fl ow from 5 L/mi nute to 2 L/mi nute
wherever possi bl e woul d save approximatel y $100 mi l l ion annual ly i n the United States.
66
Whi le a
majority of anesthesi a provi ders usual l y attempt a practical approach to cost savi ngs, they are
P.59
more frequently faced wi th di ffi cul t choi ces regardi ng methods of anesthesia that li kel y produce
si mi l ar outcomes but at substanti al l y di fferent cost. When comparing the total costs of more
expensive anestheti c drugs and techni ques to lesser expensive ones, many vari abl es need to be
added to the formul a. The cost of anestheti c drugs needs to i ncl ude the costs of additi onal
equipment such as speci al vapori zers or extra i nfusion pumps and the associ ated mai ntenance.
There are other i ndi rect costs that may be di ffi cul t to quanti tate and are commonl y overl ooked.
Some of these indirect costs include: i ncreased setup time, possi bly increasi ng room turnover
ti me, extended PACU recovery ti me, and addi ti onal expensi ve drugs required to treat side effects.
Someti mes, more expensi ve techni ques reduce i ndirect costs. A propofol i nfusi on, whil e more
expensive than vapor, commonl y resul ts i n a decreased PACU stay for a short noni nvasi ve
procedure. If fewer PACU staff are needed or patient throughput is i ncreased, the more expensive
drug can reduce overal l cost. Conversel y, using comparati vel y expensi ve propofol for a l ong
procedure defi ni tel y requi ri ng postop admi ssi on to an ICU is hardly justi fi ed. The i mpact of
shorter-acti ng drugs and those with fewer side effects i s context speci fi c. During l ong surgical
procedures, such drugs may offer l i mi ted benefi ts over ol der l ess expensive longer-acti ng
al ternatives.
67
Under these conditi ons, advocati ng cost contai nment usi ng educational efforts may
decrease drug expendi tures for several categories of drugs.
68
Drugs in the same therapeuti c class
have wi del y varying costs. The acqui si tion expenses may vary as much as 50-fol d i n some
pharmacol ogical categori es. It is esti mated that the 10 highest expenditure drugs account for
more than 80% of the anestheti c drug costs at some insti tuti ons.
69
Whi le newer more expensive
drugs may be easi er to use, no data exi sts to support or refute the hypothesi s that these drugs
provi de a better anesthetic experi ence when compared to careful l y titrated older l ess expensi ve
longer-acti ng drugs in the same class. Many experi enced cl i ni cians feel that pati ents can awaken
promptl y usi ng a wi de vari ety of general anestheti c techni ques when the agents are uti l ized
optimal l y.
Understandi ng the costbenefi t rati o for many aspects of and around anesthesi a care can be
di ffi cul t at best. Even when publ i shed studi es provi de informati on evaluati ng the outcome of a
parti cul ar new therapy or i nterventi on, determi nati on of the speci fi c cl i ni cal rel evance remains
easier sai d than done. Sampl e si ze, stati sti cs, methodol ogy, and other anal ytic i ssues often
confuse the reader, maki ng i t complex and di ffi cul t to scruti ni ze the study resul ts and pl ace them
i n thei r proper perspecti ve. What may appear a large cl i ni cal ly rel evant di fference may assume
lesser i mportance if the sampl e si ze was too smal l to achi eve stati sti cal si gnifi cance. Furthermore,
seemi ngl y smal l changes may grow to hi gh statistical si gni fi cance if the sample si ze i s l arge
enough. Careful attention must be devoted to any study proposi ng a reduction in rel ati ve ri sk to
the pati ent. For exampl e, i f i ntervention A i s associ ated

with a 25% actual reduction in the i nci dence of a compl i cation, and i nterventi on B i s associated
with a 4% actual reducti on in the i nci dence of another compl icati on, both coul d sti l l be descri bed
as produci ng the same relative i mprovement despi te different cl i ni cal appli cati on. Thi s approach
has profound importance for the analysi s of cost-effecti veness. A speci fi c anesthetic or anti emeti c
mi ght need to be admi ni stered to just four pati ents to decrease one epi sode of postop
nausea/vomi ti ng (i nterventi on A). On the other hand, one would have to use more than 100 costl y
new spi nal needl es to prevent one case of postdural puncture headache (i ntervention B).
Cal cul ati ng the mi nimum number required to achi eve the reported effect helps the cl i ni ci an
determi ne cost-effecti veness of cli ni cal al ternati ves.
2, 70

Independent of costs involved, anal ysi s of pati ent outcomes rel evant to the practi ce of anesthesi a
permi ts the anesthesi ol ogist to establ i sh whi ch aspects of care deserve attenti on. Outcome
measures are typi cal ly defi ned as those changes, either favorabl e or adverse, that occur i n actual
or potenti al health status after pri or or concurrent care.
71
Heal th status changes i ncl ude both
physi cal and physi ol ogi cal parameters (such as death, cardi ac arrest, l ength of PACU stay, postop
myocardial i nfarction, or unexpected i ntensi ve care admi ssi on), as wel l as psychosoci al functi ons
(pati ent satisfacti on, famil y i ssues, or resumption of normal l i fe). Hi stori cal l y, a great deal of
attenti on and money has been dedi cated to reduci ng adverse cl i ni cal events. Whil e l imi ti ng
severe/catastrophic adverse effects remai ns a noble and worthy cause, anesthesi a groups woul d
be well served devoti ng a si gnifi cant effort towards reduci ng common, nonli fe-threatening
P.60
adverse events rel ated to everyday OR anesthesia.
72, 73
Improved qual i ty of care and better pati ent
sati sfacti on i s a l egi ti mate yardsti ck upon whi ch to measure the val ue of anesthesia services.
Focused efforts to avoid major adverse events may domi nate an anesthesi a group' s attenti on, but
it must be acknowl edged that other factors, such as atti tude and friendli ness of the staff, may be
equal l y i f not more i mportant than some cl i ni cal outcomes.
74
A reducti on of seri ous adverse
anesthetic outcomes has a variabl e economi c i mpact on total costs, dependi ng on different
assumpti ons regardi ng case mi x, the added expense of i mprovi ng peri operati ve care and/or
preventi ng compl i cati ons, the frequency of adverse compli cations, and the rel ati ve costs of the
uncompl icated surgery.
75
Nonethel ess, reduci ng mi nor but common peri operati ve anesthesi a
rel ated i ncidents and compl i cations theoreticall y can be economi cal l y benefici al , si nce these are
si gni fi cant predi ctors of PACU uti li zati on i n terms of l ength of PACU stay.
76

Evaluati on of outcomes and their subsequent appl i cati on to cost anal ysi s can be deri ved from two
pri nci pal sources, data publ i shed i n the li terature and data col l ected from experi ence. As noted,
computerized information management systems are useful tools to track outcomes and anal yze the
impact on the costbenefi t ledger. Using the coll ated data, in the same manner as for OR
util i zati on and case load, practi tioners can readil y appl y a stati sti cal process to evaluate outcomes
in thei r practice, possi bl y i ncl udi ng correl ati on wi th cost.
2
This information may take on added
i mportance i n that publ i shed i nci dence studies may not exist for the speci fi c outcome an
anesthesi a group i s searching for. Cause and effect diagrams can track the parameters involved i n
the process and relate them to the vari ous outcomes desi red. Mul ti pl e perti nent examples coul d be
constructed from the now extensi ve body of li terature on the factors contri buting to postop nausea
and vomi ti ng and the vari ous possi bl e preventi ons and treatments, many of whi ch involve very
expensive medi cations. Of course, this can be done local ly wi thin an insti tuti on. Information would
be col lected and stored i n the database. Ideal l y, the database woul d i denti fy and track as many
vari abl es as needed/possi bl e to del i neate sources for possi bl e i mprovement and i ts ul ti mate cost
anal ysi s. Once these sources for i mprovement and the ensui ng cost impact are known, the
anesthesi a group can determi ne whether or not to pursue changi ng their practice. Outcomes
rel ated to adverse effects can also be moni tored. If anal ysi s reveal s a si gni fi cant di fference i n an
adverse outcome among practi tioners, after al l the other vari abl es such as surgeon, pati ent mi x,
and so on, are eli minated, the outcome database can i nvestigate the anestheti c techni que uti l ized
by that practi ti oner. If significant vari ati ons are identi fi ed, that practi tioner woul d be abl e to l earn
of these variations i n a non-threatening manner si nce computer-deri ved data are used as opposed
to a speci fi c case anal ysi s, whi ch mi ght l ead that practi tioner to feel si ngl ed out for publi c
criti ci sm.
Another relevant appl i cati on of such statisti cal outcome analysi s is i ts use to i mprove the qual i ty
of a heal th care process (e.g., the peri operati ve experience
2
) i n general . The pri nci ples of
conti nuous qual i ty i mprovement promoted by Deming
77
are bei ng appl i ed wi del y i n the heal th care
industry. Demi ng' s approach focuses on stati sti cal anal ysis of qual i ty assessment, speci fi cal ly
eval uating vari ati ons in outcome parameters that are deemed meani ngful to the target popul ati on
(e.g. pati ents anesthetized). Addressi ng the etiologi es of outcome vari ati ons rather than i ndi cti ng
the health care process as a whole can help resol ve probl ematical outcome i ssues di scovered i n
the anal ysi s. If the data reveal an outcome change for the worse, prompt eval uati on of the
processes i nvol ved should i mmedi ately ensue with the i ntention of identi fyi ng the cause. Steps to
el i mi nate or reduce the undesi red outcomes can be i nvestigated and i mpl emented. If a benefi ci al
change appears, the process vari ati ons then responsi bl e for the subsequent i mprovement shoul d
be identi fi ed and i mpl emented i n other areas if possi ble. The appl i cation of the spirit of thi s type
of benefi ci al conti nuous quali ty assessment and resul ting i mprovement, wi th or wi thout elaborate
stati sti cal anal ysi s, shoul d be an i ntegral ongoing component of every anesthesi a practi ce.
CONCLUSION
Practi ce and operati ng room management i n anesthesi ol ogy today i s more compl ex and more
important than ever before. Attenti on to detail s that previ ousl y ei ther di d not exi st or were
percei ved as uni mportant can li kel y make the di fference between success and fai lure in
anesthesi ol ogy practi ce.
Outl i ned here are basic descripti ons and understandi ngs of many different admi nistrati ve,
organizati onal , financi al, and personnel components and factors i n the practi ce of
anesthesiol ogy. Ongoi ng si gnifi cant changes in the heal th care system wi l l provi de a conti nuing
array of chal l enges. Appl icati on of the pri nci ples presented here wil l all ow anesthesi ol ogi sts to
extrapol ate creati vel y from these basics to thei r own indi vi dual ci rcumstances and then forge
ahead i n anesthesi ol ogy practi ce that i s effi cient, effecti ve, producti ve, coll egial , and even fun.
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P.62
> Tabl e of Contents > Secti on I - Introducti on to Anesthesi a Practi ce > Chapter 3 - Experi mental Desi gn and
Stati sti cs
Chapter 3
Experimental Design and Statistics
Nathan Leon Pace
KEY POINTS
INTRODUCTION
Medi cal journal s are repl ete with numbers. These include wei ghts, lengths, pressures,
vol umes, fl ows, concentrations, counts, temperatures, rates, currents, energies, and forces.
The analysi s and interpretati on of these numbers require the use of stati sti cal techni ques. The
desi gn of the experi ment to acquire these numbers is also part of statistical competence. The need
for these stati sti cal techni ques i s mandated by the nature of our universe, which is both orderly
and random at the same ti me. Probabi li ty and statistics have been formul ated to solve concrete
problems, such as betting on cards, understandi ng bi ol ogi c i nheri tance, and i mprovi ng food
processi ng. Studi es i n anesthesi a have even i nspired new stati sti cs. The devel opment of stati sti cal
techniques is manifest i n the increasi ng use of more sophi sti cated research designs and statistical
Stati sti cs and mathematics are the l anguage of sci entific medici ne.
Good research pl anni ng includes a cl ear bi ol ogi c hypothesis, the specificati on of
outcome vari ables, the choi ce of anti cipated stati sti cal methods, and sampl e
si ze pl anning.
To avoi d bi as i n the performance of cl i ni cal research, the cruci al el ements of
good research desi gn i ncl ude concurrent control groups; random all ocation of
subjects to treatment groups; and bl i ndi ng of random all ocation, pati ents,
caregi vers, and outcome assessors.
Descri ptive (mean, standard devi ati on, etc.) and inferential stati sti cs (t test,
confi dence i nterval , etc.) are both essenti al methods for the presentati on of
research resul ts.
The central li mit theorem al l ows the use of parametri c stati sti cs for most
stati sti cal testing.
Systematic revi ew and meta-anal ysi s can synthesi ze and summari ze the resul ts
of smal l er, nonsignificant i ndi vi dual studi es and permi t more powerful
inferences.
tests i n anesthesi a research.
If a physi ci an i s to be a practiti oner of sci entific medi cine, he or she must read the l anguage of
sci ence to be abl e to i ndependentl y assess and interpret the scienti fi c report. Wi thout excepti on,
the language of the medi cal report i s increasi ngl y stati sti cal . Readers of the anesthesi a l iterature,
whether i n a communi ty hospital or a university envi ronment, cannot and shoul d not total ly
depend on the edi tors of journal s to banish al l errors of stati sti cal anal ysis and i nterpretati on. In
addi ti on, there are regul arl y questi ons about si mpl e statistics i n examinati ons requi red for
anesthesiol ogi sts. Fi nall y, certai n stati sti cal methods have everyday appl i cations i n cl i ni cal
medici ne. Thi s chapter bri efl y scans some el ements of experi mental desi gn and stati sti cal
anal ysi s.
DESIGN OF RESEARCH STUDIES
The sci enti fi c investi gator should vi ew hi msel f or hersel f as an experi menter and not merel y as a
naturali st. The naturali st goes out i nto the fi eld ready to capture and report the numbers that fl it
into vi ew; thi s i s a worthy activity, typified by the case

report. Case reports engender interest, suspi cion, doubt, wonder, and, one hopes, the desi re to
experi ment; however, the case report is not suffi ci ent evi dence to advance scienti fi c medi ci ne.
The experimenter attempts to constrain and control, as much as possibl e, the envi ronment i n
whi ch he or she coll ects numbers to test a hypothesis.
Sampl i ng
Two words of great i mportance to statistici ans are popul ati on and sampl e. In stati sti cal l anguage,
each has a speci ali zed meani ng. Instead of referri ng only to the count of i ndi vi dual s i n a
geographi c or pol iti cal regi on, popul ati on refers to any target group of thi ngs (ani mate or
inanimate) i n whi ch there is interest. For anesthesia researchers, a typical target popul ati on mi ght
be mothers i n the fi rst stage of l abor or head-trauma vi cti ms undergoi ng crani otomy. A target
popul ati on coul d also be cel l cul tures, i sol ated organ preparations, or hospi tal bi l ls. A sampl e i s a
subset of the target popul ation. Sampl es are taken because of the i mpossi bi li ty of observi ng the
enti re population; i t i s generall y not affordabl e, convenient, or practi cal to exami ne more than a
rel ati vely small fracti on of the popul ati on. Neverthel ess, the researcher wi shes to general i ze from
the resul ts of the small sampl e group to the enti re popul ati on.
Although the subjects of a populati on are al i ke i n at l east one way, these popul ati on members are
general ly qui te diverse i n other ways. Si nce the researcher can work onl y wi th a subset of the
popul ati on, he or she hopes that the sampl e of subjects in the experiment i s representati ve of the
popul ati on' s di versi ty. Head-i njury patients can have open or closed wounds, a vari ety of
coexi sti ng di seases, and normal or i ncreased intracranial pressure. These subgroups wi thi n a
popul ati on are cal led strata. Often the researcher wi shes to i ncrease the sameness or homogenei ty
of the target popul ati on by further restri cti ng i t to just a few strata; perhaps onl y cl osed and not
open head injuri es wi ll be i ncl uded. Restri cti ng the target popul ati on to el iminate too much
di versi ty must be bal anced agai nst the desire to have the resul ts be appl i cabl e to the broadest
possi bl e popul ation of pati ents.
The best hope for a representative sample of the popul ati on woul d be real i zed if every subject in
the popul ati on had the same chance of bei ng i n the experiment; this i s cal led random sampl i ng. If
there are several strata of i mportance, random sampli ng from each stratum woul d be appropri ate.
Unfortunatel y, in most cl i ni cal anesthesi a studi es researchers are l imi ted to usi ng those pati ents
who happen to show up at thei r hospitals; thi s i s cal l ed convenience sampl i ng. Convenience
sampl i ng i s al so subject to the nuances of the surgi cal schedul e, the goodwi ll of the referring
physi ci an and attending surgeon, and the wil l i ngness of the pati ent to cooperate. At best, the
convenience sampl e i s representati ve of pati ents at that insti tuti on, with no assurance that these
patients are si mi l ar to those elsewhere. Conveni ence sampli ng is al so the rul e i n studyi ng new
anesthetic drugs; such studi es are typicall y performed on heal thy, young volunteers.
P.64
P er f or mance
The researcher must define the conditi ons to which the sample members wi ll be exposed.
Parti cul arl y i n cl i ni cal research, one must decide whether these conditi ons should be ri gi dly
standardi zed or whether the experi mental circumstances shoul d be adjusted or i ndividual i zed to
the pati ent. In anestheti c drug research, shoul d a fi xed dose be gi ven to al l members of the
sampl e or should the dose be adjusted to produce an effect or to achi eve a speci fi c end point?
Standardi zi ng the treatment groups by fi xed doses si mpl ifies the research work. There are ri sks to
this standardizati on, however: (1) a fi xed dose may produce excessi ve numbers of side effects i n
some patients; (2) a fi xed dose may be therapeuti cal ly insuffici ent in others; and (3) a treatment
standardi zed for an experimental protocol may be so artifici al that i t has no broad cl i ni cal
rel evance, even i f demonstrated to be superi or. The researcher shoul d careful l y choose and report
the adjustment/i ndi vi dual izati on of experi mental treatments.
Cont r ol Gr oups
Even if a researcher is studyi ng just one experi mental group, the results of the experiment
are usual ly not interpreted sol ely in terms of that one group but are al so contrasted and
compared with other experimental groups. Exami ni ng the effects of a new drug on bl ood pressure
duri ng anestheti c induction i s i mportant, but what is more important is comparing those resul ts
with the effects of one or more standard drugs commonly used in the same si tuati on. Where can
the researcher obtai n these comparative data? There are several possi bi li ties: (1) each pati ent
coul d recei ve the standard drug under i denti cal experi mental circumstances at another time; (2)
another group of pati ents recei vi ng the standard drug could be studi ed si mul taneousl y; (3) a
group of pati ents coul d have been studi ed previ ousl y wi th the standard drug under si mi l ar
ci rcumstances; and (4) l i terature reports of the effects of the drug under related but not
necessari ly identi cal ci rcumstances coul d be used. Under the first two possi bil i ti es, the control
group i s contemporaneousei ther a sel f-control (crossover) or paral l el control group. The second
two possi bil i ti es are exampl es of the use of hi stori cal control s.
Because histori cal control s al ready exi st, they are conveni ent and seemingly cheap to use.
Unfortunatel y, the history of medi cine i s li ttered wi th the debri s of therapies enthusiasti cal l y
accepted on the basi s of compari son wi th past experience. A classi c exampl e i s operative l igation
of the internal mammary artery for the treatment of angi na pectori sa procedure now known to
be of no val ue. Proposed as a method to i mprove coronary artery bl ood fl ow, the l ack of benefi t
was demonstrated i n a tri al where some patients had the procedure and some had a sham
procedure; both groups showed benefi t.
1
There is now firm empirical evidence that studies usi ng
hi stori cal control s usual l y show a favorabl e outcome for a new therapy, whereas studi es wi th
concurrent control s, that i s, parall el control group or sel f-control , l ess often reveal a benefit.
2

Nothi ng seems to i ncrease the enthusi asm for a new treatment as much as the omission of a
concurrent control group. If the outcome wi th an ol d treatment is not studi ed si mul taneousl y wi th
the outcome of a new treatment, one cannot know if any differences i n resul ts are a consequence
of the two treatments, or of unsuspected and unknowabl e di fferences between the pati ents, or of
other changes over ti me i n the general medi cal environment. One possible excepti on woul d be i n
studying a disease that i s uniforml y fatal (100% mortali ty) over a very short ti me.
Random Al l ocat i on of Tr eat ment Gr oups
Having accepted the necessi ty of an experi ment wi th a control group, the questi on arises as to the
method by whi ch each subject shoul d be assi gned to the predetermi ned experi mental groups.
Shoul d i t depend on the whi m of the i nvestigator, the day of the week, the preference of a
referri ng physi cian, the wi sh of the patient, the assi gnment of the previous subject,

he avail abil i ty of a study drug, a hospi tal chart number, or some other arbitrary cri teri on? Al l such
methods have been used and are stil l used, but al l can rui n the puri ty and useful ness of the
experi ment. It i s i mportant to remember the purpose of sampl ing: by exposi ng a smal l number of
subjects from the target population to the various experi mental condi tions, one hopes to make
P.65
concl usions about the enti re popul ati on. Thus, the experi mental groups should be as simi lar as
possi bl e to each other in reflecti ng the target popul ati on; i f the groups are di fferent, thi s
introduces a bi as i nto the experiment. Al though randoml y al locating subjects of a sampl e to one or
another of the experimental groups requi res addi ti onal work, thi s pri nci pl e prevents sel ection bias
by the researcher, mini mi zes (but cannot al ways prevent) the possi bil i ty that i mportant
di fferences exi st among the experi mental groups, and di sarms the cri tics' compl aints about
research methods. Random all ocation i s most commonl y accompli shed by the use of computer-
generated random numbers.
Bl i ndi ng
Blinding refers to the maski ng from the vi ew of pati ent and experi menters the experi mental group
to which the subject has been or wi ll be assi gned. In cli ni cal trials, the necessi ty for bl i ndi ng
starts even before a patient is enroll ed i n the research study; thi s i s call ed the conceal ment of
random al location. There is good evi dence that, i f the process of random all ocati on i s accessi ble to
view, the referri ng physici ans, the research team members, or both are tempted to manipulate the
entrance of speci fi c patients i nto the study to i nfl uence thei r assi gnment to a speci fi c treatment
group
3
; they do so having formed a personal opi ni on about the rel ati ve meri ts of the treatment
groups and desi ri ng to get the best for someone they favor. Thi s creates bi as i n the
experi mental groups.
Each subject should remai n, if possibl e, i gnorant of the assigned treatment group after entrance
into the research protocol . The pati ent' s expectati on of i mprovement, a pl acebo effect, i s a real
and useful part of cl i ni cal care. But when studyi ng a new treatment, one must ensure that the
fame or i nfamy of the treatments does not i nduce a bi as in outcome by changi ng pati ent
expectati ons. A researcher' s knowl edge of the treatment assi gnment can bias hi s or her abi li ty to
administer the research protocol and to observe and record data fai thfull y; thi s i s true for cli ni cal ,
animal , and in vi tro research. If the treatment group i s known, those who observe data cannot
trust themselves to record the data imparti al l y and di spassi onately. The appel l ati ons si ngl e-bl i nd
and doubl e-bl i nd to descri be bl i ndi ng are commonl y used in research reports, but often appl i ed
inconsi stentl y; the researcher shoul d careful l y pl an and report exactl y who is bl i nded.
Types of Resear ch Desi gn
Ul ti matel y, research design consi sts of choosi ng what subjects to study, what experi mental
condi ti ons and constraints to enforce, and whi ch observati ons to col l ect at what interval s. A few
key features i n thi s research desi gn largel y determi ne the strength of sci enti fi c inference on the
coll ected data. These key features all ow the cl assificati on of research reports (Tabl e 3-1). Thi s
cl assi ficati on reveals the variety of experi mental approaches and i ndicates strengths and
weaknesses of the same desi gn appl i ed to many research problems.
The fi rst di sti ncti on i s between longi tudinal and cross-secti onal studi es. The former i s the study of
changes over time, whereas the latter describes a phenomenon at a certai n poi nt i n ti me. For
exampl e, reporti ng the frequency with whi ch certai n drugs are used during anesthesi a is a cross-
secti onal study, whereas investi gati ng the hemodynamic effects of different drugs duri ng
anesthesia i s a longi tudi nal one.
Longitudi nal studies are next classi fi ed by the method wi th whi ch the research subjects are
sel ected. These methods for choosing research subjects can be either prospecti ve or
retrospecti ve; these two approaches are al so known as cohort (prospecti ve) or case-control
(retrospecti ve). A prospecti ve study assembl es groups of subjects by some i nput characteri sti c
that i s thought to change an output characteri sti c; a typi cal i nput characteri sti c woul d be the
opi oi d drug admini stered duri ng anesthesi a, for exampl e, remi fentani l or fentanyl. A retrospecti ve
study gathers subjects by an output characteristic; an output characteri sti c i s the status of the
subject after an event, for exampl e, the occurrence of a myocardi al infarcti on. A prospective
(cohort) study woul d be one in whi ch a group of patients undergoi ng neurological surgery was
di vi ded i n two groups, gi ven two different opi oi ds (remi fentani l or fentanyl), and fol l owed for the
development of a perioperative myocardi al i nfarcti on. In a retrospecti ve (case-control ) study,
patients who suffered a peri operati ve myocardi al i nfarcti on woul d be i denti fi ed from hospi tal
records; a group of subjects of si mil ar age, gender, and di sease who did not suffer a peri operati ve
myocardial infarction al so would be chosen, and the two groups would then be compared for the
rel ati ve use of the two opioi ds (remi fentani l or fentanyl). Retrospective studi es are a primary tool
of epi demi ology. A case-control study can often identi fy an associ ati on between an i nput and
output characteri sti c, but the causal li nk or rel ationship between the two is more di ffi cul t to
specify.
Prospecti ve studi es are further di vi ded into those i n whi ch the investi gator performs a del i berate
interventi on and those in which the investi gator merel y observes. In a study of del i berate
intervention, the i nvestigator woul d choose several anestheti c maintenance techni ques and
compare the inci dence of postoperati ve nausea and vomi ti ng. If i t was performed as an
observational study, the i nvestigator woul d observe a group of pati ents receiving anestheti cs
chosen at the di screti on of each pati ent' s anesthesi ol ogi st and compare the i ncidence of
postoperative nausea and vomi ting among the anesthetics used. Obvi ousl y, in thi s exampl e of an
observational study, there has been an intervention; an anestheti c has been gi ven. The cruci al
di sti ncti on i s whether the i nvestigator control l ed the i nterventi on. An observati onal study may
reveal differences among treatment groups, but whether such di fferences are the consequence of
the treatments or of other di fferences among the pati ents receiving the treatments wi l l remai n
obscure.
Studies of del iberate i ntervention are further subdi vi ded i nto those wi th concurrent control s and
TABLE 3-1 Classification of Biomedical Research Reports
I. Longitudi nal studies
A. Prospecti ve (cohort) studi es
1. Studies of del iberate i ntervention
a. Concurrent controls
b. Histori cal control s
2. Observational studies
B. Retrospective (case-control ) studi es
II. Cross-secti onal studi es
those wi th historical control s. Concurrent control s are ei ther a si multaneous paral l el control group
or a sel f-control study; hi stori cal controls

incl ude previ ous studies and l i terature reports. A randomi zed controll ed tri al i s thus a
longi tudi nal, prospective study of del iberate i ntervention with concurrent control s.
Although most of this di scussi on about experi mental desi gn has focused on human
experi mentati on, the same pri nci ples appl y and shoul d be fol l owed i n ani mal experimentati on. The
randomi zed, controll ed cl inical trial i s the most potent sci enti fi c tool for evaluati ng medical
treatment; randomizati on into treatment groups is reli ed upon to equal l y wei ght the subjects of
the treatment groups for basel ine attri butes that mi ght predi spose or protect the subjects from
the outcome of i nterest.
Hypot hesi s For mul at i on
Whether the research subjects are ti ssue preparations, ani mal s, or people, the researcher is
constantl y faced wi th fi ndi ng both si mi l ariti es and differences among the diversities of a
group of subjects. The researcher starts the work with some intuiti ve feel for the phenomenon to
be studi ed. Whether stated expl ici tl y or not, thi s is the bi ologic hypothesi s; it i s a statement of
experi mental expectati ons to be accompl i shed by the use of experimental tool s, i nstruments, or
methods accessibl e to the research team. An exampl e woul d be the hope that isofl urane woul d
produce l ess myocardi al i schemi a than fentanyl; the experi mental method mi ght be the
el ectrocardi ographi c determi nati on of ST segment changes. The biologi c hypothesis of the
researcher becomes a stati sti cal hypothesis during research planning. The researcher measures
quantiti es that can varyvari abl es such as heart rate or temperature or ST segment change. In a
stati sti cal hypothesi s, statements are made about the rel ati onship among parameters of one or
more popul ati ons. A parameter is a number descri bing a vari able of a popul ati on; Greek l etters
are used to denote parameters. The typical stati sti cal hypothesi s can be establi shed i n a
somewhat rote fashion for every research project, regardl ess of the methods, material s, or goal s.
The most frequently used method of setting up the algebrai c formul ati on of the statistical
hypothesi s i s to create two mutuall y excl usi ve statements about some parameters of the study
popul ati on (Tabl e 3-2); esti mates for the val ues for these parameters are acqui red by sampl i ng
data. In the hypotheti cal exampl e compari ng isofl urane and fentanyl,
1
and
2
woul d represent
the ST segment changes wi th i sofl urane and wi th fentanyl . The nul l hypothesis is the hypothesis of
no difference of ST segment changes between i sofl urane and fentanyl . The al ternative hypothesis
is usual l y nondirecti onal , that i s, either
1
<
2
or
1
>
2
; thi s i s known as a two-tail al ternative
hypothesi s. This i s a more conservative al ternative hypothesis than assuming that the inequali ty
can only be either l ess than or greater than.
P.66
TABLE 3-2 Algebraic Statement of Statistical Hypotheses
H
0
:
1
=
2
(nul l hypothesi s)
H
a
:
1

2
(al ternati ve hypothesi s)
1
= Parameter esti mated from sampl e of fi rst popul ati on
2
= Parameter esti mated from sampl e of second population
Logi c of P r oof
One parti cul ar deci si on strategy is used al most uni versal ly to choose between the nul l and
al ternative hypothesis. The deci sion strategy i s si mil ar to a method of i ndi rect proof used i n
mathematics called reductio ad absurdum. If a theorem cannot be proved directl y, assume that i t
is not true; show that the fal sity of this theorem wi l l lead to contradi cti ons and absurdi ties; thus,
reject the ori ginal assumption of the fal seness of the theorem. For statistics, the approach i s to
assume that the null hypothesi s i s true even though the goal of the experiment i s to show that
there i s a difference. One exami nes the consequences of this assumption by exami ni ng the actual
sampl e val ues obtained for the vari abl e(s) of i nterest. Thi s is done by cal cul ati ng what is call ed a
sampl e test stati sti c; sampl e test statistics are cal cul ated from the sampl e numbers. Associ ated
with a sampl e test statistic i s a probabi l ity. One also chooses the level of signi fi cance; the l evel of
si gni fi cance i s the probabi li ty l evel consi dered too l ow to warrant support of the null hypothesi s
bei ng tested. If sampl e val ues are suffi ci entl y unl i kely to have occurred by chance (i.e., the
probabi l ity of the sampl e test stati sti c i s l ess than the chosen level of si gnifi cance), the null
hypothesi s i s rejected; otherwise, the nul l hypothesis is not rejected.
Because the stati sti cs deal wi th probabil i ti es, not certai nti es, there i s a chance that the deci sion
concerning the nul l hypothesis i s erroneous. These errors are best di spl ayed i n tabl e form (Tabl e
3-3); Condi ti on 1 and Condi ti on 2 coul d be di fferent drugs, two doses of the same drug, or
di fferent patient groups. Of the four possi bl e outcomes, two are clearl y undesi rable. The error of
wrongly rejecting the null hypothesi s (fal se-positi ve) is call ed the type I or al pha error. The
experi menter shoul d choose a probabi l i ty value for al pha before coll ecti ng data; the experi menter
deci des how cauti ous to be about fal sel y cl aiming a di fference. The most common choi ce for the
val ue of al pha i s 0.05. What are the consequences of choosi ng an al pha of 0.05? Assumi ng that
there i s, i n fact, no di fference between the two conditi ons and that the experi ment is to be
repeated 20 times, then duri ng one of these experi mental repl i cati ons (5% of 20) a mi staken
concl usion that there i s a di fference woul d be made. The probabi l i ty of a type I error depends on
the chosen level of si gnifi cance and the exi stence or nonexistence of a difference between the two
experi mental condi tions. The small er the chosen al pha, the smal l er wil l be the ri sk of a type I
error.
The error of fai l ing to reject a fal se null hypothesi s (fal se-negati ve) is call ed a type II or beta
error. The power of a test i s 1 mi nus beta. The probability of a type II error depends on four
factors. Unfortunately, the smal l er the al pha, the greater the chance of a fal se-negati ve
concl usion; thi s fact keeps the experi menter from automaticall y choosi ng a very small al pha.
Second, the more variabi li ty there i s in the popul ati ons bei ng compared, the greater the chance of
a type II error. This i s analogous to l i steni ng to a noi sy radi o broadcast; the more stati c there i s,
the harder i t wi ll be to discri mi nate between words. Next, i ncreasing the number of subjects wi ll
lower the probabi l ity of a type II error. The fourth and most i mportant factor i s the magni tude of
the difference between the two experi mental conditi ons. The probabi l ity of a type II error goes
from very high, when there is onl y a smal l difference, to extremely l ow, when the two condi ti ons
produce l arge differences in popul ati on parameters.
Sampl e Si ze Cal cul at i ons
Discussi on of hypothesi s testi ng by stati sti cians has al ways included menti on of both type I and
type II errors, but researchers have typicall y ignored the l atter error in experi mental desi gn. The
practi cal importance of worrying about type II errors reached the consciousness of the medi cal
research communi ty several decades ago.
4
Some control l ed cli ni cal tri als that clai med to fi nd no
advantage of new therapi es compared with standard therapi es l acked suffi cient stati sti cal

power to di scri mi nate between the experi mental groups and woul d have mi ssed an i mportant
therapeutic i mprovement. There are four opti ons for decreasing type II error (increasi ng stati sti cal
power): (1) rai se al pha, (2) reduce popul ati on vari abil i ty, (3) make the sampl e bi gger, and (4)
make the di fference between the condi ti ons greater. Under most ci rcumstances, onl y the sampl e
si ze can be vari ed. Sampl e si ze planning has become an important part of research design for
control led cl ini cal tri al s. Some publ i shed research stil l fail s the test of adequate sampl e si ze
pl anning.
STATISTICAL TESTING
Stati sti cs is a method for working wi th sets of numbers, a set bei ng a group of objects. Statistics
TABLE 3-3 Errors in Hypothesis Testing: The Two-Way Truth Table
REALITY (POPULATION PARAMETERS)
CONDITIONS 1
AND 2
EQUIVALENT
CONDITIONS 1
AND 2 NOT
EQUIVALENT
Concl usi on from
Observations
(Sampl e Statistics)
Conditi ons 1
and 2
equival ent
a
Correct concl usi on Fal se-negati ve type
II error (beta
error)
Conditi ons 1
and 2 not
equival ent
b
Fal se-positi ve type
I error (al pha
error)
Correct concl usi on
a
Do not reject nul l hypothesis: Condi ti on 1 = Condi tion 2.
b
Reject null hypothesi s: Conditi on 1 Conditi on 2.
P.67
invol ves the descri ption of number sets, the comparison of number sets wi th theoreti cal model s,
comparison between number sets, and comparison of recentl y acqui red number sets wi th those
from the past. A typi cal scienti fi c hypothesis asks whi ch of two methods (treatments), X and Y, is
better. A stati sti cal hypothesi s is formulated concerni ng the sets of numbers coll ected under the
condi ti ons of treatments X and Y. Statistics provi des methods for decidi ng i f the set of values
associated wi th X are di fferent from the val ues associ ated with Y. Statistical methods are
necessary because there are sources of vari ati on i n any data set, incl udi ng random biol ogi c
vari ati on and measurement error. These errors i n the data cause di ffi cul ti es i n avoi di ng bi as and
i n bei ng preci se. Bi as keeps the true val ue from bei ng known and fosters incorrect deci sions;
precisi on deal s wi th the problem of the data scatter and wi th quanti fyi ng the uncertai nty about the
val ue in the popul ati on from whi ch a sampl e i s drawn. These statistical methods are rel ati vel y
i ndependent of the parti cul ar fiel d of study. Regardl ess of whether the numbers i n sets X and Y
are systoli c pressures, body wei ghts, or serum chl ori des, the approach for compari ng sets X and Y
is usual l y the same.
Dat a St r uct ur e
Data col lected in an experi ment i ncl ude the defining characteristi cs of the experiment and the
val ues of events or attri butes that vary over ti me or condi tions. The former are call ed explanatory
vari abl es and the l atter are cal led response variabl es. The researcher records his or her
observations on data sheets or case record forms, which may be one to many pages i n l ength, and
assembles them together for stati sti cal anal ysi s. Vari abl es such as gender, age, and doses of
accompanying drugs reflect the variabil i ty of the experi mental subjects. Expl anatory vari abl es, i t
i s hoped, expl ai n the systemati c variations i n the response vari abl es. In a sense, the response
vari abl es are dependent on the expl anatory vari abl es.
Response vari abl es are also cal l ed dependent vari abl es. Response vari ables refl ect the primary
properties of experi mental i nterest in the subjects. Research i n anesthesi ol ogy i s particul arl y
li kel y to have repeated measurement vari ables, that i s, a particul ar measurement recorded more
than once for each i ndi vi dual . Some vari abl es can be both expl anatory and response; these are
call ed intermedi ate response vari ables. Suppose an experi ment i s conducted compari ng
el ectrocardi ographi c and myocardi al responses between fi ve doses of an opioi d. One might anal yze
how ST segments depended on the dose of opi oids; here, maximum ST segment depression is a
response vari abl e. Maxi mum ST segment depressi on mi ght also be used as an expl anatory vari abl e
to address the more subtl e question of the extent to whi ch the effect of an opi oi d dose on
postoperative myocardial i nfarcti on can be accounted for by ST segment changes. The
mathemati cal characteristics of the possi bl e values of a vari abl e fi t i nto fi ve classi fi cati ons (Tabl e
3-4). Properl y assi gni ng a vari abl e to the correct data type i s essential for choosi ng the correct
stati sti cal techni que. For interval variabl es, there is equal di stance between successi ve i nterval s;
the difference between 15 and 10 is the same as the di fference between 25 and 20. Di screte
interval data can have onl y i nteger values, for example, age i n years, number of l ive chil dren, or
papers rejected by a journal . Conti nuous i nterval data are measured on a conti nuum and can be a
deci mal fracti on; for exampl e, bl ood pressure can be descri bed as accuratel y as desi red (e.g.,
136, 136.1, or 136.14 mm Hg). The same stati sti cal techni ques are used for di screte and
conti nuous data.
TABLE 3-4 Data Types
DATA TYPE DEFINITION EXAMPLES
INTERVAL
Discrete Data measured with an i nteger onl y scale Parity, number of teeth
Putti ng observations i nto two or more discrete categories derives categori cal vari ables; for
stati sti cal analysi s, numeri c val ues are assi gned as l abel s to the categori es. Di chotomous data
al low only two possi bl e val ues, for exampl e, mal e versus female. Ordi nal data have three or more
categori es that can l ogical l y be ranked or ordered; however, the ranking or ordering of the
vari abl e i ndi cates only rel ati ve and not absol ute di fferences between val ues; there i s not
necessari ly the same di fference between American Soci ety of Anesthesiol ogi sts Physi cal Status
score I and II as there i s between III and IV. Al though ordi nal data are often treated as i nterval
data in choosi ng a stati sti cal techni que, such analysi s may be suspect; al ternative techniques for
ordi nal data are avai l abl e. Nomi nal vari ables are placed i nto categori es that have no l ogi cal
orderi ng. The eye colors bl ue, hazel , and brown mi ght be assi gned the numbers 1, 2, and 3, but i t
is nonsense to say that blue < hazel < brown.

Descr i pt i ve St at i st i cs
A typical hypothetical data set coul d be a sampl e of ages (the variabl e) of 12 resi dents i n an
anesthesia trai ni ng program (the population). Al though the results of a parti cul ar experi ment
mi ght be presented by repeatedl y showi ng the enti re set of numbers, there are conci se ways of
summarizing the i nformati on content of the data set into a few numbers. These numbers are cal led
sampl e or summary statistics; summary stati sti cs are cal culated using the numbers of the sample.
By conventi on, the symbols of summary stati sti cs are Roman l etters. The two summary statistics
most frequentl y used for i nterval vari abl es are the central l ocati on and the variabi li ty, but there
are other summary stati sti cs. Other data types have analogous summary stati sti cs. Although the
first purpose of descriptive stati sti cs i s to descri be the sampl e of numbers obtained, there is al so
the desi re to use the summary statistics from the sampl e to characteri ze the popul ati on from
whi ch the sampl e was obtained. For exampl e, what can be said about the age of al l anesthesia
residents from the i nformation in a sampl e? The population al so has measures of central location
and vari abil i ty cal led the parameters of the popul ati on; as previ ousl y menti oned, popul ati on
parameters are denoted by Greek letters. Usual ly, the popul ati on parameters cannot be di rectl y
calculated, because data from al l popul ati on members cannot be obtai ned. The beauty of properl y
chosen summary statistics i s that they are the best possi bl e esti mators of the population
parameters.
These sampl i ng stati sti cs can be used in conjunction wi th a probabil i ty density functi on to
provi de addi ti onal descripti ons of the sampl e and its population. Also commonl y descri bed as
a probabi l ity distri buti on, a probabi l i ty density functi on i s an algebrai c equati on, f(x), whi ch gi ves
a theoreti cal percentage distri buti on of x. Each val ue of x has a probabi l ity of occurrence gi ven by
Conti nuous Data measured with a constant scal e
interval
Bl ood pressure,
temperature
CATEGORICAL
Dichotomous Bi nary data Mortali ty, gender
Nomi nal Qual i tati ve data that cannot be ordered or
ranked
Eye color, drug category
Ordinal Data ordered, ranked, or measured
without a constant scale interval
ASA physi cal status
score, pain score
P.68
f(x). The most i mportant probabi l ity distri buti on i s the normal or Gaussian functi on. There are two
parameters (popul ati on mean and popul ati on vari ance) i n the equati on of the normal function that
are denoted and
2
. Often cal led the normal equati on, i t can be pl otted and produces the
fami l i ar bel l -shaped curve. Why are the mathematical properties of thi s curve so important to
bi ostati sti cs? First, it has been empiri cal ly noted that when a bi ol ogi c vari abl e i s sampl ed
repeatedl y, the pattern of the numbers pl otted as a hi stogram resembl es the normal curve; thus,
most bi ol ogi c data are sai d to fol l ow or to obey a normal di stribution. Second, if it i s reasonabl e to
assume that a sampl e is from a normal population, the mathematical properties of the normal
equati on can be used with the sampli ng stati sti c esti mators of the population parameters to
descri be the sampl e and the popul ati on. Third, a mathemati cal theorem (the central li mi t theorem)
al lows the use of the assumpti on of normal ity for certai n purposes, even if the popul ati on i s not
normal ly di stri buted.
Cent r al Locat i on
The three most common summary statistics of central l ocati on for interval vari ables are the
arithmeti c mean, the medi an, and the mode. The mean i s merel y the average of the numbers i n
the data set. Being a summary stati sti c of the sample, the ari thmetic mean i s denoted by the
Roman letter x under a bar:

If al l val ues in the popul ati on coul d be obtai ned, then the popul ati on mean coul d be cal cul ated
si mi l arly. Because all val ues of the population cannot be obtai ned, the sampl e mean i s used.
(Stati sti ci ans descri be the sample mean as the unbiased, consi stent, mi ni mum vari ance, suffi ci ent
estimator of the population mean. Esti mators are denoted by a hat over a roman letter, for
example

. Thus, the sampl e mean

is the estimator

of the popul ati on mean .)
The medi an i s the middl emost number or the number that di vi des the sampl e i nto two equal parts.
The medi an i s obtai ned by fi rst ranki ng the sample values from lowest to highest and then
counti ng up hal fway. The concept of ranking i s used i n nonparametri c stati sti cs. A vi rtue of the
medi an i s that i t i s hardl y affected by a few extremel y hi gh or low val ues. The mode i s the most
popul ar number of a sampl e, that is, the number that occurs most frequently. A sampl e may have
ti es for the most common val ue and be bi - or pol ymodal ; these modes may be wi del y separated or
adjacent. The raw data shoul d be i nspected for thi s unusual appearance. The mode is al ways
menti oned in di scussi ons of descriptive stati sti cs, but i t is rarel y used i n stati sti cal practi ce.
Spr ead or Var i abi l i t y
Any set of i nterval data has variabi li ty unl ess al l the numbers are identi cal . The range of ages
from l owest to hi ghest expresses the l argest difference. Thi s spread, di versi ty, and vari abil i ty can
al so be expressed i n a conci se manner. Variabil i ty i s speci fi ed by cal cul ati ng the deviati on or
deviate of each i ndi vi dual x
i
from the center (mean) of al l the x
i
' s. The sum of the squared
deviates is al ways posi ti ve unl ess al l set val ues are i denti cal . Thi s sum is

then di vi ded by the number of indi vidual measurements. The result i s the averaged squared
deviati ons; the average squared deviati on i s ubi quitous i n stati sti cs.
The concept of descri bing the spread of a set of numbers by cal cul ati ng the average di stance from
each number to the center of the numbers appl i es to both a sampl e and a popul ati on; thi s average
squared di stance is cal led the vari ance. The popul ati on vari ance i s a parameter and i s represented
by
2
. As wi th the popul ati on mean, the population vari ance is not usual l y known and cannot be
calculated. Just as the sampl e mean i s used in pl ace of the populati on mean, the sampl e vari ance
P.69
is used in pl ace of the populati on vari ance. The sample vari ance is:

Stati sti cal theory demonstrates that if the di vi sor i n the formula for s
2
is (n - 1) rather than n, the
sampl e vari ance i s an unbi ased esti mator of the popul ati on vari ance. Whi l e the vari ance i s used
extensi vel y i n stati sti cal calcul ati ons, the uni ts of vari ance are squared uni ts of the ori ginal
observations. The square root of the variance has the same uni ts as the ori ginal observati ons; the
square roots of the sampl e and popul ati on variances are cal l ed the sampl e and popul ati on
standard devi ati ons.
It was previousl y mentioned that most bi ologi c observations appear to come from populations with
normal di stri buti ons. By accepti ng thi s assumpti on of a normal di stributi on, further meani ng can
be given to the sample summary stati sti cs (mean and standard devi ati on) that have been
calculated. Thi s involves the use of the expressi on

k s, where k = 1, 2, 3, etc. If the popul ati on from whi ch the sampl e i s taken i s unimodal and
roughl y symmetric, then the bounds for 1, 2, and 3 encompasses roughl y 68%, 95%, and 99% of
the sampl e and population members.
Conf i dence I nter val s
A confidence interval descri bes how l i kel y i t is that the popul ati on parameter i s estimated by any
parti cul ar sampl e stati sti c such as the mean. (The technical defini ti on of confi dence i nterval i s
more rigorous. A 95% confidence interval impli es that i f the experi ment were done over and over
again, then 95 of each 100 confidence i ntervals woul d be expected to contai n the true val ue of the
mean.) Confi dence i nterval s are a range of the fol lowi ng form: summary stati sti c (confi dence
factor) (precisi on factor).
The precisi on factor is derived from the sampl e i tsel f, whereas the confi dence factor i s taken from
a probabi l i ty di stri buti on and al so depends on the speci fi ed confi dence level chosen. For a sampl e
of interval data taken from a normal l y di stri buted population for whi ch confi dence interval s are to
be chosen for

, the preci si on factor i s cal led the standard error of the mean and i s obtai ned by di vi di ng s by the
square root of the sampl e si ze:

The confi dence factors are the same as those used for the dispersi on or spread of the sampl e and
are obtained from the normal distri buti on. The confidence i nterval s for confidence factors 1, 2,
and 3 have roughly a 68%, 95%, and 99% chance of contai ni ng the popul ati on mean. Strictly
speaki ng, when the standard deviation must be esti mated from sample values, the confidence
factors should be taken from the t distribution, another probabi li ty di stributi on. These coeffi cients
wil l be l arger than those used above. This i s usual ly i gnored i f the sampl e si ze i s reasonabl e, for
example, n > 25. Even when the sampl e si ze i s only fi ve or greater, the use of the coeffici ents 1,
2, and 3 is simple and sufficiently accurate for qui ck mental cal cul ations of confi dence interval s on
parameter esti mates.
Almost al l research reports incl ude the use of SE, regardless of the probabil i ty di stri buti on of the
popul ati ons sampled. Thi s use i s a consequence of the central li mi t theoremone of the most
remarkabl e theorems i n al l of mathematics. The central l i mi t theorem states that the SE can
al ways be used, i f the sampl e size i s suffi ci entl y l arge, to speci fy confidence i nterval s around the
sampl e mean containing the popul ati on mean. These confi dence interval s are cal cul ated as
descri bed above. Thi s is true even i f the popul ati on di stri buti on i s so di fferent from normal that s
cannot be used to characteri ze the dispersi on of the popul ati on members. Onl y rough gui deli nes
can be given for the necessary sample si ze; for interval data, 25 and above i s l arge enough and 4
and bel ow i s too smal l .
Although the SE i s discussed al ong wi th other descri ptive stati sti cs, it i s real ly an i nferenti al
stati sti c. Standard error and standard devi ati on are menti oned together because of their
si mi l ariti es of computation and because of the confusi on of thei r use in research reports. Thi s use
is most often of the form mean number; some confusi on resul ts from the fai l ure of the author
to speci fy whether the number after the si gn is the one or the other. More i mportant, the choi ce
between usi ng s and usi ng SE has become controversi al; because SE i s always l ess than s, i t has
been argued that authors seek to decei ve by usi ng SE to make the data look better than they
reall y are. The choi ce is actual l y si mple. When descri bing the spread, scatter, or dispersi on of the
sampl e, use the standard devi ati on; when descri bi ng the preci si on wi th whi ch the popul ati on
center is known, use the standard error.
P r opor t i ons
Categorical binary data, al so cal l ed enumerati on data, provi de counts of subject responses. Given
a sampl e of subjects of whom some have a certai n characteri sti c (e.g., death, femal e sex), a rati o
of responders to the number of subjects can be easi ly cal cul ated as p = x/n; thi s rati o or rate can
be expressed as a deci mal fracti on or as a percentage. It shoul d be cl ear that thi s is a measure of
central l ocati on of a bi nary data i n the same way that was a measure of central l ocation for
conti nuous data. In the popul ati on from which the sample is taken, the rati o of responders to total
subjects i s a popul ati on parameter, denoted ; is the measure of central l ocati on for the
popul ati on. Thi s i s not rel ated to the geometry constant pi ( = 3.14159K). As with other data
types, is usual l y not known but must be estimated from the sampl e. The sampl e ratio p is the
best esti mate of . The probabi l i ty of bi nary data i s provi ded by the bi nomial di stri buti on functi on.
Since the population is not general l y known, the experimenter usual ly wi shes to esti mate by the
sampl e ratio p and to speci fy wi th what confi dence is known. If the sample i s suffici ently l arge
(n p 5; n (1 - p) 5), advantage is taken of the central l imit theorem to derive a standard
error anal ogous to that deri ved for i nterval data:

Thi s sampl e standard error i s exactly analogous to the sampl e standard error of the mean for
interval data, except that i t i s

a standard error of the proportion. Just as a 95% confidence l i mi t of the mean was cal culated, so
may a confi dence li mit on the proportion may be obtai ned. Larger sampl es and rates cl oser to 0.5
wil l make the confi dence intervals more and more preci se.
I nf er ent i al St at i st i cs
There are two major areas of stati sti cal i nference: the esti mati on of parameters and the testi ng of
hypotheses. The use of the SE to create confidence intervals i s an exampl e of parameter
estimati on. The testi ng of hypotheses or si gni fi cance testing i s the mai n focus of i nferenti al
stati sti cs. Hypothesi s testing al l ows the experimenter to use data from the sample to make
inferences about the population. Statistici ans have created formul as that use the val ues of the
sampl es to cal cul ate test stati sti cs. Stati sti cians have al so explored the properti es of vari ous
theoreti cal probabi l i ty di stri butions. Dependi ng on the assumpti ons about how data are col l ected,
the appropri ate probabi l i ty di stri buti on i s chosen as the source of criti cal values to accept or
reject the null hypothesi s. If the val ue of the test stati sti c cal cul ated from the sampl e(s) i s
greater than the criti cal value, the nul l hypothesis i s rejected. The criti cal value i s chosen from
the appropri ate probabi l i ty di stributi on after the magni tude of the type I error i s specified.
There are parameters wi thi n the equati on that generate any particular probabi li ty di stri bution; for
the normal probabi li ty di stri buti on, the parameters are and
2
. For the normal distri buti on, each
set of values for and
2
wi l l generate a di fferent shape for the bell -li ke normal curve. All
probabi l ity di stri butions contai n one or more parameters and can be pl otted as curves; these
parameters may be di screte (i nteger onl y) or conti nuous. Each val ue or combi nation of values for
P.70
these parameters wil l create a different curve for the probabi li ty di stri buti on bei ng used. Thus,
each probabi l ity distri buti on i s actual l y a famil y of probabi l ity curves. Some addi tional parameters
of theoreti cal probabil i ty di stri buti ons have been given the speci al name degrees of freedom and
are represented by the l etters m, n, p, and s.
Associ ated wi th the formul a for computi ng a test statistic i s a rule for assi gni ng integer val ues to
the one or more parameters cal l ed degrees of freedom. The number of degrees of freedom and the
val ue for each degree of freedom depend on (1) the number of subjects, (2) the number of
experi mental groups, (3) the speci fi cs of the stati sti cal hypothesi s, and (4) the type of stati sti cal
test. The correct curve of the probabi li ty di stribution from whi ch to obtai n a cri tical value for
compari son wi th the val ue of the test statistic is obtai ned with the val ues of one or more degrees
of freedom.
To accept or reject the nul l hypothesi s, the foll owi ng steps are performed: (1) confirm that
experi mental data conform to the assumptions of the intended stati sti cal test; (2) choose a
si gni fi cance l evel (al pha); (3) cal cul ate the test statistic; (4) determine the degree(s) of freedom;
(5) fi nd the cri ti cal val ue for the chosen al pha and the degree(s) of freedom from the appropri ate
probabi l ity di stri bution; (6) if the test statistic exceeds the cri ti cal val ue, reject the null
hypothesi s; (7) i f the test stati sti c does not exceed the cri ti cal val ue, do not reject the nul l
hypothesi s. There are general gui deli nes that rel ate the vari abl e type and the experi mental desi gn
to the choi ce of statistical test (Tabl e 3-5).
Di chot omous Dat a
In the experiment negating the val ue of mammary artery li gati on, 5 of 8 pati ents (62.5%) havi ng
li gati on showed benefit whi le 5 of 9 pati ents (55.6%) havi ng sham surgery al so had benefi t.
1
Is
thi s di fference real ? Thi s experi ment sampl ed patients from two populationsthose havi ng the real
procedure and those havi ng the sham procedure; the di spl ay of such resul ts is usual l y presented
as a conti ngency tabl e (Tabl e 3-6). A vari ety of statistical techniques al l ow a comparison of the
success rate. These incl ude Fi shers exact test and (Pearson' s) chi -square test. The chi -square test
offers the advantage of bei ng computational ly simpler; it can al so anal yze conti ngency tabl es with
more than two rows and two col umns; however, certai n assumpti ons of sample si ze and response
rate are not achi eved by thi s experiment. Fishers exact test fai l s to reject the nul l hypothesis for
this data.
TABLE 3-5 When to Use What
VARIABLE
TYPE
ONE-SAMPLE
TESTS
TWO-SAMPLE TESTS MULTIPLE-SAMPLE
TESTS
Dichotomous
or nomi nal
Binomial
di stri bution
chi-square test,
Fi sher' s Exact test
chi-square test
Ordinal chi -square test chi-square test,
nonparametri c tests
chi-square test,
Conti nuous or
di screte
z di stri buti on
or t
di stri bution
Unpai red t test,
pai red t test,
Analysi s of vari ance,
nonparametri c anal ysi s
of vari ance
TABLE 3-6 Mammary Artery Ligation for Angina Pectoris
The results of such experi ments are often presented as rate ratios. The rati o of improvement for
the experi mental group (62.5%) i s di vi ded by the ratio of i mprovement for the control group
(55.6%). A rate rati o of 1.00 (100%) fail s to show a di fference of benefit or harm between the
two groups. In thi s exampl e the rate ratio i s 1.125. Thus the experi mental group had a 112.5%
chance of i mprovement compared to the control group. A confi dence interval can be cal cul ated for
the rate rati o; in thi s exampl e it i s wi dely spread to ei ther si de of the 1a confi dence i nterval of
no difference.
I nt er val Dat a
Parametric stati sti cs are the usual choi ce i n the anal ysi s of interval data, both di screte and
conti nuous. The purpose of such analysi s i s to test the hypothesi s of a difference between
popul ati on means. The popul ati on means are unknown and are estimated by the sample means. A
typi cal example would be

the comparison of the mean heart rates of pati ents receiving and not recei vi ng atropine.
Parametric test stati sti cs have been devel oped by usi ng the properti es of the normal probabi li ty
di stri buti on and two rel ated probabi li ty di stributi ons, the t and the F di stri buti ons. In usi ng such
parametric methods, the assumpti on i s made that the sample or samples i s/are drawn from
popul ati on(s) with a normal di stributi on. The parametri c test stati sti cs that have been created for
interval data al l have the form of a rati o. In general terms, the numerator of thi s rati o i s the
vari abi l ity of the means of the sampl es; the denomi nator of thi s rati o i s the vari abi l i ty among all
the members of the samples. These vari abi l iti es are si mi l ar to the vari ances devel oped for
descri ptive stati sti cs. The test statistic i s thus a rati o of vari abi l iti es or vari ances. All parametri c
test stati sti cs are used i n the same fashi on; i f the test stati sti c ratio becomes large, the null
hypothesi s of no di fference i s rejected. The cri tical values against whi ch to compare the test
stati sti c are taken from tabl es of the three rel evant probabi l i ty distri buti ons. By defi ni ti on, i n
hypothesi s testi ng, at l east one of the popul ati on means i s unknown, but the popul ati on vari ance
(s) may or may not be known. Parametri c stati stics can be di vi ded i nto two groups accordi ng to
whether or not the population vari ances are known. If the popul ati on variance i s known, the test
stati sti c used i s call ed the z score; cri tical val ues are obtai ned from the normal di stri buti on. In
most bi omedi cal appl i cati ons, the population vari ance is rarely known and the z score i s li ttl e
used.
T TEST
An i mportant advance in statistical inference came earl y in the twentieth century wi th the creation
of Student's t test stati sti c and the t di stri buti on, which allowed the testing of hypotheses when
the population vari ance is not known. The most common use of Student's t test i s to compare the
TREATMENT
OUTCOMES ACTUAL LIGATION SHAM LIGATION
Improved 5 (62.5%) 5 (55.6%)
Not improved 3 (37.5%) 4 (44.4%)
Fi shers exact test: p >> 0.05.
Rate Ratio = 62.5%/55.6% = 1.125, 95% Confi dence Interval (0.47 to 2.7); p >> 0.05.
P.71
mean values of two popul ati ons. There are two types of t test. If each subject has two
measurements taken, for exampl e, one before (x
i
) and one after a drug (y
i
), then a one sampl e or
pai red t test procedure is used; each control measurement taken before drug admi nistrati on i s
pai red with a measurement in the same pati ent after drug admi ni strati on. Of course, this i s a sel f-
control experi ment. Thi s pai ring of measurements i n the same pati ent reduces vari abi l i ty and
increases stati sti cal power. The di fference d
i
= x
i
- y
i
of each pai r of values is calcul ated and the
average

is cal cul ated. In the formul a for Student' s t stati sti c, the numerator is

, whereas the denomi nator is the standard error of

(SE

):

Al l t stati sti cs are created i n this way; the numerator i s the di fference of two means, whereas the
denominator is the standard error of the two means. If the difference between the two means i s
large compared with their variabi li ty, then the null hypothesis of no difference is rejected. The
criti cal val ues for the t stati sti c are taken from the t probabi l i ty distri buti on. The t di stri buti on i s
symmetri c and bel l -shaped but more spread out than the normal distri buti on. The t di stri buti on
has a si ngl e i nteger parameter; for a pai red t test, the val ue of thi s singl e degree of freedom i s
the sampl e si ze minus one. There can be some confusi on about the use of the l etter t. It refers
both to the val ue of the test stati sti c cal cul ated by the formul a and to the criti cal value from the
theoreti cal probabi l ity distri buti on. The criti cal t value i s determi ned by l ooki ng i n a t tabl e after a
si gni fi cance l evel i s chosen and the degree of freedom i s computed.
More commonly, measurements are taken on two separate groups of subjects. For example, one
group recei ves bl ood pressure treatment (x
i
), whereas no treatment i s gi ven to a control group
(y
i
). The number of subjects i n each group mi ght or mi ght not be i denti cal ; regardl ess of this, in
no sense is an indi vi dual measurement in the fi rst group matched or pai red with a specific
measurement in the second group. An unpai red or two-sampl e t test is used to compare the means
of the two groups. The numerator of the t stati sti c i s

-

. The denomi nator i s a weighted average of the SEs of each sampl e. The degree of freedom for an
unpai red t test i s calculated as the sum of the subjects of the two groups minus two. As wi th the
pai red t test, i f the t ratio becomes l arge, the null hypothesi s is rejected.
Mul t i pl e Compar i sons and Anal ysi s of Var i ance
Experiments in anesthesi a, whether they are wi th humans or wi th ani mals, may not be l imited to
one or two groups of data for each vari able. It is very common to fol l ow a vari abl e l ongi tudinal l y;
heart rate, for example, mi ght be measured fi ve ti mes before and duri ng anestheti c i nducti on.
These are al so cal led repeated measurement experiments; the experi menter wi ll wish to compare
changes between the i ni ti al heart rate measurement and those obtained during i nducti on. The
experi mental desi gn mi ght al so i nclude several groups receiving di fferent i nducti on drugs, for
exampl e, compari ng heart rate across groups i mmediatel y after l aryngoscopy. Researchers have
mi stakenl y handl ed these anal ysi s problems wi th the t test. If heart rate i s collected five times,
these coll ecti on times coul d be l abel ed A, B, C, D, and E. Then A coul d be compared wi th B, C, D,
and E; B coul d be compared wi th C, D, and E; and so forth. The total of possi bl e pai rings is ten;
thus, ten pai red t tests coul d be cal cul ated for al l the possi ble pai ri ngs of A, B, C, D, and E. A
si mi l ar approach can be used for comparing more than two groups for unpai red data.
The use of t tests in thi s fashion is inappropri ate. In testi ng a stati sti cal hypothesi s, the
experi menter sets the level of type I error; this i s usual ly chosen to be 0.05. When usi ng many t
tests, as i n the example gi ven earl ier, the chosen error rate for performi ng al l these t tests is
much hi gher than 0.05, even though the type I error i s set at 0.05 for each i ndi vi dual compari son.
In fact, the type I error rate for al l t tests si multaneously, that is, the chance of fi ndi ng at l east
one of the multi ple t test

stati sti cs si gni fi cant merel y by chance, i s given by the formul a = 1 - 0.95
k
. If 13 t tests are
performed (k = 13), the real error rate is 49%. Appl yi ng t tests over and over agai n to all the
possi bl e pai rings of a vari abl e wil l mi sleadingl y i dentify stati stical si gnifi cance when there is, i n
fact, none.
The most versati l e approach for handli ng compari sons of means between more than two groups or
between several measurements i n the same group is call ed anal ysis of variance and is frequently
cited by the acronym ANOVA. Anal ysi s of vari ance consi sts of rul es for creati ng test stati sti cs on
means when there are more than two groups. These test stati sti cs are cal l ed F rati os, after Ronal d
Fi sher; the criti cal values for the F test stati sti c are taken from the F probabi l i ty di stri buti on that
Fi sher deri ved.
Suppose that data for three groups are obtained. What can be sai d about the mean val ues of the
three target popul ati ons? The F test i s actual l y aski ng several questions si multaneously: is group
1 different from group 2; i s group 2 di fferent from group 3; and i s group 1 di fferent from group 3?
As with the t test, the F test stati sti c i s a rati o; i n general terms, the numerator expresses the
vari abi l ity of the mean val ues of the three groups, whereas the denomi nator expresses the
average vari abi l ity or di fference of each sampl e val ue from the mean of al l sampl e val ues. The
formulas to create the test stati sti c are computati onal l y el egant but are rather hard to appreci ate
intuiti vel y. The F stati sti c has two degrees of freedom, denoted m and n; the val ue of m is a
function of the number of experi mental groups; the val ue for n is a function of the number of
subjects i n al l experi mental groups. The anal ysi s of multi group data i s not necessaril y fi ni shed
after the ANOVAs are cal culated. If the nul l hypothesis i s rejected and i t is accepted that there are
di fferences among the groups tested, how can i t be deci ded where the di fferences are? A vari ety
of techni ques are avail able to make what are cal led mul tipl e compari sons after the ANOVA test is
performed.
Robust ness and Nonpar amet r i c Test s
Most stati sti cal tests depend on certain assumptions about the nature of the di stri buti on of val ues
i n the underl yi ng popul ations from whi ch experi mental samples are taken. For the parametri c
stati sti cs, that i s, t tests and anal ysi s of vari ance, i t is assumed that the populations fol low the
normal di stributi on. However, for some data, experience or historical reasons suggest that these
assumpti ons of a normal di stributi on do not hold; some exampl es include proportions,
percentages, and response ti mes. What should the experi menter do i f he or she fears that the
data are not normal l y di stributed?
The experimenter might choose to i gnore the probl em of nonnormal data and i nhomogenei ty of
vari ance, hoping that everythi ng wi l l work out. Such insouci ance is actual l y a very practi cal and
reasonable approach to the probl em. Parametri c stati sti cs are cal led robust stati sti cs; they stand
up to much adversity. To a stati sti ci an, robustness i mpl i es that the magnitude of type I errors is
not seri ousl y affected by i ll -condi ti oned data. Parametric stati sti cs are suffici ently robust that the
accuracy of deci si ons reached by means of t tests and anal ysi s of vari ance remai ns very credibl e,
even for moderatel y severe departures from the assumpti ons.
Another possi bi li ty woul d be to use statistics that do not requi re any assumptions about
probabi l ity di stri butions of the popul ati ons. Such stati sti cs are known as nonparametri c tests; they
can be used whenever there is very serious concern about the shape of the data. Nonparametric
stati sti cs are al so the tests of choi ce for ordi nal data. The basi c concept behi nd nonparametri c
stati sti cs i s the abil i ty to rank or order the observati ons; nonparametri c tests are al so cal led order
stati sti cs.
Most nonparametri c stati sti cs sti ll requi re the use of theoretical probabi l ity distri buti ons; the
criti cal val ues that must be exceeded by the test stati sti c are taken from the binomial , normal,
and chi -square di stri buti ons, dependi ng on the nonparametri c test bei ng used. The nonparametri c
P.72
si gn test, Mann-Whi tney rank sum test, and Kruskal -Wal l is one-way anal ysi s of vari ance are
anal ogous to the paired t test, unpai red t test, and one-way analysi s of vari ance, respecti vel y.
The currentl y avail able nonparametri c tests are not used more commonly because they do not
adapt well to compl ex stati sti cal model s and because they are l ess able than parametri c tests to
di sti ngui sh between the nul l and al ternati ve hypotheses if the data are, in fact, normal l y
di stri buted.
I nt er pr et at i on of Resul t s
Sci enti fi c studi es do not end wi th the stati sti cal test. The experi menter must submi t an opi nion as
to the generali zabil i ty of his or her work to the rest of the worl d. Even i f there i s a stati sti cal l y
si gni fi cant difference, the experi menter must deci de i f thi s difference is medi cal l y or
physi ol ogi cal l y i mportant. Stati sti cal significance does not al ways equate with biol ogi c rel evance.
The questions an experi menter shoul d ask about the interpretati on of results are highl y dependent
on the speci fi cs of the experi ment. Fi rst, even smal l, cl i ni cal ly uni mportant differences between
groups can be detected if the sample si ze i s suffici ently l arge. On the other hand, if the sample
si ze i s small , one must always worry that i denti fi ed or uni dentified confoundi ng vari abl es may
explai n any di fference; as the sample si ze decreases, randomi zation is l ess successful in assuri ng
homogenous groups. Second, i f the experi mental groups are gi ven three or more doses of a drug,
do the resul ts suggest a steadi ly i ncreasi ng or decreasi ng dose-response rel ationship? Suppose
the observed effect for an intermedi ate dose i s ei ther much hi gher or much l ower than that for
both the hi ghest and l owest dose; a dose-response rel ationship may exi st, but some skepti ci sm
about the experimental methods i s warranted. Thi rd, for cl ini cal studies compari ng di fferent drugs,
devices, and operati ons on pati ent outcome, are the pati ents, cl i ni cal care, and studi ed therapi es
suffi ci entl y si mi l ar to those provi ded at other l ocati ons to be of i nterest to a wi de group of
practi ti oners? Thi s is the di sti ncti on between effi cacydoes i t work under the best (research)
ci rcumstancesand effecti venessdoes i t work under the typical ci rcumstances of routi ne cl ini cal
care. Fi nal ly, i n compari ng al ternative therapi es, the confidence that a clai m for a superi or
therapy i s true depends on the study desi gn. The strength of the evi dence concerni ng effi cacy wil l
be least for an anecdotal case report; next i n i mportance wi l l be a retrospective study, then a
prospecti ve series of pati ents compared wi th hi stori cal controls, and fi nall y a randomi zed,
control led cl ini cal tri al . The greatest strength for a therapeuti c cl ai m i s a seri es of randomized,
control led cl i ni cal tri als confi rmi ng the same hypothesi s. There i s now consi derabl e enthusi asm for
the formal synthesi s and combining of resul ts from two or more tri al s.
READING JOURNAL ARTICLES
Thousands of words are wri tten each year i n journal arti cl es rel evant to anesthesia. No one can
read them al l. How shoul d the cl ini ci an determi ne whi ch arti cl es are useful? Al l that i s possi ble i s
to l earn to rapi dly skip over most articl es and concentrate on the few selected for thei r importance
to the reader. Those few should be chosen according to thei r rel evance and credi bil i ty. Relevance
is determi ned by the specifics of one' s anestheti c practi ce. Credi bi li ty i s a functi on of the meri ts of
the research methods, the experi mental desi gn, and the stati sti cal

anal ysi s; the more profi cient one' s stati sti cal ski l ls, the more rapi dl y one can accept or reject the
credibi l ity of a research arti cl e.
Gui del i nes
Six easi ly remembered apprai sal cri teri a for cl ini cal studi es can be fashi oned from the words WHY,
HOW, WHO, WHAT, HOW MANY, and SO WHAT: (1) WHY: Is the biologi c hypothesis cl early stated?
(2) HOW: What i s the research desi gn? (3) WHO: Is the target popul ati on cl earl y defi ned? (4)
WHAT: How was the therapy admini stered and the data col l ected? (5) HOW MANY: Are the test
stati sti cs convincing? (6) SO WHAT: Is i t cl i ni cal l y relevant to my pati ents? Al though the
stati sti cal knowledge of most physi cians i s l imited, these ski ll s of cri tical apprai sal of the
l i terature can be l earned and can tremendousl y increase the efficiency and benefit of journal
reading.
P.73
Resources i n journal readi ng, pri nt and el ectronic, are now wi del y avai l abl e. For exampl e, The
Evi denced-Based Medi ci ne Worki ng Groupa group of mainl y Canadi an physi ci ans and stati sti cians
from McMaster Uni versity, Ontario, Canadahas been organi zed to de-emphasi ze a foundati on of
unsystemati c cli ni cal experi ence, cl inical intui ti on, and pathophysi ol ogic rati onal e as the basi s for
medical deci sion and to teach the systemati c evaluati on of publ i shed evi dence. Now combi ned i n a
si ngl e vol ume, detai led topics range from How to Use an Arti cl e about Therapy or Prevention to
How to Use an Arti cl e about Disease Probabi l ity for Di fferenti al Di agnosi s.
5
Thi s materi al i s al so
avai labl e interacti vely (http://www.ugi .usersgui des.org/UGI/defaul t.asp accessed 30-JUL-2004).
St at i st i cal Resour ces
Accompanyi ng the exponenti al growth of medi cal i nformati on si nce World War II has been the
creati on of a wealth of biostati sti cal knowl edge. Textbooks wi th exposi ti ons of basi c, intermedi ate,
and advanced stati sti cs abound.
6, 7, 8
There are new journals of bi omedi cal stati sti cs, including
Cli nical Tri als, Stati sti cs i n Medici ne, and Stati sti cal Methods i n Medi cal Research, whose
audiences are both statistici ans and biomedi cal researchers. Some medi cal journal s, for example,
the Bri tish Medical Journal , regul arl y publ i sh exposi ti ons of both basi c and newer advanced
stati sti cal methods. Extensi ve Internet resources can be linked from the home page of the long
establ i shed American Stati sti cal Associ ati on (http://0-www.amstat.org.i nnopac.up.ac.za:80/
accessed 30-JUL-2004) and at the StatLi b (http://0-www.lib.stat.cmu.edu.innopac.up.ac.za:80/
accessed 30-JUL-2004) of Carnegie Mel l on University including el ectroni c textbooks of basi c
stati sti cal methods, onl ine stati sti cal calcul ators, standard data sets, revi ews of stati sti cal
software, and so on.
Exampl e of Newer St at i st i cs
Reports usi ng a new type of research methodthe systematic revi ewhave become
commonplace over the l ast 15 years in anesthesi a journals. (As of Jul y 2004, a l iterature
search for systemati c review AND anesthesi a in PubMed at the Nati onal Li brary of Medi ci ne
returned 695 citati ons out of a total of 82,484 citati ons for systemati c revi ews [http://0-
www.ncbi.nlm.nih.gov.innopac.up.ac.za:80/entrez accessed 15-JUL-2004].) In systemati c revi ews,
a focused question dri ves the research, for exampl e, (1) Transient neurologic symptoms (TNS)
fol l owing spi nal anaesthesi a with li docai ne versus other l ocal anaesthetic
9
or (2) Venti l ati on wi th
lower ti dal vol umes versus tradi ti onal ti dal vol umes i n adul ts for acute lung i njury and acute
respiratory distress syndrome.
10
These ti tles reveal some of the research desi gn of a systemati c
revi ew. There i s a popul ation of interest: (1) pati ents havi ng spi nal anesthesi a and (2) adults
[wi th] acute l ung injury and acute respi ratory distress syndrome. There is an interventi on versus a
compari son group: (1) li docaine versus other l ocal anaesthetics and (2) ventil ati on wi th l ower
ti dal vol umes versus tradi tional ti dal vol umes. There is an outcome for choosing success or
fai l ure: (1) occurrence of transi ent neurologic symptoms (TNS) and (2) 28-day mortali ty (l i sted i n
text).
To answer the experimental questi on, data are obtai ned from randomi zed control led trial s al ready
in the medi cal l i terature rather than from direct experi mentati on; the basi c uni t of anal ysi s of this
observational research i s the publi shed study. The researchers, al so call ed the revi ewers, proceed
through a structured protocol , which includes i n part: (1) choice of study i ncl usion/excl usion
criteri a, (2) expli citl y defi ned li terature searchi ng, (3) abstraction of data from included studi es,
(4) appraisal of data quali ty, (5) systemati c pool i ng of data, and (6) discussion of inferences.
Bi nary outcomes (yes/no, al ive/dead, presence/absence) wi thi n a study are usuall y compared by
the rel ati ve risk (rate rati o) statistic. If there i s suffi cient cl i ni cal si mi lari ty among the i ncluded
studi es, a summary relative ri sk of the overall effect of the compari son treatments i s esti mated by
meta-anal ysi s; meta-anal ysi s i s a set of stati sti cal techni ques for combi ni ng resul ts from different
studi es. The calcul ati ons for the stati sti cal anal yses of a meta-anal ysi s are unfami li ar to most, but
are not diffi cult. The resul ts of a meta-anal ysi s are usual ly present i n a figure call ed a forest pl ot
(see Fi g 3-1).
9
The l eft-most col umn identi fi es the i ncl uded studi es and the observed data. The
hori zontal l i nes and diamond shapes are graphi cal representations of i ndi vi dual study rel ati ve ri sk
and summary rel ati ve ri sk, respectively; the ri ght-most col umn of the fi gure li sts the rel ati ve risks
wi th 95% Confi dence Interval s for the i ndi vidual studi es and the summary statistics. There are
al so descri pti ve and inferential stati sti cs concerni ng the stati sti cal heterogenei ty of the meta-
anal ysi s and the si gnifi cance of the summary stati sti cs.
An examination of Figure 3-1 shows that many of the i ndi vi dual studi es (8 of 12) had wi de,
nonsignificant confi dence interval s that touch or cross the rel ati ve ri sk of i dentity (RR = 1). In
this systematic revi ew of TNS there were three subgroup compari sons: spi nal l i docai ne versus
bupi vacai ne, pri l ocai ne, and procaine; for each subgroup the rel ative ri sk of TNS was 6 to 7 ti mes
hi gher for l i docaine and the overal l rel ati ve ri sk cal cul ated from all studi es was 7.13 with a 95%
Confi dence Interval [3.92, 12.95]. The power of summary statistics to combi ne evidence i s clear.
The revi ewers concl uded: Lidocai ne can cause transient neurologic symptoms (TNS) in every
seventh pati ent who receives spi nal anaesthesia. The rel ati ve ri sk of developi ng TNS i s about
seven times hi gher for l i docaine than for bupi vacai ne, pri l ocaine, and procaine. These painful
symptoms di sappear compl etel y by the tenth postoperati ve day.
9

The promotion of systematic revi ews comes from several sources. Many come from the i ndi vi dual
initi ati ve of researchers who publi sh thei r resul ts as stand al one reports i n the journals of
medici ne and anesthesi a. The American Society of Anesthesi ol ogists has devel oped a process for
the creati on of practi ce parameters that i ncl udes among other things a vari ant form of systematic
revi ews. The most prominent proponent of systemati c reviews i s the Cochrane Col l aboration,
Oxford, UK. The Cochrane Coll aborati on i s an international non-profi t and independent
organizati on, dedicated to maki ng up-to-date, accurate i nformati on about the effects of health
care readi l y avai l abl e worl dwi de. It produces and di ssemi nates systemati c reviews of health care
i nterventi ons and promotes the search

for evi dence i n the form of cli ni cal tri als and other studi es of interventi ons. The Cochrane
Col l aboration was founded i n 1993 and named for the Bri tish epi demi ologi st, Archi e
FIGURE 3-1. Forest pl ot modi fi ed from Graph 02/01 i n Zari c D, Chri sti ansen C, Pace NL,
Punjasawadwong Y. Transi ent neurologi c symptoms (TNS) foll owi ng spi nal anaesthesi a wi th
li docaine versus other l ocal anaestheti cs (Cochrane Revi ew). In: The Cochrane Li brary, Issue
3. Chi chester, UK: John Wi l ey & Sons, Ltd., 2004. Copyri ght Cochrane Li brary, reproduced
with permission.
P.74
Cochrane (http://www.cochrane.org, accessed Jul y 31, 2004).
There are more than 50 col laborati ve revi ew groups that provide the editori al control and
supervi sion of systematic revi ews; one of these, l ocated in Copenhagen, prepares and maintai ns
the accessi bil i ty of systematic revi ews of the effects of health care i nterventi ons in the areas of
anesthesia, peri operati ve medi ci ne, i ntensi ve care medi cine, and so on (http://www.cochrane-
anaesthesi a.sui te.dk, accessed Jul y 31, 2004). The Cochrane Col l aboration has extensi ve
documentation avai l abl e electroni cal ly expl ai ning the techni ques of systemati c revi ews and meta-
anal ysi s. Introductory textbooks of biostati sti cs now i ncl ude expositi ons on systemati c revi ews
al so.
5

CONCLUSION
One intent of thi s chapter i s to present the scope of support that the di sci pli ne of stati sti cs can
provi de to anesthesi a research. Although an intui ti ve understandi ng of certai n basi c pri nci pl es i s
emphasized, these basic pri nci ples are not necessari l y si mpl e and have been devel oped by
stati sti ci ans wi th great mathematical ri gor. Academi c anesthesia needs more workers to immerse
themsel ves i n these stati sti cal fundamentals. Havi ng done so, these stati sti cal l y knowledgeable
academic anesthesiologi sts wi l l be prepared to improve thei r own research projects, to assist thei r
col l eagues i n research, to effi cientl y seek consul tation from the professional stati sti cian, to
strengthen the edi tori al revi ew of journal arti cl es, and to expound to the cli nical reader the whys
and wherefores of statistics. The cl i ni cal reader al so needs to expend hi s or her own effort to
acqui re some basic statistical skil l s. Journal s are increasi ngl y difficult to understand wi thout some
basic stati sti cal understandi ng. Some cli nical probl ems can be best understood wi th a perspecti ve
based on probabi l i ty. Fi nal l y, understandi ng pri nci pl es of experi mental desi gn can prevent
premature acceptances of new therapies from faulty studi es.
References
1. Cobb LA, Thomas GI, Di l l ard DH, Merendi no KA, Bruce RA: An eval uati on of internal -
mammary-artery l i gati on by a doubl e-bl i nd technic. N Engl J Med 260:11151118,1959
2. Sacks H, Chal mers TC, Smith HJ: Randomi zed versus hi stori cal controls for cli ni cal tri als.
Am J Med 72:233240,1982
3. Schulz KF, Chalmers I, Hayes RJ, Altman DG: Empi rical evi dence of bias. Di mensi ons of
methodol ogi cal qual i ty associ ated wi th esti mates of treatment effects i n control led trial s.
JAMA 273:408412, 1995
4. Freiman JA, Chalmers TC, Smi th HJ, Kuebl er RR: The importance of beta, the type II error
and sampl e si ze i n the desi gn and interpretati on of the randomi zed control trial . Survey of 71
negati ve trial s. N Engl J Med 299:690694, 1978

5. Rennie D, Guyatt G: Users Guides Manual for Evidence-Based clinical Practice.
Chicago, AMA Press, 2002
6. Altman DG, Trevor B, Gardner MJ, Machin D: Statistics with Confidence. London,
BMJ Books, 2000
7. Dawson B, Trapp R: Basic & Clinical Biostatistics. New York, McGraw-Hill/Appleton
& Lange, 2004
P.75
8. Glantz S: Primer of Biostatistics. New York, McGraw-Hill/Appleton & Lange, 2001
9. Zaric D, Christiansen C, Pace NL, Punjasawadwong Y: Transient neurologi c symptoms (TNS)
fol l owing spinal anaesthesi a wi th l idocai ne versus other l ocal anaestheti cs (Cochrane Revi ew),
In: The Cochrane Library. Chi chester, UK, John Wil ey & Sons, Ltd, Issue 3, 2004
10. Petrucci N, Iacovel li W: Venti lation wi th l ower ti dal vol umes versus traditi onal tidal
vol umes in adul ts for acute lung i njury and acute respi ratory distress syndrome (Cochrane
Revi ew), In: The Cochrane Library. Chi chester, UK, John Wi ley & Sons, Ltd, Issue 3, 2004
Title: Clinical Anesthesia, 5th Edition
> Tabl e of Contents > Secti on I - Introducti on to Anesthesi a Practi ce > Chapter 4 - Occupati onal Heal th
Chapter 4
Occupational Health
Arnold J. Berry
Jonathan D. Katz
KEY POINTS
Wi th the use of scavengi ng equi pment, routine machine maintenance, and
appropri ate work practi ces, exposure to waste anestheti c gases can be reduced
to l evel s bel ow those recommended by National Insti tute for Occupational
Safety and Health (NIOSH).
Twenty-four percent of anesthesi a personnel manifest evi dence of contact
dermatiti s in response to l atex exposure and approximatel y 15% are sensi ti zed
and vulnerable to all ergi c reacti ons.
Vigi l ance i s one of the most cri tical tasks performed by anesthesiologi sts. The
vigi l ance task i s adversely affected by several factors including poor equi pment
engi neeri ng and desi gn, excessi ve noi se i n the operati ng room, i mpedi ments to
interpersonal communicati on, producti on pressure, and fati gue.
Sl eep depri vati on and fatigue are common among anesthesi ol ogi sts. Sleep
depri vati on can have del eteri ous effects on cogni ti on, performance, mood, and
heal th.
The risk of exposure to infecti ous pathogens can be reduced by the routi ne use
of standard precautions, appropri ate isolation precauti ons for infected patients,
and safety devi ces desi gned to prevent needl esti ck i njuri es.
Hepati ti s B vaccine i s recommended for all anesthesia personnel because of the
increased risk for occupational transmi ssi on of thi s bl oodborne pathogen.
Many consi der chemi cal dependency to be the pri mary occupati onal hazard
among anesthesi ol ogists. An i nci dence of 1 to 2% of control l ed substance abuse
has been repeatedl y reported wi thi n anesthesi a trai ni ng programs.
It remains controversi al whether anesthesi ol ogists are, on average, vul nerabl e
to premature death. However, by correcti ng for the fact that l i vi ng
anesthesiol ogi sts are, on average, younger than most other special ists, it i s
Anesthesi a personnel spend l ong hours, i n fact, most of their waki ng days, i n an environment fil l ed
with many potenti al hazardsthe operati ng room. This setti ng i s uni que among workpl aces as a
resul t of the potenti al exposure to chemi cal vapors, i onizing radi ati on, and infecti ous agents.
Additi onal l y, anesthesi a personnel are subject to hei ghtened l evel s of psychol ogical stress
engendered by the hi gh-stakes nature of the practi ce. Al though such physi cal hazards as fi res and
explosions from flammabl e anestheti c agents are currently of l imited concern, occupati onal
il l nesses, such as alcohol and drug abuse, are well recogni zed as signi ficant wi thi n the anesthesi a
communi ty. Some hazards, such as exposure to trace levels of waste anesthetic gases, have been
extensi vel y studi ed. Others, l i ke sui ci de, have been recogni zed but not adequatel y pursued. Onl y
wi thi n the past few decades have epi demi ol ogic surveys been conducted to assess the heal th of
anesthesia personnel. In general , the potenti al heal th ri sks to those worki ng i n the operati ng room
may be si gnifi cant, but wi th awareness of the problems and the use of proper precautions, they
are not formi dable.
PHYSICAL HAZARDS
Anesthetic Gases
Although the i nhal ati on anesthetics diethyl ether, ni trous oxide, and chl oroform were first used in
the 1840s, the bi ologi c effects of occupati onal exposure to anesthetic agents were not investi gated
unti l the 1960s. Reports on the effects of chronic environmental exposure to anestheti cs have
incl uded epi demi ologi c surveys, in vi tro studies, cel lular research, and studi es i n l aboratory
animal s and humans. Areas addressed i ncl ude the potenti al infl uence of trace anestheti c
concentrations on the

i nci dence i n affected popul ati ons of the foll owing: death, inferti l ity, spontaneous aborti on,
congeni tal mal formati ons, cancer, hematopoieti c di seases, l i ver di sease, neurol ogi c disease,
psychomotor, and behavi oral changes.
Anesthetic Levels in the Operating Room
Earl y i nvesti gators establi shed that si gnificant l evels of ether were present i n the operating room
when the open drop technique was used, but the fi rst report of occupati onal exposure to modern
anesthetics was by Li nde and Bruce i n 1969.
1
They sampl ed air at vari ous distances from the pop-
off val ve of anesthesi a machines and noted an average concentrati on of hal othane of 10 parts per
mi l l i on (ppm) and of ni trous oxi de of 130 ppm. (Parts per mi ll i on i s a vol ume-per-vol ume uni t of
measurement; 10,000 ppm equal s 1%.) End-expired air samples taken from 24 anesthesiol ogi sts
after work reveal ed 0 to 12 ppm of hal othane. It was l ater demonstrated that wi th appropri ate
scavengi ng equipment and adequate ai r exchange i n the operati ng room, l evel s of waste
apparent that anesthesi ol ogi sts do not di e younger.
P.77
anesthetic gases coul d be si gni fi cantl y reduced.
Waste anesthetic concentrati ons i n modern operating rooms where routi ne scavenging i s
performed are consi derabl y l ess than those found i n the early studies.
2, 3
Thi s rai ses the questi ons
of whether chronic exposure to these l ow l evel s of waste anestheti c gases actual ly consti tutes a
si gni fi cant occupati onal hazard and whether resul ts from studi es performed i n unscavenged
operating rooms are appl icable to current practice.
Epidemiologic Studies
Epi demi ol ogi c surveys were among the first studi es to suggest the possibi l ity of a hazard resul ti ng
from exposure to trace l evel s of anesthetics. Al though epi demi ol ogic studi es may be useful in
assessing probl ems of thi s type, they have the potenti al for errors associ ated wi th the col lection
of data and their i nterpretation. Val i d epi demi ol ogi c studi es requi re appropri ate desi gn strategi es
i ncl udi ng the presence of an appropri ate control group for the cohort bei ng studi ed. When
questi onnai res are used to obtain personal medi cal informati on, the data may be mi sl eadi ng
because i ndi vi dual s may knowi ngly or unknowingly give incorrect information based sol el y on
remembered data. Cause-and-effect relationships or causal i ty cannot be documented by
epi demi ologi c studi es unless al l other possi bl e eti ol ogies (confounders) can be ruled out or other
li nes of evi dence are used for substanti ati on. Few epidemiol ogi c studi es on the effects of
occupati onal exposure to waste anestheti c gases ful fi l l these desi gn criteri a.
Reproductive Outcome. One of the l argest epidemiol ogi c studi es to assess the effects of trace
anesthetics on reproducti ve outcome was conducted by the Ameri can Soci ety of Anesthesiol ogi sts
(ASA).
4
Questi onnaires were sent to 49,585 operati ng room personnel who had potenti al exposure
to waste anestheti c gases (members of the ASA, the Ameri can Association of Nurse Anestheti sts,
the Associ ati on of Operati ng Room Nurses, and the Associ ati on of Operating Room Techni ci ans). A
nonexposed group of 23,911 from the Ameri can Academy of Pedi atrics and the American Nurses'
Associ ati on served as controls. Anal yses of these data indicated that there was an i ncreased ri sk
of spontaneous aborti on and congenital abnormali ties i n chi ldren of women who worked in the
operati ng room and an i ncreased risk of congenital abnormali ties i n offspring of unexposed wi ves
of male operating room personnel. Several reviews have i dentified inconsi stenci es in the data used
to compare exposed and unexposed groups and to make wi thi n-group compari sons. Expected
level s of anestheti c exposure di d not correl ate wi th reproductive outcome.
The ASA subsequentl y commi ssi oned a group of epi demi ol ogi sts and bi ostatisti ci ans to eval uate
and assess confl i cti ng data from publ i shed epi demiol ogi c surveys.
5
After anal ysis of methods, they
found onl y fi ve studi es on spontaneous aborti on and congeni tal abnormal iti es i n offspri ng of
anesthesia personnel that were free of errors i n study design or stati sti cal anal ysi s. From these
studi es, the rel ati ve ri sks (the rati o of the rate of di sease among those exposed to that found i n
those not exposed) of spontaneous abortion for femal e physi ci ans and femal e nurses worki ng in
the operati ng room were 1.4 and 1.3, respecti vel y (a rel ati ve ri sk of 1.3 represents a 30%
increase i n ri sk when compared wi th the ri sk of the control popul ati on). The i ncreased rel ati ve risk
for congeni tal abnormal i ti es was of borderl i ne statistical si gni fi cance for exposed physi cians onl y.
Although they found a stati sti cal ly significant rel ati ve ri sk of spontaneous abortion and congenital
abnormali ties i n women worki ng i n the operati ng room, the relative ri sk was small compared with
other, better-documented envi ronmental hazards. They al so poi nted out that duration and level of
anesthetic exposure were not measured i n any of the studi es and that other confounding factors,
such as stress, i nfections, and radi ati on exposure, were not consi dered.
Because personnel worki ng in some dental operatories have exposure to nitrous oxi de, the dental
li terature has al so addressed these i ssues. One pertinent study used data col lected vi a tel ephone
intervi ews wi th 418 femal e dental assi stants to assess the effect of ni trous oxi de exposure on
fertil i ty.
6
Fecundabil i ty (the abi l ity to concei ve, whi ch i s measured by the time to pregnancy
duri ng peri ods of unprotected sexual intercourse) was si gni fi cantl y reduced i n women wi th 5 or
more hours of exposure to unscavenged ni trous oxi de per week. In another study of 7,000 femal e
dental assi stants, questi onnai res were used to determi ne rates of spontaneous aborti on.
7
There
was an increased rate of spontaneous aborti on among women who worked for 3 or more hours per
week i n offices not using scavenging devi ces for nitrous oxi de (rel ative ri sk [RR] = 2.6, adjusted
for age, smoki ng, and number of amal gams prepared per week). These findi ngs must be viewed
with cauti on because the esti mates of nitrous oxi de exposure were based sol ely on respondents'
reports, and measurements of ni trous oxi de concentrati ons in the work space were not performed.
Therefore, doseeffect relationships cannot be confirmed. It i s important to note that i n both
studi es of femal e dental assi stants, use of ni trous oxi de in offi ces with scavengi ng devices was not
associated wi th an increased ri sk for adverse reproducti ve outcomes.
6, 7

A meta-anal ysi s of 19 epi demi ologi c studi es, which incl uded hospi tal workers, dental assi stants,
and veteri nari ans and veterinary assistants, demonstrated an i ncreased ri sk of spontaneous
aborti on in women wi th occupati onal exposure to anesthetic gases (RR = 1.48; 95% confi dence
interval, 1.40 to 1.58).
8
Additi onal anal ysis demonstrated that the rel ati ve ri sk of 1.48
corresponded to an i ncreased absolute ri sk of aborti on of 6.2%. Strati fi cation by job category
indicated that the rel ati ve ri sk was greatest for veterinari ans (RR = 2.45), fol l owed by dental
assi stants (RR = 1.89) and hospital workers (RR = 1.30). When the meta-anal ysi s was confined to
five studies that control led for several nonoccupati onal confoundi ng vari abl es, had appropri ate
control groups, and had suffici ent response rate, the rel ati ve ri sk for spontaneous aborti on was
1.90 (95% confidence interval, 1.72 to 2.09). The author noted that the routine use of scavengi ng
devices has been i mpl emented si nce the ti me that most of the studi es in thi s analysi s were
performed and that there was no ri sk of spontaneous aborti on i n studi es of personnel that worked
i n scavenged envi ronments.
Retrospective surveys of l arge numbers of women who worked duri ng pregnancy i ndi cate that
negati ve reproducti ve outcomes may be rel ated to job-associated condi tions other than exposure
to trace anesthetic gases. A survey of 3,985 Swedi sh midwives demonstrated that ni ght work was
si gni fi cantl y associ ated wi th spontaneous abortions after the twelfth week of pregnancy (OR =
3.33), whi le exposure to ni trous oxide appeared to have no effect.
9
Using a case-control

study desi gn, Luke et al
10
found that i ncreased work hours, hours worked whi l e standi ng, and
occupati onal fati gue were associ ated wi th preterm birth i n obstetric and neonatal nurses. These
and other studi es have provi ded data that li nk spontaneous abortion in women working i n heal th
care to job-rel ated factors other than exposure to trace anestheti c gases. Thi s casts doubt on the
val i dity of earl ier studies that did not control for occupati onal stresses such as fati gue, long work
hours, and ni ght shi fts.
Although many of the existing epidemiol ogi c studies have potential fl aws in desi gn, the evi dence
taken as a whol e suggests that there is a sli ght increase i n the rel ati ve ri sk of spontaneous
aborti on and congeni tal abnormal iti es i n offspri ng for femal e physi ci ans worki ng in the operati ng
room.
11
Whether these findi ngs are attributabl e to anestheti c exposure or other work-rel ated
condi ti ons cannot be defi ni tel y determi ned from thi s type of i nvesti gation. Wel l -desi gned surveys
of large numbers of personnel and appropri ate control groups, controll ed for other factors such as
work hours and ni ght shi fts, are necessary to li nk trace anestheti c exposures to adverse
reproductive outcomes. The routine use of scavengi ng techniques has general ly l owered
envi ronmental anestheti c l evel s i n the operati ng room and may make i t more di fficul t to prove any
adverse reproductive effects using epi demi ol ogi c data. Al though it i s easy to measure and quanti fy
the level s of anestheti c i n the operating room ai r, it i s harder to measure and assess the effect of
other possibl e factors, such as stress, al terati ons i n worki ng schedule, and fati gue.
Neoplasms and Other Nonreproductive Diseases. One of the fi rst surveys enumerati ng causes
of death among anesthesi ol ogi sts was reported by Bruce et al in 1968.
12
The authors compared
the death rates of members of the ASA from 1947 to 1966 wi th those for Ameri can men and mal e
pol icyhol ders of a large insurance company. There was a higher death rate among male
anesthesiol ogi sts from mal i gnancies of the lymphoi d and reti cul oendothel ial ti ssues and from
suici de, but a l ower death rate from l ung cancer and coronary artery di sease.
In a subsequent prospecti ve study, Bruce et al
13
compared the causes of death i n ASA members
duri ng the years 1967 to 1971 with those of men i nsured by one company. The overall death rate
for ASA members was lower than for the control s, and contrary to the previ ous resul ts, there was
P.78
no increase i n death rates from mal i gnanci es of lymphoi d and reti cul oendothel i al ti ssues. The
authors concl uded that their data provi ded no evi dence to support the speculation that l ymphoi d
mali gnanci es were an occupational hazard for anesthesiologi sts.
An ASA-sponsored study, publ ished i n 1974, found no di fferences i n cancer rates between men
exposed and those not exposed to trace concentrati ons of anestheti c gases.
4
For women
respondents, there was a 1.3-fol d to 2-fol d i ncrease i n the occurrence of cancer i n the exposed
group, resul ti ng predomi nantly from an i ncrease i n l eukemi a and lymphoma. The analysi s of
Buri ng et al
5
of these data confirmed an increase i n rel ati ve risk of cancer in exposed women (1.4)
but attri buted the i ncrease sol ely to cervi cal cancer(
2, 8
). They also noted that the ASA study di d
not assess the effect of confoundi ng vari abl es, such as sexual hi story or smoki ng, that may have
contri buted to the fi ndi ngs. It i s doubtful that the carci nogeni c effect of anesthetics woul d be sex
rel ated, and the confli cti ng resul ts for men and women, especi all y in l ight of the l ow stati sti cal
si gni fi cance of the data, cast doubt that anestheti cs were the causati ve agents.
Another ASA-sponsored mortal ity study of anesthesi ol ogi sts, covering the period from 1976 to
1995, uti l i zed data on cause of death from the National Death Index.
14
The mortality risks of a
cohort of 40,242 anesthesi ologists were compared to a matched cohort of interni sts. There was no
di fference between the two groups i n overal l mortali ty ri sk or mortal i ty because of cancer or heart
di sease, but the mean age at death for decedents was si gni fi cantl y lower for anesthesiol ogi sts
compared to interni sts (66.5 years versus 69.0 years). In a subsequent study, Katz
15
used data
from the American Medi cal Association (AMA) to concl ude that there was no stati sti cal di fference
in age-specific mortali ty among anesthesiol ogi sts, i nternists, and other physici ans when ages of
the li vi ng members of the physici an groups were considered in the anal yses.
Epi demi ol ogi c studies are useful tool s for attempti ng to identi fy adverse effects of the operati ng
room envi ronment, i ncl udi ng exposure to many substances, of which waste anestheti c gases
comprise but one factor. The data from epidemiol ogi c surveys can, at best, suggest associations
but can never prove cause-and-effect relationships between an exposure to a condi ti on or
substance and a di sease process. There are shortcomings in many surveys that attempt to assess
the effects of waste anestheti c gases, and these have resulted in confl icting conclusi ons. Overal l,
there appears to be some evi dence that the operati ng room envi ronment produces a sli ght
increase i n the rate of spontaneous aborti on and cancer i n femal e anesthesi ol ogists and nurses.
5

Mortali ty ri sks from cancer and heart di sease for anesthesi ol ogi sts do not di ffer from those for
other medi cal speci al i sts.
Laboratory Studies
Along with epidemiol ogi c studi es, i nvestigators have been acti ve in the l aboratory, assessing the
effects of anesthetic agents on cell, tissue, and ani mal model s. It is thought that thi s work mi ght
provi de the sci enti fi c evi dence li nki ng anestheti c exposure to the adverse effects that have been
suggested by some epi demi ol ogic surveys.
Cellular Effects. Ni trous oxi de admini stered i n cli ni cal l y useful concentrati ons affects
hematopoietic and neural cel l s by i rreversi bly oxi di zing the cobal t atom of vi tamin B
12
from an
acti ve to i nacti ve state. Thi s i nhibi ts methi onine synthetase and prevents the conversion of
methyl tetrahydrofolate to tetrahydrofol ate, whi ch is required for DNA synthesis, assembly of the
myel in sheath, and methyl substi tutions i n neurotransmitters. Inhibi tion of methi oni ne synthetase
i n i ndi vi dual s exposed to hi gh concentrati ons of ni trous oxi de may resul t i n anemi a and
pol yneuropathy, but chroni c exposure to trace l evel s does not appear to produce these effects.
16

Many studies have been performed in ani mals to assess the carci nogeni city of anesthetics. A
prel iminary study suggested that isofl urane produced hepatic neopl asi a when admi ni stered to mice
duri ng gestati on and early li fe, but a subsequent, wel l -control led study fail ed to reproduce these
resul ts.
17
Research using mi ce and rats found no carcinogenic effect of hal othane, ni trous oxi de,
or enfl urane.
Several investi gators have used the Ames bacteri al assay system for studying the mutagenici ty of
anesthetics. Thi s assay i s rapi d, i nexpensi ve, and has a hi gh true-positi ve rate when compared
with in vi vo tests. Hal othane, enfl urane, methoxyfl urane, i sofl urane, and uri ne from pati ents
anesthetized wi th these agents was not mutageni c usi ng thi s assay.
18
Uri ne from peopl e worki ng
i n scavenged or unscavenged operating rooms was al so negati ve for mutagens.
19

Other studies have used anal yses of sister chromati d exchanges (SCE) or formati on of
mi cronucl eated l ymphocytes to assess for genotoxici ty in associ ati on wi th anestheti c exposure.
These tests may be of i nterest because there may be an association between these geneti c
changes and cancer. The majori ty of studies usi ng SCE testing have been negati ve for enflurane,
isoflurane, and sevoflurane exposure.
20
Anestheti sts at an i nstituti on where waste gas scavenging
was not used had an increased fracti on of micronucleated lymphocytes compared to those
practi ci ng in a hospi tal where waste anestheti c

gases were scavenged.
21
Low-level exposure as occurs i n scavenged operati ng rooms i s not
associated wi th i ncreased formation of mi cronucl eated lymphocytes. The predictive value for the
association of this test to the incidence of cancer is unclear.
The data from several l ines of evi dence indicate that occupational exposure to the l ow level s of
anesthetics found wi th effecti ve waste gas scavengi ng is not associ ated with si gnifi cant cel l ul ar
effects.
Reproductive Outcome. Because of the suggesti on from epi demi ol ogi c data that occupati onal
exposure to waste anestheti c gases may have resul ted in an i ncreased rate of spontaneous
aborti on and congeni tal abnormal iti es, numerous studi es have been performed i n l aboratory
animal s to assess reproducti ve outcome. Most animal experi ments fai l to demonstrate al terati ons
i n femal e or mal e ferti l i ty or reproducti on wi th exposure to subanestheti c concentrations of the
currently used anestheti c agents. It i s important to reali ze that data from l aboratory
investi gati ons in ani mals may not be directl y appl icable to humans.
Effects of Trace Anesthetic Levels on Psychomotor Skills
Several studi es have been conducted to attempt to cl ari fy whether low concentrations of
anesthetics alter the psychomotor ski l ls requi red for provi di ng hi gh-quali ty care. In one
investi gati on, psychomotor tests were used to assess the effect of ni trous oxi de (500, 50, or 25
ppm) al one or wi th hal othane (10, 1.0, or 0.5 ppm).
22
After exposure to the hi ghest
concentrations of nitrous oxi de and halothane, subjects' performance decl i ned on four of the seven
tests. Interestingly, there was a decrease i n abi li ty i n si x of seven tests after exposure to the
same l evel of ni trous oxi de al one. Exposure to the l owest concentrati ons studi ed, 25 ppm ni trous
oxi de and 0.5 ppm hal othane, produced no effects as measured by thi s battery of tests.
Other i nvesti gators, using simil ar protocol s, have found no effect on psychomotor test
performance after exposure to trace concentrati ons of hal othane or ni trous oxide. The reason for
di fferences i n outcome between studi es i s uncl ear, but Bruce, one of the ori gi nal investi gators,
has attri buted the psychologi cal effects of l ow l evel s of anesthetics to unusual sensi tivity i n the
group of pai d volunteers used i n the study.
23

Recommendations of the National Institute for Occupational
Safety and Health
The Nati onal Institute for Occupati onal Safety and Health is the federal agency responsibl e for
ensuri ng that workers have a safe and healthful worki ng envi ronment. It meets these goals
through the conduct and fundi ng of research, through educati on of empl oyers and employees
about occupational il l nesses, and through establi shi ng occupati onal heal th standards. A second
federal agency, the Occupati onal Safety and Health Admi nistrati on (OSHA), i s responsibl e for
enacting job heal th standards, investi gati ng work si tes to detect vi ol ati on of standards, and
enforci ng the standards by ci ti ng vi ol ators. In 1977, NIOSH publ ished a criteri a document that
recommended that waste anestheti c exposure shoul d not exceed 2 ppm (1-hour cei l ing) of
halogenated anestheti c agents when used al one, or 0.5 ppm of a hal ogenated agent and 25 ppm of
ni trous oxide (time-weighted average during use).
24
In additi on, i t stated that operati ng room
employees shoul d be advi sed of the potenti al harmful effects of anesthetics. The gui deli nes
P.79
proposed that annual medi cal and occupati onal histori es be obtai ned from al l personnel and that
any abnormal outcomes of pregnanci es should be documented. The publ icati on al so i ncl uded
information on scavengi ng procedures and equi pment and methods for moni tori ng concentrations
of waste anestheti c gases i n the ai r.
The 1977 NIOSH criteri a document has not been adopted by OSHA, whi ch currently does not have
a standard for waste anestheti c gases. Some states, however, have i nsti tuted regulations call i ng
for routi ne measurement of ambient ni trous oxide in operati ng rooms and have mandated that
levels not exceed an arbitrary maximum.
In 1994, NIOSH publi shed an al ert to warn health care personnel that exposure to nitrous oxi de
may produce harmful effects.
25
In thi s document, NIOSH recommends the foll owi ng to reduce
ni trous oxide exposure: (1) moni tori ng the ai r in operati ng rooms; (2) impl ementati on of
appropriate engi neering control s, work practi ces, and equi pment mai ntenance procedures; and (3)
insti tuti on of a worker educati on program.
Since publ icati on of the NIOSH cri teri a document, several volatil e anestheti c agents (enfl urane,
isoflurane, sevofl urane, and desfl urane) have been introduced i nto cl ini cal practi ce. Al though the
NIOSH document addressed hal ogenated agents (hal othane), the agents most commonly used i n
current practi ce have potenci es, chemi cal characteri sti cs, and rate and products of metabol ism
that differ significantly from older anestheti cs. One must question whether the exposure
thresholds ci ted by NIOSH i n 1977 should al so apply to agents that were not avai labl e at the ti me.
It i s important to note that other organi zati ons and agencies i n the United States and Europe have
set occupational exposure l i mi ts for waste anestheti c gases and i n most cases, these are greater
than those recommended by NIOSH (Tabl e 4-1).
In vi ew of the confli cti ng sci entifi c data and publ i shed recommendati ons, it i s reasonabl e to
ask what is an acceptable exposure l evel for waste anestheti c gases. Al though i t may be
di fficul t to be certai n of a threshold concentration bel ow whi ch

chroni c exposure i s safe, it i s prudent to insti tute measures that reduce waste anestheti c level s
in the operati ng room envi ronment without compromi sing pati ent safety. Methods for reduci ng and
TABLE 4-1 Examples of Recommended Threshold Limits
a
for Occupational Exposure to
Anesthetic Agents
Country Nitrous Oxide Halothane Enflurane Isoflurane
U.S. (NIOSH) 25 2 2 2
U.S. (ACGIH) 50 50 75 N
Great Bri tai n 100 10 50 50
Norway 100 5 2 2
Sweden 100 5 10 10
a
Ti me-wei ghted average i n parts per mi l l i on.

NIOSH, Nati onal Insti tute of Occupati onal Safety and Heal th; ACGIH, Ameri can
Conference of Governmental Industri al Hygi eni sts; N, not determi ned.
P.80
moni tori ng waste gases i n the operati ng room have been suggested.
3
Through the use of
scavengi ng equipment, equi pment maintenance procedures, al tered anestheti c work practi ces, and
effi ci ent operati ng room venti lation systems, the envi ronmental anestheti c concentrati on can be
reduced to mi ni mal l evel s. To ensure reduced occupati onal exposure, departmental programs
should incorporate the abil i ty to moni tor for detecti on of leaks i n the hi gh- and low-pressure
systems of anestheti c machi nes, contami nati on as a resul t of faul ty anestheti c techni ques such as
poor mask fit or leaks around the cuffs of endotracheal tubes and laryngeal mask ai rways, and
scavengi ng system mal functi ons (Tabl e 4-2). When there have been leaks of anestheti c gases,
di spersi on and removal of the pol l utants are dependent on the adequacy of room venti l ati on.
Standards for operati ng room constructi on from the Ameri can Insti tute of Architects requi re 15 to
21 ai r exchanges per hour wi th 3 bri ngi ng i n outsi de ai r.
26
Envi ronmental l evels of anesthetics can
be measured using i nstantaneously col l ected samples, conti nuous air moni tori ng, or ti me-weighted
averages.
3
With appropri ate care, envi ronmental level s of anestheti cs i n the operati ng room can
be reduced to compl y wi th those suggested by NIOSH.
TABLE 4-2 Sources of Operating Room Contamination
ANESTHETIC TECHNIQUES
fai l ure to turn off gas fl ow control val ves at the end of an anestheti c
turni ng gas fl ow on before pl aci ng mask on pati ent
poorl y fitting masks, especi al l y with mask i nduction of anesthesi a
flushi ng of the ci rcuit
fil l i ng of anesthesia vapori zers
uncuffed or leaki ng tracheal tubes (e.g., pedi atri c) or poor-fitting l aryngeal mask
ai rways
pedi atric ci rcui ts (e.g., Jackson-Rees versi on of the Mapl eson D system)
si destream sampl i ng carbon dioxi de and anestheti c gas anal yzers
ANESTHESIA MACHINE DELIVERY SYSTEM AND SCAVENGING SYSTEM
open/closed system
occl usi on/malfunction of hospi tal di sposal system
maladjustment of hospi tal di sposal system vacuum
leaks
hi gh-pressure hoses or connectors
ni trous oxide tank mounting
O ri ngs
CO
2
absorbent cani sters
low-pressure ci rcui t
OTHER SOURCES
cryo surgery uni ts
cardi opul monary bypass ci rcui ts
Modified from Task Force on Trace Anestheti c Gases of the Committee on Occupati onal
Heal th of Operating Room Personnel : Waste Anestheti c Gases: Information for
Management i n Anestheti zi ng Areas and the Postanesthesi a Care Unit (PACU). Park
Ri dge, Il l, Ameri can Soci ety of Anesthesi ol ogi sts, 1999, with permission from the
Anesthetic Levels in the Postanesthesia Care Unit
As patients awaken from general anesthesi a in the postanesthesia care unit (PACU), waste
anesthetic gases are rel eased i nto this envi ronment. In a 1998 study, the time-weighted average
concentrations for i sofl urane, desflurane, and nitrous oxi de were 1.1 ppm, 2.1 ppm, and 29 ppm,
respectively, in the breathi ng zone of PACU nurses.
27
Half of the pati ents were intubated on arri val
in the PACU, suggesti ng that they were sti ll parti al l y anesthetized and were exhal ing a greater
concentration of anestheti c gases than i f they had already awakened. In contrast, other
investi gators reported ti me-weighted ni trous oxide l evel s less than 2.0 ppm from two PACUs.
28

The practi ce i n these i nstituti ons was to routi nel y di sconti nue ni trous oxi de at the end of surgery,
approxi mately 5 mi nutes before the pati ent l eft the operati ng room. Al so, there was adequate
ventil ati on documented i n the PACUs. NIOSH threshol d l i mi ts for anestheti c gases can be obtained
in the PACU by ensuring adequate room ventilati on and fresh gas exchange and by di sconti nui ng
the anestheti c gases in suffici ent time pri or to leavi ng the operati ng room.
Chemicals
Methyl Methacrylate
Methyl methacryl ate i s commonl y used to cement prostheses to bone or to repai r bone defects.
Known cardiovascular compl i cations of methyl methacryl ate i n surgi cal pati ents i ncl ude
hypotensi on, bradycardi a, and cardi ac arrest. The effects of occupational exposure are less wel l
documented. Reported ri sks from repeated occupational exposure to methyl methacrylate include
al lergi c reacti ons and asthma, dermatiti s, eye i rritati on i ncl udi ng possi bl e corneal ul cerati on,
headache, and neurological si gns. In one report, a heal th care worker suffered si gni fi cant l ower
li mb neuropathy after repeated occupati onal exposure to methyl methacrylate.
29

OSHA has establ i shed an 8-hour, ti me-weighted average al l owabl e exposure of 100 ppm.
Concentrati ons as high as 280 ppm have been measured when methyl methacryl ate i s prepared for
use in the operating room, but peak envi ronmental concentration can be decreased by 75% when
scavengi ng devi ces are properl y used.
Allergic Reactions
In addi tion to concerns about toxi c effects associated wi th exposure to volatil e anestheti cs or
chemi cal s, anesthesi ol ogi sts may devel op sensi tiviti es or all ergi c reacti ons to substances found i n
the health care envi ronment.
Halothane. Repeated bouts of hepati ti s i n a smal l number of anesthesi ologists have been
attri buted to hypersensi ti vi ty reacti ons rather than to a di rect toxi c effect of hal othane. Anal yses
of sera from pediatri c and general anesthesi ol ogists demonstrated that exposure to hal othane was
Ameri can Soci ety of Anesthesi ol ogists. A copy of the full text can be obtai ned from the
ASA, 520 N. Northwest Hi ghway, Park Ri dge, Il l i noi s 60068-2573.
associated wi th an i ncreased preval ence of autoanti bodi es to cytochrome P450 2E1 and hepati c
endopl asmi c reti cul um protein (ERp58).
30
Despi te the presence of these autoanti bodi es, onl y 1 of
105 pedi atric anesthesiol ogi sts had symptoms of hepati c i njury. These data suggest that al though
autoanti bodies may occur i n anesthesi ol ogi sts exposed to volatil e anestheti cs, they do not appear
to be the cause of anestheti c-induced hepati tis.
Latex. Latex i n surgi cal and exami nation gloves has become a common source of all ergi c
reacti ons among operati ng room personnel . In many cases, heal th care workers who are
al lergi c to latex experience thei r fi rst adverse reacti ons whi le they are pati ents undergoing
surgery. The preval ence of l atex

sensi ti vi ty among anesthesi ol ogi sts i s esti mated to be 12.5 %
31
to 15.8%.
32

Latex i s a compl ex substance composed of pol yi soprenes, l i pi ds, phosphol i pi ds, and protei ns. A
number of addi ti onal substances, including preservatives, accelerators, antioxi dants, vul canizing
compounds, and lubri cati ng agents (such as cornstarch or tal c), are added in the manufacture of
the fi nal product. The protei n content of l atex i s responsibl e for the vast majori ty of general i zed
al lergi c reacti ons to l atex-contai ning surgical gl oves. These reacti ons are exacerbated by the
presence of powder that enhances the potenti al of l atex parti cles to aerosol i ze and to spread to
the respiratory system of personnel and to envi ronmental surfaces during the donni ng or removal
of gloves.
Irri tant or contact dermati tis accounts for approxi matel y 80% of reacti ons resul ting from weari ng
latex-contai ning gl oves (Tabl e 4-3). In the study reported by Brown et al ,
31
24% of anesthesi a
personnel were found to manifest evi dence of contact dermati tis. True al lergi c reacti ons present
as T-cel l medi ated contact dermatiti s (Type IV) or as an IgE-mediated anaphyl acti c reacti on.
P.81
TABLE 4-3 Types of Reactions to Latex Gloves
REACTION SIGNS/SYMPTOMS CAUSE MANAGEMENT
Irri tant Contact
Dermati ti s
Scal i ng, dryi ng,
cracki ng of skin
Di rect ski n
irri tati on by
gl oves, powder,
soaps
Identi fy reacti on,
avoi d i rritant,
possi bl e use of
gl ove l i ner, use of
al ternative product
Type IV
Del ayed
Hypersensi ti vi ty
Itchi ng, bl i steri ng,
crusti ng (del ayed 6
72 hours)
Chemical
addi ti ves used
in
manufacturing
(such as
accel erators)
Identi fy offendi ng
chemi cal , possi bl e
use of al ternative
product wi thout
chemi cal addi ti ve,
possi bl e use of
gl ove li ner
Type I
Immedi ate
Hypersensi ti vi ty
A. Local i zed
Contact
Urti cari a
B. General i zed
Reacti on

A. Itchi ng, hi ves i n
area of contact wi th
latex (i mmediate)
B. Runny nose,
swol len eyes,
general ized rash or
hi ves, bronchospasm,
Protei ns found
in l atex
Identi fy reacti on,
avoi d l atex-
contai ning products,
use of nonl atex or
powder-free, l ow-
protei n gl oves by
coworkers
Anti hi stami nes,
Anesthesi ol ogists who bel ieve that they are all ergi c to latex shoul d take i mmedi ate steps to assess
this possi bil i ty.
33
A careful cl ini cal hi story combined wi th laboratory eval uati on hel ps to correlate
the al l ergi c symptoms wi th l atex exposure. Once the di agnosi s of all ergy has been establ i shed, the
affected anesthesi ol ogi st must avoid al l direct contact wi th l atex-contai ning products. It i s also
important that coworkers wear nonl atex or powderl ess, l ow latex-al lergen gl oves to l i mi t the
level s of ambi ent al l ergens. Because sensi tizati on i s an i rreversi ble process, li mited exposure and
pri mary preventi on of al lergy i s the best overall strategy.
33
Anaphylacti c reacti ons to l atex can be
life threatening.
Radiation
Many modern surgical procedures rely heavi ly on fl uoroscopi c gui dance techniques. As a resul t,
anesthesiol ogi sts are at ri sk for bei ng exposed to an excessi ve dose of radiation. The magnitude of
radiation absorbed by anesthesia personnel i s a functi on of three variables: (1) total radi ation
exposure i ntensi ty and ti me, (2) di stance from the source of radiation, and (3) the use of
radiation shiel di ng. The l atter two are amenabl e to modi fi cati on by the i ndi vi dual. Unfortunately,
the lead aprons and thyroi d col l ars commonly worn in operati ng rooms leave exposed many
vul nerabl e si tes, such as the l ong bones of the extremiti es, the crani um, the ski n of the face, and
the eyes. Because radi ati on exposure i s i nversel y proporti onal to the square of the di stance from
the source, i ncreasi ng this di stance i s more uni versal ly protecti ve. Radiation exposure becomes
mi ni mal at a di stance greater than 36 inches from the source, a distance that i s easi ly attai nabl e
in most anesthetizing l ocati ons.
The U.S. Regul atory Commi ssi on has establ ished an occupati onal exposure l i mi t of 5,000
mrem/year. Occupational exposure among anesthesi a personnel have been reported to be
consi derably below this l imi t.
34
However, these studi es were conducted before the introducti on of
many of the modern surgical procedures that rel y heavi l y on fl uoroscopic guidance techni ques,
such as major spine surgery, endovascul ar repair of aortic aneurysms, and i nvasive cardiol ogy
procedures. Pregnant workers present speci al concerns, and the dose to the fetus should be less
than 500 mrem during the gestation peri od.
Oncogenesis, teratogenesi s, and l ong-term geneti c defects can occur wi th suffici ently hi gh
exposure to radiation. However, even l ow l evel s of radi ati on exposure are not i nconsequenti al. The
stochasti c bi ol ogi c effects of radi ati on are cumul ati ve and permanent. (A stochasti c effect i s one
for whi ch the probabil i ty of the occurrence i ncreases with an increasi ng dose but the severity of
the resul ti ng di sease does not depend on the magni tude of the dose.) There are no publ i shed data
that define the lower threshold for radi ati on-i nduced di sease. Therefore, the general admoni tion
regardi ng occupati onal radi ati on exposure and the basi s of protecti on programs is as l ow as
reasonably achievabl e (ALARA).
Radi ati on exposure shoul d be moni tored with fi l m badges or pocket dosi meters i n anesthesi a
personnel at ri sk. Monthl y
anaphyl axi s topical/systemic
steroids
Anaphyl axi s protocol
Reproduced from Natural Rubber Latex Al lergy: Considerati ons for Anesthesi ol ogi sts,
copyrighted 1999, Task Force on Latex Sensi tivity of the Commi ttee on Occupati onal
Heal th of Operati ng Room Personnel . Park Ridge, Il li noi s, American Soci ety of
Anesthesi ol ogists. http://www.asahq.org/publi cati onsAndServices/physi ci an.htm wi th
permi ssi on from the Ameri can Soci ety of Anesthesi ol ogi sts. A copy of the ful l text can be
obtai ned from the ASA, 520 N. Northwest Hi ghway, Park Ri dge, Il l i noi s 60068-2573.

documentation al l ows for recogni tion of personnel wi th hi gh l evel s of exposure. When warranted,
work practi ces can be evaluated and reassignment to work areas with l ess radi ati on exposure
consi dered. Educati onal programs on the effects of radi ati on and techni ques for preventi ng
exposure are i mportant parts of radi ati on safety programs.
Noise Pollution
A potenti al heal th hazard that is vi rtual l y uncontroll ed i n the modern hospital and speci fi cal ly in
the operati ng room is noi se pol l ution. Noi se pol l ution is quanti fi ed by determi ni ng both the
intensi ty of the sound in deci bel s (dB) and the durati on of the exposure. NIOSH has establ i shed a
maxi mum level for safe noise exposure of 90 dB for 8 hours.
35
Each i ncrease in noi se of 5 dB
halves the permissibl e exposure ti me, so that 100 dB i s acceptabl e for just 2 hours per day. The
maxi mum all owabl e exposure i n an industri al setti ng i s 115 dB.
The noi se level i n many operati ng rooms i s surpri si ngly cl ose to what consti tutes a heal th
hazard.
36
Ventil ators, sucti on equi pment, musi c, and conversati on produce background noise at a
level of 75 to 90 dB. Superi mposed on thi s are sporadi c and unexpected noi ses as dropped
equipment, surgi cal saws and dri ll s, and moni tor al arms. Resultant noi se l evel s frequently exceed
those of a freeway and even of a rock-and-roll band.
Excessi ve l evel s of noise can have an adverse i nfl uence on the anesthesi ol ogi st' s capacity to
perform hi s or her chores. Noi se can i nterfere with an anesthesiol ogi st' s abi l ity to di scern
conversati onal speech and even to hear auditory al arms. Mental efficiency and short-term memory
are dimi ni shed by exposure to excess noi se.
36
Compl ex psychomotor tasks associ ated wi th
anesthesiol ogy, such as moni toring and vigi l ance, are particul arl y sensi ti ve to the adverse
infl uences of noi se pol luti on.
There are al so chroni c rami fi cati ons of long-term exposure to excessive noi se i n the workplace. At
the very l east, noi se pol luti on i s an important factor i n decreased worker producti vi ty. At hi gher
noise l evels, workers are l ikely to show si gns of i rri tabi l i ty and demonstrate evi dence of stress,
such as el evated bl ood pressure. Ulti mately, heari ng loss may ensue.
Conversel y, musi c can provi de benefi cial effects as a different ki nd of background noi se. Music
has proved advantageous as a suppl ement to sedati on for awake pati ents duri ng surgery. Sel f-
sel ected background musi c can contribute to reduci ng autonomic responses in surgeons and
i mprovi ng thei r performance. The benefi ci al effects are l ess pronounced when the musi c i s chosen
by a thi rd party. Unfortunately, thi s is often the case for the anesthesi ol ogi st.
Human Factors
The work performed by an anesthesi ologi st i s intri cate and i ncl udes a number of compl ex tasks. A
l arge body of research has evol ved wi th the goal of appl yi ng hi gh-technol ogy sol uti ons to assi st
the anesthesi ol ogi st in managi ng thi s demanding workl oad. Less attenti on has been given to
appl yi ng human factor technol ogy to i mprove our workpl ace and ensure pati ent safety. Human
error has been i denti fied as a cause of pati ent morbi di ty and mortal ity.
37

A number of human factor probl ems potenti al l y exist i n the operati ng room. For exampl e, the
desi gn and posi ti oni ng of equi pment can be an impediment to the successful completi on of all of
an anesthesi ol ogist's obl i gatory tasks. Anesthesi a moni tors are frequentl y pl aced so that attenti on
is directed away from the patient. Indeed, nearl y half of the anesthesi ologi st' s ti me is spent
performing tasks away from the patientsurgeon fi el d and not di rectl y rel ated to pati ent care.
38

Thi s was wel l demonstrated by observations that reveal ed that the insertion and moni toring of a
transesophageal echocardi ograph added signi fi cantl y to the anesthesi ol ogi st' s workl oad and
di verted attenti on away from other pati ent-specific tasks. The abil i ty to respond to cri tical
inci dents and to sustain compl ex moni toring tasks, such as mai ntai ni ng vigi l ance (vigi l ance i s the
abi li ty to detect changes in a sti mul us duri ng prol onged monitori ng tasks when the subject has no
pri or knowledge of whether or when any changes mi ght occur), are among those tasks that are
most vulnerabl e to the di stracti ons created by poor equi pment desi gn or pl acement. The cri ti cal
P.82
importance of the vigi l ance task to the practi ce of anesthesi ol ogy i s evidenced by the fact that
the seal of the Ameri can Soci ety of Anesthesiologi sts bears as i ts only motto, Vigi l ance (Fi g. 4-
1), and the offi ci al motto of the Australi an Society of Anaesthetists is Vi gi la et Ventil a.
Several aspects of the vigi l ance task deserve attention. By definiti on, thi s functi on i s
repeti tive and monotonous. The task does not full y occupy the anesthesi ol ogi st' s mental
acti vi ty, but nei ther does it l eave hi m or her free to perform other mental functions. Fi nal ly, the
task i s compl ex, requi ring vi sual attention as wel l as manual dexteri ty.
Vigi l ance tasks are general l y performed at the l evel of 90% accuracy.
39
In a setting where the
stakes are as high as that of anesthesia, thi s l eaves an unacceptabl e margin of error. In fact,
human error, in part resul ting from l apses i n attenti on, accounts for a large proportion of the
preventable deaths and seri ous i njuri es resul ting from anestheti c mi shaps i n the United States
annual ly.
In addi ti on to poor equi pment design, a number of other factors conspi re to hamper the abi li ty of
the anesthesi ol ogi st to perform mul tipl e tasks that demand cogniti ve ski ll s. Any factor that
requi res the expendi ture of excessi ve energy to perform a gi ven task produces a predi ctabl e
decrement i n performance. Even the most tri vi al aspect of an operator' s performance plays a
si gni fi cant role over the course of ti me. For example, if the anesthesi ol ogist must make frequent
rapid changes in observati on from a di m, di stant screen to a bri ght, nearby one, the conti nuous
muscul ar acti vi ty requi red for pupi l di lati on and constriction and l ens accommodati on promotes
fati gue and hi nders performance.
Excessi ve energy expendi ture need not be entirel y physical. As more functi ons are moni tored and
more data processed duri ng the course of a surgical procedure, increasi ngl y l arger amounts of
mental work are expended. The mental work vari es

di rectl y wi th the diffi culty encountered i n extracti ng i nformation from the moni tors and di spl ays
competing for the anesthesi ol ogi st' s attenti on. Engi neeri ng of the moni tor di spl ays, such as si gnal
frequency and strength, as well as the mode of presentation of the i nput al so si gni fi cantl y
infl uence the operator's performance.
Even the alarms that have been devel oped wi th the speci fi c goal of suppl ementing the task of
vigi l ance have considerabl e drawbacks. In general, al arms are nonspecifi c (the same al arm
FIGURE 4-1. Offi ci al Seal of the Ameri can Soci ety of Anesthesi ol ogists. VIGILANCE has
al ways been recogni zed as the most criti cal of the anesthesi ologist' s tasks.
P.83
si gnal i ng as many as 12 di fferent devi ati ons from normal ) and can be a source of frustrati on and
confusion. They are also susceptibl e to artifacts and frequent fal se-positi ve alarms that can
di stract the observer from more cl i ni cal l y signi fi cant i nformati on and, therefore, it i s not unusual
for frequentl y di stracti ve alarms to be inactivated.
Noise can have a detrimental i nfluence on the anesthesiol ogi st worki ng at mul ti pl e tasks. The
average noise l evel of 77 deci bel s found in operati ng rooms can reduce mental effi ciency and
short-term memory. In general , obtrusive noises, such as l oud tal ki ng, excessive clangi ng of
instruments, and broadband noise, are associated wi th decrements i n performance.
Organizati onal i ssues, such as communicati on among team members, can have a detri mental
effect on the abi l ity of the anesthesi ol ogist to perform wel l. The potenti al for di saster as a resul t
of poor communi cati on has been well il l ustrated i n a number of ai rli ne catastrophes. The
possi bi li ty for mi scommunicati on and resul tant acci dent i s hei ghtened i n the operati ng room
where, i n contrast to the structure inherent i n an ai rl i ne crew, there is an absence of a wel l -
defined hi erarchical organizati on and there are overl aps in areas of expertise and responsi bi li ty.
Producti on pressure is an organizati onal concern that has the potenti al to create an envi ronment
in which issues of producti vity supercede those of safety.
40
Producti on pressure has been
associated wi th the commi ssi on of errors resul ti ng from haste and/or del iberate devi ati ons from
known safe practi ces.
The appli cati on of simul ati on technol ogy has proven to be very useful i n the study of human
performance issues i n anesthesi ology.
41
Much remai ns to be done in bringing human factor
research to the anesthesi ol ogi st' s work environment.
Work Hours and Night Call
Prolonged work hours that resul t i n sl eep depri vati on and fati gue are a ubi qui tous component of
many anesthesiol ogi sts' professional l ives. Ten- to 12-hour workdays are common. Addi ti onal
emergency and on-cal l coverage frequentl y result i n 24- to 32-hour shi fts. Gravenstei n reported
the average anesthesi ol ogi st' s work week was 56 hours.
42
Seventy-four percent of the study
respondents reported that they had worked without a break for longer periods than they
personal l y thought was safe and 64% attri buted an error in anesthetic management to fatigue.
Long hours of work and ni ght call are especial ly chall engi ng for the aging anesthesi ol ogist. Older
i ndi vi dual s are parti cularly sensiti ve to disturbances of the sl eepwake cycl e and are i n general
better sui ted to phase advances (morning work) than phase del ays (nocturnal work).
43
Demands
associated wi th ni ght call have been identi fi ed as the most stressful aspect of practi ce and most
frequently ci ted impetus toward retirement.
43

Sl eep depri vati on and ci rcadi an di srupti on have deleteri ous effects on cogniti on, performance,
mood, and health.
44
Both acute sl eep l oss (24 hours of on-call duty) and chronic parti al sl eep
depri vati on (less than 6 hours of sl eep) resul t in a si mil ar degree of neurobehavi oral i mpai rment.
The nature and degree of i mpai rment wi th acute sleep depri vati on bears a stri ki ng si mi larity to
that seen wi th al cohol intoxi cati on.
45

The del eterious effect of sleep l oss and fati gue on work effi ci ency and accuracy is well
documented in many i ndustri es.
41, 46
Sl eep depri vati on has been i mpli cated as a contri buti ng
factor i n many wel l -publ ici zed i ndustri al accidents such as those that occurred at Chernobyl and
Three Mi l e Isl and. Complex cogni tive tasks that are speci fi c to anesthesi ol ogy, such as monitori ng
and accurate cli nical deci si on making, may be adversely affected by sleep deprivation. Surveys of
anesthesia personnel have li nked fati gue and anestheti c errors, but these contai n sel f-reported
data that may not be veri fi abl e.
42, 47
In a study of performance on an anesthesi a si mul ator,
residents i n the sl eep-depri ved conditi on demonstrated progressi ve i mpai rment of al ertness,
mood, and performance and had l onger response latency to vigi l ance probes.
41
In spi te of thi s,
there were no significant di fferences i n the cli ni cal management of the si mul ated pati ents between
the rested and sleep-depri ved groups. Additi onal studi es shoul d be performed i n thi s area to
determi ne the rol e of sl eep depri vati on i n adverse cl i ni cal events.
Subsequent to a peri od of sl eep depri vati on, performance does not return to normal l evel s unti l 24
hours of rest and recovery has occurred. An interesti ng phenomenon i s the end-spurt, in which
previ ously deteriorated performance shows improvement when the subject real izes that the task is
90% compl eted. The converse undoubtedl y also occurs, a let-down with addi tional deterioration
in performance when the procedure i s unexpectedl y prol onged.
An addi ti onal area of concern i s the potenti al effect of sl eep depri vati on and chroni c fati gue on
heal th and psychosoci al adjustment. Work schedul es that di srupt circadi an rhythms are associated
with impaired health, emoti onal problems, and a decl i ne i n performance. Howard et al
48

demonstrated that residents i n their routi ne, nonpost-call state suffered from chroni c sl eep
depri vati on and had the same degree of sl eepi ness as measured i n residents fi nishi ng 24 hours of
in-house cal l.
The sleep-loss pattern experi enced by anesthesi ologi sts who take ni ght cal l i s compl ex and
incl udes el ements of each of the three general cl asses of sleep deprivation: total , partial , and
sel ecti ve sleep deprivati on. Sel ecti ve sl eep deprivation resul ting from frequent i nterrupti ons is
most di srupti ve to important components of sl eep incl udi ng sl ow wave sl eep (associated wi th
body repai r) and rapi d eye movement sleep (mi nd repai r). Indicators of psychosoci al distress,
incl udi ng irritabi l i ty, displ aced anger, depression, and anxi ety, have al l been i dentified in house
officers sufferi ng from sl eep depri vati on.
49

Nati onal attention was focused on the problems associated wi th sl eep-depri ved medi cal housestaff
by the wel l -publ ici zed Li bby Zion case.
50
A l arge portion of thi s cl ai m hi nged on the al l egati on that
fatal , avoi dabl e mi stakes were made by exhausted, unsupervi sed resi dents. A number of medi cal
organizati ons and state legi sl atures subsequentl y took acti on to l i mi t excessi ve work hours and
resul tant sl eep depri vati on among physi cians, especi all y trai nees. For example, the Accreditati on
Counci l for Graduate Medi cal Educati on (ACGME) has set uni versal standards that l imit resi dent
duty hours to an average of 80 hours per week and no more than 30 hours at any one time, l imit
the frequency of i n-house cal l, and mandate that off-duty time be provi ded. Unfortunately, no
regul ati ons pertain to the practi cing anesthesi ol ogist or nurse anesthetist. In thi s area, medi cine
remai ns si gnifi cantly behi nd other industri es, most notably the transport and airl ine industri es, in
i denti fyi ng and regul ati ng work practices that permi t excessively long shi fts.
44

Unti l changes can be made in staffing patterns, there are several strategies that can be used to
prevent fati gue and the effects of sl eep depri vati on duri ng l ong work peri ods.
44
Personnel shoul d
be educated on the problems associated wi th poor

sl eep habi ts outsi de the hospi tal . Naps pri or to the start of cal l as wel l as the use of caffei ne can
improve alertness duri ng long shi fts.
INFECTION HAZARDS
Anesthesi a personnel are at ri sk for acquiri ng i nfecti ons both from pati ents and from other
personnel .
51
Vi ral infecti ons, reflecting thei r prevalence in the communi ty, are the most si gnifi cant
threat to heal th care workers. Most commonl y, these are spread through the respi ratory routea
mechani sm that is, unfortunatel y, the most diffi cult to control effectively wi th environmental
al terati ons. Other infecti ons are propagated by hand-to-hand transmission, and hand washing i s
consi dered the si ngl e most i mportant i ntervention for protecti on agai nst thi s form of contagion.
52

Immuni ty agai nst some vi ral pathogens can be provided through vacci nation.
53
Bl oodborne
pathogens such as hepatiti s and human immunodefi ci ency virus cause seri ous infecti ons, but
transmi ssi on can be prevented wi th mechani cal barri ers bl ocki ng portal s of entry or, i n the case of
hepati ti s B, by produci ng immuni ty by vacci nati on.
54
Current recommendations from the Centers
for Di sease Control and Preventi on (CDC) for preempl oyment screeni ng, infecti on control
practi ces, vacci nati on, postexposure treatment, and work restrictions for i nfected personnel
should be consul ted for specific i nformati on rel ated to each pathogen.
54, 55, 56

Respiratory Viruses
Respi ratory vi ruses, whi ch are responsi bl e for many community-acqui red infecti ons, are usual l y
P.84
transmi tted by two routes. Smal l-parti cle aerosol s produced by coughi ng, sneezing, or talking can
propel vi ruses over large distances. The i nfl uenza and measles viruses are spread i n thi s way. The
second mechani sm invol ves l arge dropl ets produced by coughi ng or sneezi ng, contaminati ng the
donor's hands or an i nanimate surface, whereupon the vi rus is transferred to the oral , nasal , or
conjunctival mucous membranes of a susceptibl e person by self-inocul ati on. Rhinovirus and
respiratory syncytial vi rus (RSV) are spread by thi s process.
Influenza Viruses
Because i nfluenza viruses are easi l y transmi tted, community epidemics of i nfl uenza are common,
with large outbreaks occurri ng annual ly. Acutel y il l pati ents shed vi rus through smal l -parti cle
aerosol s by coughing or sneezi ng for as l ong as 5 days after the onset of symptoms. Respi ratory
isol ati on precauti ons can be used for the durati on of the cl ini cal il l ness in an attempt to prevent
spread to suscepti ble i ndi vi dual s. Because of their contact wi th nasopharyngeal secreti ons,
anesthesiol ogi sts can pl ay a rol e in the spread of i nfl uenza vi rus in hospi tals.
Infl uenza rarel y produces si gni fi cant morbi dity i n healthy heal th care workers but can result i n
hi gh rates of absenteei sm. Hospital staff, especi al l y those who care for pati ents i n hi gh-ri sk
groups, shoul d be i mmunized annual l y (October or November) wi th the i nacti vated (ki l led vi rus)
infl uenza vi rus vacci ne.
56
Anti geni c vari ati on of infl uenza vi ruses occurs over ti me, so that new
viral strai ns (usual ly two Type A and one Type B) are sel ected for incl usi on i n each year' s vaccine.
During hospi tal outbreaks of i nfluenza A, the antiviral agents amantadi ne and ri mantadine are
reasonably effective in preventing i nfluenza A infecti on i n unvacci nated hospi tal personnel and, if
administered wi thi n 48 hours of the onset of i l lness, can reduce the durati on and severi ty of
il l ness.
57
The neuraminidase i nhi bi tors zanami vi r and osel tami vi r have been shown to be effective
in preventing and treating both infl uenza A and B.
57
Because of possibl e morbi di ty to hospi tal ized
patients and to hospital personnel , i t is recommended that duri ng community infl uenza epi demi cs,
hospi tal s shoul d consi der l i mi ting elective admissions and surgery.
Respiratory Syncytial Virus
Respi ratory syncyti al virus i s the most common cause of serious bronchi oli tis and lower
respiratory tract di sease in i nfants and young chi l dren worl dwi de. Duri ng peri ods when RSV is
prevalent in the communi ty (usual ly l ate November through May in the Uni ted States), many
hospi tal ized i nfants and chi ldren may carry the vi rus. Large numbers of vi rus are present in
respiratory secreti ons of infected chil dren, and al though viabl e vi rus can be recovered for up to 6
hours on contami nated envi ronmental surfaces, i t i s readil y inactivated wi th soap and water and
di si nfectants. Infection of susceptibl e people occurs by sel f-inocul ati on when RSV in secreti ons i s
transferred to the hands, which then contact the mucous membranes of the eyes or nose.
58

Al though most chi l dren have been exposed to RSV early i n l i fe, i mmunity is not permanent and
rei nfecti on i s common.
Respi ratory syncyti al virus i s shed for approximatel y 7 days after infecti on. Hospi tali zed pati ents
with the vi rus shoul d be i sol ated, but duri ng seasonal outbreaks l arge numbers of pati ents may
make i sol ati on impracti cal .
59
Careful hand washing and the use of gowns, gl oves, masks, and
goggl es (standard precauti ons) have al l been shown to reduce RSV i nfection in hospital personnel .
Herpes Viruses
Varicel la-zoster virus (VZV), herpes simplex vi rus Types 1 and 2, and cytomegal ovirus (CMV) are
members of the Herpetovi ri dine fami l y. Close personal contact i s requi red for transmission of al l
the herpes viruses except for VZV, whi ch i s spread by di rect contact or smal l -parti cle aerosol s.
After pri mary i nfection wi th herpes vi ruses, the organi sm becomes l atent and may reacti vate at a
later time. Most people i n the United States have been i nfected wi th all of the herpes viruses by
mi ddle age. Therefore, nosocomi al transmi ssi on is uncommon except in the pedi atri c popul ati on
and i n i mmunosuppressed pati ents.
Varicella-Zoster Virus. Vari cel l a-zoster vi rus produces both chi cken pox and herpes zoster
(shi ngl es). Although the pri mary i nfection (chi cken pox) i s usual l y uncompli cated i n heal thy
chil dren, VZV i nfecti on i n adul ts may be associated wi th major morbi dity or death. Infecti on
duri ng pregnancy may resul t in fetal death or, rarel y, in congeni tal defects. Heal th care workers
with active VZV infecti on can transmi t the vi rus to others.
After the pri mary infecti on, VZV remai ns l atent in dorsal root or extramedul l ary cranial gangl ia.
Herpes zoster resul ts from reacti vati on of the VZV i nfecti on and produces a painful vesi cul ar rash
in the i nnervated dermatome. Anesthesi ologi sts working i n pai n cl inics may be exposed to VZV
when cari ng for pati ents who have discomfort from herpes zoster.
Varicel la-zoster virus i s hi ghl y contagious, especi all y from pati ents wi th chi cken pox or
di ssemi nated zoster. The CDC esti mates that the peri od of communicabil i ty begi ns 1 to 2 days
before the onset of the rash and ends when al l the lesi ons are crusted, usual l y 4 to 6 days after
the rash appears.
60
Because VZV may be spread through ai rborne transmission, respiratory
isol ati on shoul d be used for patients wi th chi cken pox or dissemi nated herpes zoster.
59
Use of
gl oves to avoid contact wi th vesi cul ar fl uid is adequate to prevent VZV spread from pati ents with
local ized herpes zoster.
Most adults i n the Uni ted States have protective antibodi es to VZV. Because there have been many
reports of nosocomial transmi ssi on of VZV, i t is recommended that al l heal th care workers (HCW)
have i mmuni ty to the vi rus. Anesthesi a

personnel shoul d be questioned about pri or VZV i nfecti on, and those wi th a negative or unknown
hi story of such i nfection shoul d be serologi call y tested.
55
Al l employees wi th negative ti ters shoul d
be restri cted from cari ng for pati ents wi th acti ve VZV i nfecti on and shoul d consider i mmuni zation
with li ve, attenuated vari cel l a vacci ne.
60
Suscepti bl e personnel wi th a si gni fi cant exposure to
peopl e wi th VZV infecti on are candi dates for vari cel l a zoster immune gl obul in (VZIG), whi ch i s
most effective when admi ni stered wi thin 96 hours after exposure.
60
Personnel wi thout VZV
immuni ty shoul d be reassi gned to alternati ve l ocati ons so that they do not care for patients who
have acti ve VZV i nfecti ons.
Herpes Simplex. Herpes si mpl ex vi rus (HSV) infecti on i s qui te common i n adul ts. After viral entry
through the mucous membranes of the mouth, the primary infecti on wi th HSV Type 1 is usual l y
cl i ni cal ly i napparent but may i nvol ve severe oral l esi ons, fever, and adenopathy. In heal thy
peopl e, the primary i nfecti on subsides and the vi rus persi sts in a l atent state wi thi n the sensory
nerve gangl ion i nnervati ng the si te of i nfection. Any of several mechani sms can reacti vate the
virus to produce recurrent infecti on, whi ch mani fests in the vi cini ty of the primary lesi on.
A second HSV, Type 2, i s usual l y associ ated wi th geni tal i nfections and i s spread by sexual
contact. Newborns may become i nfected with HSV Type 2 duri ng vagi nal del i very.
Heal th care personnel may be i nocul ated by di rect contact wi th body fl ui ds carryi ng either herpes
si mpl ex virus Type 1 or 2.
Herpetic i nfecti on of the fi nger, herpetic paronychia or herpeti c whi tlow, is an occupati onal hazard
for anesthesi a personnel . The i nfecti on usual ly begins at the portal of vi ral entry, a site on the
di stal fi nger where the i ntegri ty of the ski n has been broken, and resul ts i n vesi cl e formation.
Wi thi n 3 weeks, the throbbi ng pai n lessens, and the l esions begi n to heal . Use of acycl ovir, an
anti vi ral drug that inhi bi ts repli cati on of HSV, may shorten the course of the pri mary cutaneous
viral infecti on. Personnel wi th HSV infecti ons of the fingers or hands shoul d not contact pati ents
unti l their lesi ons are heal ed.
Cytomegalovirus. Cytomegal ovi rus (CMV) i nfects between 50 and 85% of i ndi vi dual s i n the
Uni ted States before age 40, with most infections producing mini mal symptoms. After the primary
infecti on, the vi rus remai ns dormant, and recurrent di sease only occurs wi th compromi se of the
individual ' s immune system. Transmi ssi on of CMV can take pl ace through cl ose contact with an
i ndi vi dual excreti ng the vi rus or through contact wi th contami nated sal iva or urine. It is unl i kely
that aerosol s or small dropl ets play a role i n CMV transmission.
Primary or recurrent CMV infection duri ng pregnancy resul ts i n fetal i nfection in up to 2.5% of
occurrences. Congeni tal CMV syndrome may be found in up to 10% of i nfected i nfants. Thus,
P.85
al though CMV i nfection usuall y does not result i n morbi dity in heal thy adul ts, it may have
si gni fi cant sequel ae in pregnant women. CMV i nfecti on can also be deadl y in i mmunocompromi sed
patients, such as those undergoing bone marrow transpl antati on.
The two major popul ati ons wi th CMV infecti on i n the hospi tal include i nfected infants and
immunocompromised pati ents, such as those who have undergone organ transpl ants or those on
oncology uni ts. Routi ne infecti on control procedures (standard precauti ons) are suffi ci ent to
prevent CMV infecti on i n health care workers (Tabl es 4-4 and 4-5).
55
Pregnant personnel shoul d be
made aware of the risks associ ated with CMV i nfecti on duri ng pregnancy and of appropri ate
infecti on control precauti ons to be used when caring for hi gh-ri sk pati ents. There is no evi dence to
indicate that i t is necessary to reassi gn pregnant women from pati ent care areas i n whi ch they
may have contact with CMV-positi ve pati ents.
TABLE 4-4 Prevention of Occupationally Acquired Infections
55, 59, 62

INFECTIOUS AGENT PREVENTIVE MEASURES
a
Cytomegalovirus Standard precauti ons
Hepati ti s B Vaccine; hepati ti s B immune gl obuli n, standard
precauti ons
Hepati ti s C Standard precauti ons
Herpes simplex Standard precauti ons; contact precauti ons if di ssemi nated
di sease
Human immunodeficiency
virus
Standard precauti ons; postexposure prophyl acti c
anti retrovi ral s
Infl uenza Vaccine; prophyl acti c anti retrovi ral s; dropl et precautions
Measles Vaccine; ai rborne i nfection i sol ati on precautions
Rubell a Vaccine; droplet precautions
Severe acute respi ratory
syndrome (SARS)
Standard precauti ons; ai rborne i nfection isolation
precauti ons
Tubercul osi s Airborne i nfecti on i sol ati on precautions; i soni azi d
ethambutol for PPD conversion
Varicel la-zoster Vaccine; vari cel la-zoster i mmune gl obuli n; ai rborne
infecti on i sol ati on and contact precauti ons; standard
precauti ons i f local i zed di sease
a
Isol ati on precautions outli ned in Tabl e 4-5.
TABLE 4-5 Hospital Isolation Precautions
59

STANDARD PRECAUTIONS
These are to be used for the care of al l pati ents regardl ess of their di agnosi s or
presumed infecti on status.
Standard precauti ons shoul d be used i n conjuncti on wi th other forms of i sol ati on
precauti ons (see bel ow) for the care of speci fi c pati ents.
1. Hand washing
After touchi ng bl ood, body flui ds, or contami nated items even i f gl oves are worn.
2. Gl oves
Wear gloves when touchi ng bl ood, body fl ui ds, or contami nated i tems.
Change gl oves between tasks on the same pati ent when there i s l i kel y to be a hi gh
concentration of organi sms.
Remove gloves after use, before touching noncontaminated i tems and
envi ronmental surfaces.
3. Mask, eye protection, face shiel d
Use during procedures l i kely to generate spl ashes of bl ood or body fluids that may
contami nate face or mucous membranes.
4. Gown
Use during procedures l i kel y to generate spl ashes of blood or body fl uids that may
contami nate cl othi ng or arms.
5. Patient-care equipment
Handle soi led equipment i n a manner that prevents ski n, mucous membrane,
cl othing, or envi ronmental contami nati on.
6. Envi ronmental control
Contami nated environmental surfaces shoul d routi nel y be cl eaned and/or
di si nfected.
7. Li nen
Soi l ed li nen shoul d be handled i n a manner that prevents contami nation of
personnel , other pati ents, and envi ronmental surfaces.
8. Occupati onal heal th and bl oodborne pathogens
Use care to prevent i njuri es when usi ng or di sposi ng of needl es and sharp devices.
Contami nated needl es should not be recapped or mani pul ated by usi ng both hands.
If recappi ng is necessary for the procedure bei ng performed, a one-handed scoop
technique or mechani cal devi ce for hol di ng the needl e sheath should be used.
Contami nated needl es should not be removed from disposabl e syri nges by hand.
Do not break or bend contami nated needl es before di sposal .
After use, di sposable syri nges and needl es and other sharp devices shoul d be
pl aced i n appropri ate puncture-resistant contai ners l ocated as cl ose as practi cal to
the area in which the i tems were used.
Mouthpieces, resuscitati on bags, or other venti l ati on devi ces shoul d be avai labl e
for use as an alternati ve to mouth-to-mouth ventil ati on.
9. Patient placement
Pri vate rooms should be used for patients who are l i kel y to contami nate the
envi ronment.
TRANSMISSION-BASED PRECAUTIONS
These should be used along wi th standard precauti ons for patients known or suspected
to be i nfected or col oni zed wi th hi ghl y transmi ssi bl e pathogens requi ri ng addi ti onal
precauti ons.
AIRBORNE INFECTION ISOLATION PRECAUTIONS
These should be used for pati ents known or suspected to be i nfected wi th
mi croorganisms transmitted by airborne droplet nucl ei (parti cles 5 m or smal l er i n si ze)
that can be di spersed over l arge distances by ai r currents.
The pati ent shoul d be pl aced i n a pri vate room wi th (1) documented negati ve ai r
pressure relative to surroundi ng areas, (2) 6 to
12 ai r changes per hour, (3) di scharge of ai r outdoors or monitored high-effi ci ency
fil tration of room ai r before the ai r i s ci rculated to other areas i n the hospi tal .
The door to the room shoul d be kept cl osed and the pati ent shoul d remai n in the
room.
2. Respi ratory protection
Respi ratory protecti on shoul d be worn when entering the room of a patient wi th
known or suspected i nfecti ous pul monary tubercul osi s.
Suscepti ble personnel shoul d not enter the room of patients known or suspected to
have measles or vari cel la i f other i mmune caregi vers are avai l abl e. If suscepti bl e
persons must enter the room of a pati ent known or suspected to have measl es or
vari cel l a, they shoul d wear respi ratory protecti on. Persons i mmune to measles or
vari cel l a need not wear respiratory protection.
3. Patient transport
Patients shoul d be transported from the i sol ati on room onl y for essenti al purposes.
When transport is necessary, a surgical mask shoul d be pl aced on the pati ent to
prevent di spersal of droplet nuclei .
4. Patients with tubercul osi s
Current CDC guidelines should be consul ted for addi tional precautions.
81

DROPLET PRECAUTIONS
These should be used for pati ents known or suspected to be i nfected wi th
mi croorganisms transmitted by l arge-parti cle dropl ets (parti cles l arger than 5 m) that
can be generated duri ng coughi ng, sneezi ng, tal ki ng, or by performi ng certai n
procedures.
The pati ent shoul d be pl aced i n a pri vate room.
2. Respi ratory protection
Personnel shoul d wear a mask when working wi thi n 3 feet of the pati ent.
Patients shoul d be transported from the i sol ati on room onl y for essenti al purposes.
When transport is necessary, a surgical mask shoul d be pl aced on the pati ent to
prevent di spersal of droplets.
CONTACT PRECAUTIONS
These should be used for pati ents known or suspected to be i nfected or coloni zed with
epi demi ologi call y important mi croorganisms transmi tted by di rect contact wi th the
patient or indi rect contact wi th envi ronmental surfaces or patient-care items.
The pati ent shoul d be pl aced i n a pri vate room.
2. Gl oves and hand washing
In addi ti on to weari ng gl oves as outl i ned under standard precauti ons, gl oves
(nonsteri l e) shoul d be worn when entering the patient' s room.
Gl oves shoul d be changed after contacting i nfective material that may contai n hi gh
concentrations of microorgani sms.
Gl oves shoul d be removed before l eaving the pati ent' s envi ronment and hands
should be washed i mmedi atel y with an antimicrobi al agent or a waterl ess anti septi c
agent.
After removal of gl oves and hand washi ng, care shoul d be taken so that
contami nated envi ronmental surfaces shoul d not be touched to avoid transfer of
mi croorganisms to other pati ents.
3. Gown
In addi ti on to weari ng a gown as outl i ned under standard precauti ons, a gown
(nonsteri l e) should be worn when enteri ng the room when i t i s anti cipated that
cl othing wi l l have contact with the pati ent, environmental surfaces, or
contami nated items or if the pati ent i s i nconti nent or has di arrhea, an il eostomy, a
col ostomy, or wound drai nage not contai ned by a dressing.
The gown shoul d be removed before l eavi ng the pati ent's envi ronment.
Clothi ng should not contact potenti al l y contami nated surfaces after removal of the
gown.
The pati ent shoul d be transported from the room for onl y essenti al purposes.
If it i s necessary to transport the patient, precauti ons shoul d be mai ntained to
mi ni mi ze the ri sk of transmi ssi on of mi croorgani sms to other pati ents and
contami nati on of envi ronmental surfaces or equipment.
Rubella
Outbreaks of rubel l a, or German measles, i n hospi tal personnel have resul ted in signi fi cant l oss i n
empl oyee worki ng ti me, employee morbidi ty, and cost to the hospi tal . Al though most adul ts i n the
Uni ted States are immune to rubell a, up to 20% of women of chi l dbeari ng age are sti l l susceptibl e.
Rubell a infecti on duri ng the fi rst tri mester of pregnancy i s associ ated wi th congeni tal
malformations or fetal death.
Rubell a i s transmi tted by contact wi th nasopharyngeal dropl ets spread by i nfected i ndi vi dual s
coughing or sneezing. Pati ents are most contagious whi le the rash i s erupti ng but can transmi t the
virus from 1 week before to 5 to 7 days after the onset of the rash. Dropl et precauti ons shoul d be
used to prevent transmi ssi on (Tabl e 4-5).
55

Ensuri ng i mmunity at the ti me of employment (evidence of pri or vacci nati on with li ve rubel l a
vaccine or serol ogi c confi rmation) shoul d prevent nosocomial transmi ssi on of rubel l a to personnel .
It has been shown that hi story is a poor i ndi cator of i mmunity. A l ive, attenuated rubell a vi rus
vaccine, contained i n measl es, mumps, rubell a vacci ne (MMR), is avai labl e to produce immuni ty i n
suscepti bl e personnel .
53, 61
Many state or l ocal health departments mandate rubel l a immuni ty for
al l HCW, and local regul ati ons should be consulted.
Measles (Rubeola)
Measles vi rus i s hi ghl y transmissi bl e both by l arge dropl ets and by the airborne route. The
virus i s found i n the mucus of the nose and pharynx of the i nfected i ndi vi dual and i s spread
by coughi ng and sneezi ng. The disease can be transmi tted from

4 days pri or to the onset of the rash to 4 days after its onset. Airborne precauti ons shoul d be used
for i nfected pati ents (Tabl e 4-5).
55
Introducti on of the measl es vacci ne i n the United States has
successful ly eli mi nated i ndi genous cases of measl es but i mportati on of measl es from other
countries continues to occur.
Heal th care workers are at i ncreased ri sk for acqui ring measles and transmi tti ng the vi rus to
suscepti bl e coworkers and patients. The CDC recommends that medi cal personnel have adequate
immuni ty to measl es, as documented by one of the fol lowi ng: evi dence of two doses of l ive
measl es vacci ne, a record of physi cian-di agnosed measl es, or serologi c evidence of measl es
immuni ty (Tabl e 4-4).
55
Suscepti ble personnel born i n or after 1957 should receive two doses of
the l i ve measl es vacci ne at the time of empl oyment.
61

Severe Acute Respiratory Syndrome
Severe acute respi ratory syndrome (SARS) is an emergi ng respiratory tract i nfection produced by
5. Patient-care equipment
Dedi cate the use of noncri tical pati ent-care equipment (e.g., bl ood pressure cuffs)
to a si ngl e pati ent to avoi d transmission of mi croorganisms to another pati ent. If
use of common equipment is unavoidabl e, then items shoul d be adequately cl eaned
or di si nfected before use on another pati ent.
P.86
P.87
a coronavi rus, SARS-associated coronavi rus (SARS-CoV). After the fi rst cases were reported from
Asi a in l ate 2002, the disease qui ckl y spread global l y i n 2003 before bei ng controll ed. SARS
typi cal l y presents wi th a hi gh fever, greater than 38.0C, and i s fol l owed wi th symptoms of
headache, generali zed aches, and cough. Severe pneumoni a may l ead to acute respi ratory di stress
syndrome (ARDS) and death.
SARS is spread by close person-to-person contact through vi rus carri ed i n l arge respi ratory
dropl ets and possi bl y by ai rborne transmi ssi on. The vi rus can al so be spread when an i ndi vi dual
touches a contami nated object and then i nocul ates thei r mouth, nose, or eyes. Aerosol izati on of
respiratory secreti ons during coughi ng or endotracheal sucti oni ng has been associ ated with
transmi ssi on of the di sease to HCW, i ncludi ng anesthesi ologi sts and cri tical care nurses. It
appears that some i nfected i ndivi dual s are super-shedders of the vi rus and present a greater
ri sk for transmi ssion to contacts.
One of the most important i nterventions to prevent the spread of SARS i n the health care setti ng
is earl y detecti on and i sol ati on of pati ents who may be i nfected wi th SARS-CoV.
62
Standard and
Droplet Precauti ons should be used when contacti ng pati ents wi th symptoms of a respi ratory
il l ness (Tabl e 4-5) unti l it i s determi ned that the cause of the pneumonia i s not contagious.
Contact and Ai rborne Infecti on Isol ati on (AII) shoul d be used for pati ents wi th l aboratory evidence
of SARS or those strongly suspected of havi ng SARS-CoV i nfecti on. Gl oves, gown, respiratory
protecti on (as a mi ni mum, use a NIOSH-certi fi ed N-95 fil teri ng respi rator), and eye protecti on
shoul d be donned before enteri ng a SARS pati ent's room or duri ng procedures l ikel y to generate
respiratory aerosols.
62

Viral Hepatitis
Although many vi ruses may produce hepati ti s, the most common are Type A or i nfecti ous
hepati ti s, Type B (HBV) or serum hepati ti s, and Type C (HCV), whi ch is responsi ble for most cases
of parenterall y transmi tted non-A, non-B hepatiti s (NANBH) i n the United States. Del ta hepatiti s,
caused by an incomplete vi rus, occurs only i n people infected with HBV. Outbreaks of an
enteri cal ly transmi tted NANBH (hepatiti s E) have been reported from outsi de the United States
and are usual l y caused by contaminated water. The greatest risks of

occupati onal transmission to anesthesi a personnel are associated wi th HBV and HCV.
Hepatitis A
About 20 to 40% of vi ral hepatiti s in adul ts i n the United States i s caused by the Type A vi rus.
Hepati ti s A i s usual ly a sel f-li mi ted il l ness, and no chroni c carri er state exi sts. Spread is
predomi nantly by the fecal oral route, ei ther by person-to-person contact or by i ngestion of
contami nated food or water. Outbreaks are usuall y found in i nsti tuti ons or other cl osed groups
where there has been a breakdown in normal sani tary condi ti ons. Hospi tal personnel do not
appear to be at i ncreased risk for hepatiti s A and nosocomi al transmi ssi on i s rare.
Personnel exposed to pati ents wi th hepati tis A shoul d receive immune gl obul in i ntramuscularl y as
soon as possi bl e but not greater than 2 weeks after the exposure to reduce the l ikeli hood of
infecti on.
63
Immune gl obul in provi des protection agai nst hepati tis A through passi ve transfer of
anti bodi es and i s used for postexposure prophylaxi s. Hepati tis A vaccine i s not routinely
recommended for HCW except for those that may be worki ng in countri es where hepatiti s A i s
endemi c.
53, 63

Hepatitis B
Hepati ti s B i s a significant occupational hazard for nonimmune anesthesi ol ogi sts and other medi cal
personnel who have frequent contact wi th blood and bl ood products. The preval ence (the
proporti on of people who have or have had the condi tion at the ti me of the survey) of hepati tis B
in the general population of the United States i s 3 to 5%, and the carri er rate i s 0.2 to 0.9%
based on serol ogi c screening. Serosurveys i ncl udi ng more than 2400 unvaccinated anesthesi a
P.88
personnel conducted i n the United States and several other countries demonstrated a mean
prevalence of HBV serol ogic markers of 17.8% (range, 3.248.6%).
64
The range of seroposi ti ve
findi ngs i n anesthesia personnel i n vari ous l ocations probably reflects the preval ence of HBV
carri ers i n the referral population for the area. Wi thi n the United States, studies conducted before
the wi despread usage of hepati ti s B vacci ne i ndi cated that the preval ence of hepatiti s B serol ogi c
markers in anesthesi a personnel ranged from 19 to 49%.
Acute HBV i nfecti on may be asymptomati c and usuall y resol ves wi thout si gni fi cant hepati c
damage. Less than 1% of acutely i nfected pati ents devel op ful mi nant hepatiti s. Approxi matel y
10% become chronic carriers of HBV (i .e., serol ogi c evi dence demonstrated for more than 6
months). Withi n 2 years, hal f of the chroni c carri ers resolve their i nfection wi thout si gni fi cant
hepati c i mpai rment. Chronic acti ve hepati ti s, which may progress to ci rrhosi s and i s li nked to
hepatocel l ul ar carcinoma, is found most commonl y i n individual s wi th chroni c vi ral i nfection for
more than 2 years. The implementati on of routi ne vacci nati on, use of standard precauti ons, use of
safety devi ces, and postexposure prophyl axis have si gni fi cantl y reduced the ri sk of occupational ly
acqui red HBV i nfecti on and i ts sequel ae i n HCW.
The di agnosi s and classi fi cation of the stage of HBV i nfection can be made on the basis of
serol ogi c testi ng. Anti body to the surface anti gen (anti -HBs) appears wi th resol uti on of the acute
infecti on and confers lasti ng immuni ty agai nst subsequent HBV i nfections. Chronic HBV carriers
are likely to have hepatitis B surface anti gen (HBsAg) and anti body to the core antigen (anti -HBc)
present in serum sampl es. The presence of hepati ti s B e anti gen (HBeAg) i n serum i s i ndi cative of
acti ve vi ral repl icati on i n hepatocytes.
Anesthesi a personnel are at ri sk for occupational ly acquired HBV infecti on as a resul t of acci dental
percutaneous or mucosal contact wi th bl ood or body fl uids from i nfected pati ents. Pati ent groups
wi th a hi gh preval ence of HBV include immigrants from endemic areas, users of il l ici t parenteral
drugs, homosexual men, and pati ents on hemodi alysi s.
54
Carri ers are frequentl y not i denti fi ed
duri ng hospital i zati on because the cl i ni cal history and routine preoperative laboratory tests may
be insufficient for diagnosis. The ri sk for infecti on after an HBV-contami nated percutaneous
exposure, such as an acci dental needle sti ck, i s 37 to 62% i f the source patient is HBeAg-positi ve
and 23 to 37% i f HBeAg-negati ve. HBV can be found i n sal iva, but the rate of transmission is
si gni fi cantl y less after mucosal contact wi th infected oral secreti ons than after percutaneous
exposures to bl ood. HBV i s a hardy vi rus that may be i nfecti ous for at l east 1 week i n dri ed bl ood
on envi ronmental surfaces.
Hepatitis B Vaccine. Use of hepati tis B vacci ne i s the pri mary strategy to prevent
occupati onal transmi ssi on of HBV to anesthesia personnel and other HCW at i ncreased ri sk.
54

Admi ni strati on of three doses of vacci ne i nto the del toi d muscl e resul ts in the producti on of
protecti ve anti bodies (anti -HBs) in more than 90% of heal thy HCW. Hospitals or anesthesia
departments should have poli cies for educati ng, screeni ng, and counsel ing personnel about their
ri sk of acquiri ng HBV i nfecti on and shoul d make vacci nati on avai labl e for suscepti bl e
personnel .
54, 65

To ensure adequate postvaccinati on i mmunity, serol ogi c testi ng for anti -HBs shoul d take place
within 1 to 2 months after the third dose of vacci ne.
54
Protecti ve anti bodi es devel op in 30 to 50%
of nonresponders (i .e., anti -HBs <10 mIU/mL) wi th a second 3-dose vacci ne seri es.
Nonresponders to vacci nation, who are HBsAg-negati ve, remain at ri sk for HBV infecti on and
should be counsel ed on strategi es to prevent infecti ons and the need for postexposure
prophyl axi s.
Vaccine-induced antibodies decli ne over ti me, with maxi mum titers after vacci nation correlating
di rectl y wi th duration of anti body persi stence. The CDC states that for vacci nated adults wi th
normal i mmune status, routine booster doses are not necessary and periodi c moni tori ng of
anti body concentrati on is not recommended.
54

When suscepti bl e or nonvacci nated anesthesia personnel have a documented exposure to a
contami nated needle or to bl ood from an HBsAg-positi ve pati ent, postexposure prophyl axis with
HBV hyperimmune gl obuli n (HBIG) i s recommended.
54
Hepati ti s B vacci ne should be offered to any
unvaccinated, suscepti bl e person who sustai ns a bl ood or body fl ui d exposure.
Hepatitis C
Hepati ti s C virus causes most cases of parenteral ly transmi tted NANBH and i s a l eadi ng cause of
chroni c li ver di sease in the Uni ted States. Al though anti body to HCV (anti -HCV) can be detected i n
most pati ents wi th hepati tis C, i ts presence does not correlate wi th resolution of the acute
infecti on or progressi on of hepati ti s, and i t does not confer immuni ty agai nst HCV infecti on.
66

Seropositi vi ty for HCV RNA, usi ng polymerase chain reaction, is a marker of chroni c i nfection and
conti nued vi ral presence.
Most cases of acute HCV infecti on are asymptomati c, but i nfected indi vi duals have a hi gh rate of
progressi on to chroni c hepatiti s. Up to 60% of HCV-infected pati ents wi l l have bi opsy-proven
chroni c hepati tis, with many developi ng ci rrhosis. HCV RNA can sti l l be detected i n more than 75%
of patients after resoluti on of acute hepati tis C.
66
Combi nati on therapy wi th i nterferon and
ri baviri n has been effecti ve i n the treatment of some cases of chroni c hepati tis C. In a l imi ted
cl i ni cal tri al , interferon al fa-2b was effecti ve i n preventi ng chroni c hepati tis C i n pati ents wi th
acute i nfection.
67

Li ke HBV, HCV i s transmi tted through bl ood and sexual contact, but the rate of occupational HCV
infecti on i s less than for HBV. Al though HCV transmi ssi on has been documented in heal th care
setti ngs, the preval ence of anti -HCV i n HCW i n the

Uni ted States i s not greater than that found in the general popul ati on. The greatest risk of
occupati onal HCV transmi ssion i s associ ated wi th exposure to bl ood from an HCV-positi ve source,
and the average rate of seroconversi on after accidental percutaneous exposure i s 1.8%.
54
HCV has
been transmi tted through blood spl ashes to the eye and wi th exposure via nonintact skin. HCV i n
dri ed blood on envi ronmental surfaces may remain i nfectious for up to 16 hours, but
envi ronmental contaminati on does not appear to be a common route of transmi ssi on. Al though
HCV can be found i n the sal i va of i nfected i ndi vi dual s, i t i s not beli eved to represent a great ri sk
for occupational transmi ssi on.
54

There i s no vaccine or effecti ve postexposure prophyl axi s avai l able to prevent HCV i nfection, and
use of i mmune gl obul in i s no l onger recommended after a known exposure.
54
The effecti veness of
interferon has not been documented as effecti ve prophyl axis after occupati onal exposure.
Preventi on of exposures remai ns as the pri mary strategy for protecti ng HCW against HCV
infecti on. Personnel who have had a percutaneous or mucosal exposure to HCV-posi ti ve bl ood
should have serologi c testi ng for anti -HCV and al ani ne ami notransferase and counsel ing at the
ti me of the exposure and at 6 months.
54

Pathogenic Human Retroviruses
HIV Infection and AIDS
The agent that produces acqui red i mmunodefici ency syndrome (AIDS) is the human
immunodefici ency virus (HIV), one of several pathogeni c human retrovi ruses. Current estimates
suggest that 650,000 to 900,000 people in the United States are i nfected wi th HIV. According to
CDC data, from 1981 through December 2002 there have been 859,000 cases of AIDS i n the
United States.
68

The i ni ti al infecti on with HIV presents cl i ni cal l y as a mononucl eosi s-li ke syndrome with
l ymphadenopathy and rash. Al though the pati ent then enters an asymptomati c peri od, monocyte-
macrophage cel ls serve as a reservoi r for the virus throughout the body, and CD4+ T cell s harbor
the vi rus in the bl ood. Wi thi n a few weeks after i nfecti on, an anti body may be detected by the
enzyme-li nked immunosorbent assay (ELISA) and i s confi rmed usi ng the more speci fi c Western
bl ot test. After a variabl e l ength period of asymptomati c HIV infecti on, there i s an i ncrease in vi ral
ti ter and i mpai red host i mmuni ty, resul ting i n opportunistic i nfections and mal i gnanci es
characteri sti c of AIDS. As the use of highl y acti ve anti retrovi ral therapy became wi despread i n the
P.89
Uni ted States i n 1996, the average l ength of survi val after HIV i nfecti on increased.
HIV is spread by sexual contact (especi al l y homosexual mal es), peri natal l y from i nfected mother
to neonate, and through i nfected bl ood (transfusi on or shared needles) and bl ood products.
Although the virus can be found in sal i va, tears, and uri ne, these body fl uids have a low risk for
viral transmi ssi on. Many HIV-infected pati ents i n heal th care setti ngs may not be identi fi ed as
such by thei r i ni ti al or presenti ng di agnosi s.
Risk of Occupational Human Immunodeficiency Virus Infection. Al though there are several
modes of transmission for HIV infecti on i n the communi ty, the most important source for
occupati onal transmi ssi on of HIV to HCW i s bl ood contact.
54
The rate of seroconversi on i n heal th
care workers sustaining a percutaneous exposure (needl e sti ck i njury) to HIV-infected bl ood i s
estimated to be 0.3%,
69
whi l e the rate after a mucous membrane exposure i s 0.09%.
70

Transmi ssi on has occurred after bl ood exposure to noni ntact ski n, but although the rate i s
unknown, it i s li kel y less than for mucous membrane exposure.
A case-control study has demonstrated that speci fi c factors are associ ated wi th an increased rate
of HIV transmi ssi on after a percutaneous injury.
71
Increased ri sk was associ ated wi th a deep
i njury, vi si bl e bl ood on the devi ce produci ng the i njury, a procedure i n whi ch the needl e was
pl aced in an artery or vein, and termi nal il l ness (death from AIDS within 2 months) in the source
patient. Therefore, the risk of occupati onal HIV transmi ssi on i s greatest after a deep i njury wi th a
bl ood-fil l ed, l arge-gauge, holl ow-bore needl e used on a pati ent i n the termi nal phase of AIDS.
The occupational ri sk of HIV infecti on i s a functi on of the annual number of blood exposures, the
rate of HIV transmi ssi on wi th each exposure to infected bl ood, and the preval ence of HIV infecti on
in the speci fi c pati ent population. Greene et al prospectively col lected data on 138 contami nated
percutaneous injuries to anesthesi a personnel .
72
The rate of contaminated percutaneous i njuri es
per year per full -ti me equival ent anesthesi a worker was 0.42, and the average annual ri sk of HIV
and HCV infecti on was esti mated to be 0.0016 and 0.015%, respecti vel y.
Anesthesi a personnel are frequentl y exposed to bl ood and body fl ui ds during i nvasive procedures
such as inserti on of vascul ar catheters, arteri al punctures, and endotracheal intubati on.
51, 72, 73

Although many exposures are mucocutaneous and can be prevented by the use of gloves and
protecti ve cl othing, these barri ers do not prevent percutaneous exposures such as needl e sti ck
injuries, whi ch carry a greater risk for pathogen transmi ssi on. Because of the tasks they perform,
anesthesia personnel are l ikel y to use and be i njured by l arge-bore, hol low needl es such as IV
catheter stylets and needl es on syringes.
72, 74
Needl eless or protected needle safety devi ces can be
used to repl ace standard devi ces to reduce the risk of needl e sti ck i njuri es. Al though safety
devices usual ly are more expensi ve than a comparable nonsafety item, they may be more cost-
effecti ve when the cost of needle sti ck i njury investi gati on and medi cal care for i nfected personnel
is consi dered.
Percutaneous injuries have now been accepted as a si gnificant occupati onal ri sk for health care
workers.
51
The Needlestick Safety and Prevention Act of 2000 mandated that OSHA update i ts
Bl oodborne Pathogen Standard to require that exposure control pl ans i ncl ude a process for
eval uating and i mpl ementi ng the use of commerci all y avai l abl e safety medi cal devi ces.
65

Empl oyers were also required to mai ntain a sharps injury l og to coll ect data to evaluate
exposure risks and the effectiveness of safety devi ces. Because federal regul ati ons require the use
of safety devi ces, as new technologi es become avail able, cl ini ci ans must assess these within thei r
practi ce to determi ne whi ch are most effective for specific tasks.
Postexposure Treatment and Prophylactic Antiretroviral Therapy. When personnel have been
exposed to pati ents' bl ood or body fl ui ds, the i nci dent shoul d i mmedi atel y be reported to the
employee heal th service or the designated i ndi vi dual wi thi n the i nstituti on. Based on the nature of
the injury, the exposed worker and the source i ndi vi dual shoul d be tested for serol ogi c evi dence of
HIV, HBV, and HCV infection.
54
Current local l aws must be consul ted to determi ne pol i ci es for
testi ng the source pati ent, and confi denti al i ty must be mai ntai ned. When the source pati ent i s
found to be HIV-positi ve, the employee shoul d be retested for HIV antibodi es at 6 and 12 weeks
and at 6 months after exposure, al though most i nfected peopl e are expected to undergo
seroconversi on wi thi n the fi rst 6 to 12 weeks. Duri ng thi s peri od, the exposed empl oyee should
fol l ow CDC recommendations for preventing transmi ssi on of HIV to fami l y members and pati ents.
54

If the source pati ent i s found to be HIV-negati ve, no additi onal treatment is requi red.
The U.S. Publ i c Heal th Servi ce recommends that antiretroviral postexposure prophyl axis (PEP) be
offered to HCW who have i ncurred a si gni fi cant percutaneous exposure to HIV-i nfected bl ood.
54

The speci fi c antiretroviral regi men is

based on the severity of exposure and the source pati ent. Because protocol s for chemoprophyl axi s
are li kel y to change with addi tional research and the i ntroduction of new anti retrovi ral drugs, the
most current recommendati ons, such as those provi ded on the CDC website (http://0-
www.cdc.gov.i nnopac.up.ac.za:80/niosh/topi cs/bbp), shoul d be consulted pri or to i nsti tuti ng
postexposure prophylacti c therapy. To be most effecti ve, PEP shoul d be i ni ti ated as soon as
possi bl e after exposure (l ess than 24 hours) and conti nued for 4 weeks. HCW should be counsel ed
on the potenti al toxic effects of antiretrovirals so that they can make an i nformed deci sion on the
ri sks associ ated wi th PEP. Fai l ure of PEP has been attri buted to large vi ral inoculum, use of a
si ngl e antiviral agent, drug resistance in the vi rus from the source pati ent, and del ayed i ni ti ati on
or short durati on of PEP therapy.
Occupational Safety and Health Administration Standards,
Universal Precautions, and Isolation Precautions
In the l ate 1980s the CDC formul ated recommendati ons, or uni versal precautions, for preventing
transmi ssi on of bl oodborne i nfecti ons (i ncl udi ng HIV, HBV, and HCV) to HCW. The gui deli nes were
based on the epi demi ol ogy of HBV as a worst-case model for transmi ssi on of bl oodborne i nfecti ons
and current knowl edge of the epi demi ol ogy of HIV and HCV. Because some carri ers of bl oodborne
viruses could not be identi fi ed, uni versal precautions were recommended for use during all pati ent
contact. Al though exposure to blood carri es the greatest ri sk of occupati onal l y related
transmi ssi on of HIV, HBV, and HCV, i t was recogni zed that uni versal precauti ons shoul d also be
appl ied to semen, vagi nal secreti ons, human ti ssues, and the fol l owi ng body fl ui ds: cerebrospi nal ,
synovial , pl eural , peri toneal , peri cardi al , and amni oti c. Subsequentl y, the CDC synthesized the
major features of uni versal precautions into standard precauti ons, a si ngl e set of precauti ons that
should be appl i ed to al l pati ents (Tabl e 4-5).
59
Standard precautions were i ncl uded i n a more
compl ete set of i sol ati on precautions, whi ch contai n gui del i nes (ai rborne precautions, dropl et
precauti ons, and contact precautions) to reduce the risk of transmi ssi on of bl oodborne and other
pathogens i n heal th care setti ngs.
59

Standard precauti ons i ncl ude the use of gloves when an HCW contacts mucous membranes and
oral fl ui ds, such as duri ng endotracheal i ntubati on and pharyngeal sucti oning. The sel ecti on of
specific barri ers or personal protecti ve equi pment should be commensurate wi th the task bei ng
performed. Gloves may be al l that is necessary duri ng i nserti on of a peri pheral intravenous
catheter, whereas gl oves, gown, mask, and face shi el d may be requi red duri ng endotracheal
intubati on i n a pati ent with hematemesi s. Gl oves shoul d be removed after they become
contami nated to prevent dissemi nati on of bl ood or body fl ui ds to equi pment or other i tems that
may be contacted by ungl oved personnel . Waterless anti septi cs should be avai l abl e to permi t
anesthesia personnel to wash thei r hands after gl ove removal without l eaving the operati ng room.
OSHA has promul gated Standards to protect empl oyees from occupati onal exposure to bl oodborne
pathogens.
65
Employers subject to OSHA must compl y wi th these federal regulations. The
Standard requi res that there must be an Exposure Control Plan speci fi cal ly detai li ng the methods
that the employer is providi ng to reduce empl oyees' risk of exposure. The empl oyer must evaluate
engineeri ng control s such as needl eless devi ces to el i mi nate hazards. Work practi ce control s are
encouraged to reduce bl ood exposures by al tering the manner i n whi ch personnel perform tasks
(e.g., an i nstrument rather than fi ngers shoul d be used to handle needles). The employer must
furni sh appropri ate personal protecti ve equi pment (e.g., gl oves, gowns) in various si zes to permi t
employees to compl y wi th uni versal precauti ons. The HBV vaccine must be offered at no charge to
personnel . A mechanism for postexposure treatment and fol l ow-up must be provi ded. An annual
educational program shoul d i nform empl oyees of thei r ri sk for bl oodborne i nfecti on and the
P.90
resources avai l abl e to prevent bl ood exposures. Impl ementati on of standard precauti ons and OSHA
regul ati ons have been effecti ve i n decreasi ng the number of exposure inci dents that resul t in HCW
contact wi th pati ent bl ood and body fl ui ds.
Creutzfeldt-Jakob Disease
Creutzfel dt-Jakob di sease (CJD), caused by an infectious protein or pri on, may be unsuspected i n
patients presenti ng wi th dementi a.
75
More recentl y, i t has been recogni zed that the pri on strain
associated wi th bovi ne spongiform encephal opathy has i nfected humans to produce a vari ant CJD.
Iatrogenic transmission of CJD to pati ents has taken pl ace through contaminated bi ol ogic products
and surgi cal i nstruments and vi a blood transfusi on. The ri sk of transmi ssi on to hospi tal personnel
is unknown because survei ll ance i s compl i cated by the l ong period from the ti me of i nfecti on unti l
the onset of symptoms. Uni versal precauti ons shoul d be used. Tissues wi th greatest ri sk of
infecti vi ty are brai n, spi nal cord, and eyes.
The prion is di ffi cul t to eradi cate from equi pment, and speci al steri l i zati on methods are requi red
for i nstruments that come i nto contact with hi gh-infecti vi ty tissues. The Worl d Heal th Organi zation
has developed i nfecti on control and steri l ization gui deli nes for CJD (http://0-
www.who.int.innopac.up.ac.za:80/emc-documents/tse/docs/whocdscsraph2003.pdf). The pri on i s
not transmitted through respi ratory routes.
Tuberculosis
The i nci dence of tubercul osi s i n the Uni ted States has decl ined si nce 1992, reversi ng the increase
in reported cases that had begun in 1986. Al though most i ndi vi duals i nfected wi th tubercul osis are
treated on an outpatient basis, undi agnosed pati ents may be hospitali zed for the workup of
pul monary pathol ogy. Hospi tal personnel are especi ally at risk for infection from unrecognized
cases.
76, 77
Groups wi th a hi gher prevalence of tubercul osi s include (1) personal contacts of people
with active tubercul osi s; (2) people from countries with a high preval ence of tubercul osi s; and (3)
al cohol ics, homel ess people, and i ntravenous drug users.
76

Mycobacteri um tuberculosis is transmitted through vi able bacil l i carri ed on airborne parti cles, 1 to
5 m i n si ze, by coughi ng, speaki ng, or sneezi ng. Airborne infecti on i sol ati on shoul d be used for
hospi tal ized pati ents suspected of havi ng tubercul osi s unti l they are confirmed as nontransmi tters
by sputum exami nati on that demonstrates no baci ll i .
76
Appropri ate chemotherapy i s the most
effecti ve means to prevent spread of tuberculous infection.
78
El ecti ve surgery shoul d be postponed
unti l infected patients have had an adequate course of chemotherapy. If surgery is requi red,
fil ters shoul d be used on the anestheti c breathi ng ci rcuit for pati ents wi th tuberculosis.
76, 79

Several hospi tal outbreaks of mul ti drug-resistant M. tubercul osi s infection have been reported.
77, 80

Mortali ty associated wi th these outbreaks is high. Factors responsibl e for nosocomial transmi ssi on
i ncl ude del ayed di agnosi s of tubercul osi s so that multi ple patients and personnel were exposed
and delayed recogni tion of drug resi stance resul ting i n i nadequate ini ti al drug therapy.
Effective prevention of spread to HCW requi res earl y identi fi cati on of i nfected pati ents and
immedi ate i ni ti ati on of ai rborne i nfecti on i sol ati on (negati ve-pressure rooms with

ai r vented outsi de; see Tabl e 4-5).
76, 79
Pati ents must remai n i n i sol ati on until adequate treatment
i s documented. If pati ents with tubercul osi s must l eave their rooms, they should wear face masks
to prevent spread of organi sms into the ai r. HCW shoul d wear respi ratory protecti ve devices when
they enter an i sol ati on room or when performi ng procedures that may i nduce coughing, such as
endotracheal intubati on or tracheal sucti oni ng.
76
The CDC recommends that respi ratory protecti ve
devices worn to protect against M. tubercul osi s shoul d be abl e to fi l ter 95% of particl es 1 mm i n
size at flow rates of 50 li ters per mi nute and should fi t the face with a leakage rate around the
seal of l ess than 10% documented by fi t testi ng.
76
Hi gh-effi ci ency parti cul ate air respi rators
(cl assi fi ed as N95) are NIOSH-approved devi ces that meet the CDC cri teri a for respi ratory
protecti ve devices agai nst M. tubercul osi s.
81

Routi ne periodi c screening of empl oyees for tuberculosi s shoul d be i ncl uded as part of a hospi tal ' s
P.91
employee heal th pol icy with the frequency of screeni ng dependent on the preval ence of i nfected
patients i n the hospitali zed population. When a new conversi on i s detected by ski n testi ng, a
hi story of exposure shoul d be sought to determi ne the source pati ent. Treatment or preventi ve
therapy i s based on the drug-suscepti bi l ity pattern of the M. tubercul osi s in the source patient, if
known. Personnel who have been exposed to a pati ent wi th acti ve tubercul osi s shoul d be foll owed
by ski n testi ng.
Viruses in Smoke Plumes
The l aser is commonl y used for vapori zing carci nomatous and vi ral tumors. Use of lasers and
el ectrosurgi cal devi ces i s associ ated wi th several hazards, both to pati ents and to operati ng room
personnel . Risks i ncl ude thermal burns, eye injuries, el ectrical hazards, and fires and expl osi ons.
There i s evi dence that the smoke plumes resulti ng from ti ssue vapori zation contain toxic
chemi cal s such as benzene and formal dehyde, and i n 1996, NIOSH rel eased a Heal th Hazard Al ert
on the dangers of smoke plumes.
82

Cli nical and laboratory studies have demonstrated that when the carbon di oxi de l aser i s used to
treat verrucae (papi l loma and warts), i ntact vi ral DNA coul d be recovered from the pl ume. Vi able
viruses can be found i n pl umes produced by both carbon di oxi de and argon l aser vapori zation of a
virus-loaded culture pl ate, but viabl e vi ruses are carri ed on l arger parti cles that travel l ess than
100 mm from the si te bei ng vapori zed.
83

A case report descri bes laryngeal papi ll omatosis i n a surgeon who had used a l aser to remove
anogeni tal condyl omas from several patients.
84
Al though DNA anal ysi s of the surgeon' s papi l l omas
revealed a viral type si mi l ar to that of the condyl omas, proof of transmi ssi on is l acking.
To protect operati ng room personnel from exposure to the vi ral and chemi cal content of the l aser
pl ume, i t i s recommended that a smoke evacuati on system be util i zed with the sucti on nozzl e
bei ng hel d as cl ose as possi ble to the ti ssue bei ng vapori zed.
85
In addi ti on, operati ng room
personnel working i n the vici ni ty of the l aser pl ume shoul d wear gloves, goggl es, and hi gh-
effi ci ency fil ter masks.
73

EMOTIONAL CONSIDERATIONS
Stress
Stress i s a wel l -recognized element of the operati ng room workpl ace. However, there i s very l i ttle
objecti ve information speci ficall y directed toward understanding the nature of job-rel ated stress
among anesthesi ol ogi sts.
86

Stress i s a nonspeci fi c response to any change, demand, pressure, chal l enge, threat, or trauma.
87

There are three distinct components of the stress response: the i ni tiating stressors, the
psychol ogi cal fil ters that process and evaluate the stressors, and the copi ng mechani sms that are
employed i n an attempt to control the stressful si tuati on.
Stress on the job i s unavoi dabl e and to a certai n degree i s desirabl e. A moderate, manageable
level of stress is the fuel necessary for indi vi dual achi evement. Hans Seyl e, one of the pioneering
sci enti sts i n the modern study of stress, descri bed a benefi ci al effect resul ting from mil d, bri ef
and control l abl e epi sodes of stress.
88
In Seyl e's words, The absence of stress i s death. On the
other hand, extreme degrees of stress can be associated wi th di sorders of the psychologi cal
homeostati c mechani sm and consequentl y can l ead to physi cal or mental disease. Exactl y how an
i ndi vi dual responds to a parti cul ar stressor is the product of a seri es of factors, including age,
gender, experi ence, preexi sti ng personali ty styl e, avail able defense and copi ng mechani sms,
support systems, and concomi tant events (such as sl eep depri vati on).
A number of circumstances that cl assi cal ly defi ne a stressful workpl ace are characteri sti c of the
practi ce of anesthesiol ogy. There i s a background of chroni c, l ow-level stress punctuated by
intermi ttent epi sodes of extreme stress. The demands are external l y paced, usual ly out of the
anesthesiol ogi st' s control . Habi tuati on to the demands i s diffi cult. Perturbati ons are i ntermittentl y
but conti nuousl y inserted into the system. Fi nal l y, fai lure to meet the demands i mposed by the
workpl ace produces grave consequences.
Certai n stressors are speci fi c to the practi ce of anesthesi ol ogy. Concerns about l iabi li ty, l ong
worki ng hours and ni ght cal l , producti on pressures, economi c uncertainty, and i nterpersonal
rel ati ons are frequentl y ci ted as sources of chroni c stress for anesthesiol ogi sts. The process of
inducing anesthesi a (parti cul arl y wi th a di fficul t airway) can be among the most profound sources
of acute stress to anesthesi ol ogists. Physi ol ogi c changes, including heart rate and rhythm,
el evati ons i n bl ood pressure, and myocardi al ischemia, are not uncommon. One study reported
i ncreases i n the bl ood pressure and heart rate of anesthesiol ogi sts duri ng al l stages of the
anesthetic procedure, especial l y duri ng the i nducti on.
89
There was an i nverse rel ati onship between
the years of experience of the anesthesi ol ogi st and the degree of stress as mani fested by heart
rate change.
Interpersonal relationshi ps i mpose a set of demands that can be a major source of stress to an
anesthesiol ogi st. The operati ng room i s unique as one of the few hospital si tes where two co-equal
physi ci ans simul taneousl y share responsibi l ity for the care of a pati ent. This creates a si tuati on i n
whi ch there are overl appi ng realms of cl i ni cal responsi bil i ty that can upset the customary
hi erarchy of command. To many anesthesi ologi sts, as well as surgeons, thi s shared responsibi l ity
is the source of greatest confl i ct and professi onal stress. Other workpl ace setti ngs, most notabl y
the ai rli ne industry, have made better progress i n i denti fyi ng and correcti ng sources of
interpersonal fri cti on that faci li tate stress and lead to professi onal errors.
90

Several personal i ty traits, i n many cases i denti fi abl e before entrance to medi cal school, can be
predi cti ve of the potenti al toward maladapti ve responses to stress. Promi nent among these is the
obsessi ve-compulsi ve, dependent character structure. These i ndi vi dual s typicall y mani fest
pessimi sm, passi vi ty, sel f-doubt, and feeli ngs of insecuri ty. Commonly they respond to stress by
i nternal i zi ng anger and becomi ng hypochondri acal and depressed. Undergraduate students who
demonstrate these characteri sti cs were more l i kel y to have thei r medi cal careers di srupted by
al cohol ism or drug abuse, psychi atric i ll ness, and mari tal disturbances.
91
McDonal d et al
92
appl i ed
some of these considerati ons i n an attempt to identi fy psychol ogical attri butes that may be of
val ue in the sel ection

process for anesthesiol ogy residents. A large number of adaptive copi ng functions have been
advocated for successful stress management.
87
Only when appropriate coping mechanisms become
overwhel med by the magni tude of the stress do the defenses tend to become i nappropri ate. Thi s
si tuati on may give ri se to mal adapti ve behavi or and the personal and professi onal deteri orati on
that can l ead to disorders such as drug addi cti on, professi onal burnout, and sui ci de.
Substance Use, Abuse, and Dependence
Il l ici t drug use remai ns one of our soci ety' s major affl i cti ons. It is estimated that 20 mi ll i on
Ameri cans are drug abusers, with some 5 million addicted. Substance abuse i s characteri zed by
si gni fi cant adverse consequences resulti ng from the repeated use of a substance.
93
With chemi cal
dependence, the i ndi vi dual conti nues to use a substance i n spi te of havi ng si gni fi cant substance-
rel ated probl ems i ncludi ng symptoms of withdrawal, the need for l arger amounts of the substance,
unsuccessful attempts to control its use, and the need to spend i ncreasing amounts of time
seeki ng the substance. With ti me, chemi cal dependence l eads to health, social , and economi c
problems.
Epidemiology
The abuse of drugs and consequent chemi cal dependency by physi ci ans has attracted considerabl e
media attenti on and notori ety. Recogni tion of the probl em of substance dependence among
physi ci ans i s not new. In the fi rst editi on of The Pri nci pl es and Practi ce of Medici ne, edited by Sir
Wi l li am Osler and publi shed i n 1892, it i s stated: The habi t (morphi a) i s parti cul arl y preval ent
among women and physi cians who use the hypodermi c syri nge for the all evi ati on of pain, as i n
neural gi a or sci ati ca.
P.92
It i s debatabl e whether substance abuse is more preval ent among physi ci ans than the general
popul ati on. Hughes et al
94
found that physici ans abused al cohol , minor opi ates, and
benzodiazepi ne tranqui li zers more frequently than the general popul ati on. In many cases, the
prescripti on drugs were sel f-prescri bed and were consi dered by the physi ci an to be sel f-
treatment. On the other hand, physi cians were l ess l i kely to use tobacco or i ll i ci t substances. A
report from the National Institute on Drug Abuse concl udes that HCW suffer from chemi cal
dependency (i ncluding alcohol abuse) at a rate roughl y equi valent to that of the general
popul ati on (8 to 12%).
95

In the event that a drug-rel ated probl em does exi st, physici ans are less l ikel y than the popul ati on
in general to seek professi onal assi stance. Deni al pl ays a major rol e i n this reluctance to undergo
counsel i ng or therapy. Medical students l earn early in thei r educati on to uti l ize deni al to enable
them to endure long, sl eepless nights and the personal shortcomings that i nevitably accompany
the practi ce of medi ci ne. These wel l -devel oped denial mechani sms enable the physi ci an-addi ct to
concl ude that hi s or her probl em is minor and that sel f-treatment i s possi ble. Physi ci ans typi cal ly
enter programs for treatment only after they have reached the end stages of thei r i l lness.
It i s commonly reported that chemi cal dependency i s a speci fic probl em for the special ty of
anesthesi ol ogy and represents i ts pri mary occupati onal hazard.
96
One exampl e of the
increased i nci dence of substance abuse reported among anesthesiol ogi sts comes from the Medi cal
Associ ati on of Georgi a Disabled Doctors' Program.
97
Anesthesi ologi sts consti tuted 12% of
physi ci an pati ents treated at the center although they represented onl y 3.9% of Ameri can
physi ci ans. On the other hand, other studies have failed to identify an overal l excess preval ence
of substance abuse among anesthesi ol ogists wi th the notabl e excepti on of major opi ates.
98, 99

One very troubl i ng aspect of thi s problem i s the increased incidence of substance abuse reported
among anesthesi ol ogy resi dents. In the report from the Medi cal Association of Georgia Di sabl ed
Doctors' Program,
97
anesthesi ol ogy resi dents constituted 33.7% of the resi dent popul ati on of the
treatment group, despite representing onl y 4.6% of the resi dent popul ati on.
The i nci dence of control l ed substance abuse wi thi n anesthesi ology training programs is esti mated
to be 1 to 2%.
100
Thi s stati sti c i s parti cul arl y troubl i ng because it has persi sted despi te the
increased emphasi s placed on educati on and accountabi l ity of control l ed substances in the recent
decade. ACGME requi rements mandate that anesthesi ology residency programs have a written
pol icy and an educati onal program regarding substance abuse, but these efforts have not
successful ly addressed the problem of substance abuse i n trai ni ng programs.
The Disease of Substance Dependence
What accounts for thi s unacceptably hi gh preval ence of substance dependence among
anesthesiol ogi sts? To answer thi s, it i s i mportant to understand substance dependence as a
chroni c psychosoci al, biogenetic disease.
101
Addiction shares many characteri sti cs wi th other
common chronic i l lnesses: (1) it i s a pri mary condi tion (not a symptom), (2) it has establ ished
eti ol ogi es, (3) it i s associ ated wi th specifi c anatomi c and physiol ogi c changes, (4) i t has a set of
recogni zabl e si gns and symptoms, and (5) if left untreated, i t has a predi ctabl e, progressi ve
course.
The causative factors i n thi s di sease process i nvol ve a genetic predi spositi on as well as the
envi ronment. The disease results from a dynamic interpl ay between a suscepti ble host and a
favorabl e envi ronment. Vul nerabi l ity in the host i s an important factor. What consti tutes an
i nsti gati ng exposure to a drug i n one person may have absol utel y no effect on another.
Unfortunatel y, there i s not a predi cti ve tool to i denti fy the susceptibl e i ndi vi dual until he or she
gets the di sease.
Causative factors thought to be speci fi c to certain anesthesi ol ogi sts i ncl ude job stress, an
orientati on toward sel f-medicati on, lack of external recogniti on and self-respect, the avai labil i ty of
addi cti ng drugs, and a suscepti bl e premorbi d personal ity. Sel f-prescripti on and recreational use of
drugs are commonly seen as a prel ude to more extensi ve substance abuse and dependence. Of
concern are the i ncreasi ng recreati onal use of drugs among younger physi ci ans and medi cal
students and the choi ce of more potent drugs wi th enhanced potenti al for addiction, such as
cocai ne, the synthetic opi oi ds, propofol , and some of the newer i nhal ati on anestheti cs.
Anesthesi ol ogists work in a cl i mate in which l arge quanti ti es of powerful psychoacti ve drugs are
freel y avai lable. Anesthesi ologi sts are uni que because they usual ly prescri be as well as personal l y
administer these drugs i n contrast to most other physici ans who prescri be whi le others admi nister.
The experi ence from sol di ers i n the Uni ted States Army i n Vi etnam suggests that when there i s
easy access to narcotics, alcohol use decl i nes i n favor of use of opi ates. As each new syntheti c
opi oi d, anesthetic i nducti on agent, and inhal ati on anestheti c has become avai lable for cl inical use,
it has also become a drug of choice of abusi ng anesthesiologi sts. Because avai l abi l ity of drugs
does pl ay a role i n the onset of this di sease, attenti on has been di rected toward programs to
enforce i ncreased accountabi l ity and regulation of control led substances.
102
However, despi te
widespread appl i cation of protocol s to enforce greater accountabil i ty, such as satel li te pharmaci es
for operati ng sui tes, the frequency of substance abuse has changed li ttl e, i f at all , i n recent
years.
100

There i s an apparent associati on between behavi or before entering medical school and subsequent
development of

substance abuse.
103
Personal i ty profi l es of anesthesi ol ogi sts have suggested that a di sturbi ngl y
hi gh proporti on that may be associated wi th a predi spositi on toward mal adapti ve behavior. Tal bott
et al
97
have observed that many of the anesthesi a resi dents i n their treatment program
specificall y chose the speci alty of anesthesi ol ogy because of the known avail abil i ty of powerful
drugs.
The consequences of untreated chemi cal dependence are ul timatel y devastati ng. There i s a
gradual and i nexorabl e deterioration in professional , fami ly, and soci al rel ati onships. The
substance abuser becomes increasi ngl y wi thdrawn and i sol ated, first i n hi s or her personal l ife,
and ul timately i n hi s or her professi onal exi stence (Tabl e 4-6). Every attempt is made to mai ntai n
a facade of normal i ty at work, because discovery means isolation from the source of the abused
drug. When professi onal conduct i s fi nall y impai red such that i t i s apparent to the physi ci an' s
coll eagues, the disease i s approachi ng i ts end stage.
P.93
TABLE 4-6 Signs of Substance Abuse and Dependence
WHAT TO LOOK FOR OUTSIDE THE HOSPITAL
1. Addi cti on i s a di sease of lonel i ness and i solation. Addicts qui ckl y wi thdraw from
famil y, friends, and l ei sure acti vi ti es.
2. Addicts have unusual changes i n behavi or, i ncl udi ng wi de mood swi ngs and peri ods
of depressi on, anger, and i rri tabi li ty al ternating wi th peri ods of euphori a.
3. Unexpl ained overspendi ng, legal probl ems, gambl ing, extramari tal affai rs, and
i ncreased probl ems at work are commonl y seen i n addi cts.
4. An obvi ous physi cal sign of alcoholi sm i s the frequent smell of al cohol on the
breath.
5. Domestic stri fe, fights, and arguments may i ncrease i n number and i ntensi ty.
6. Sexual dri ve may significantly decrease.
7. Chi l dren may devel op behavi oral probl ems.
8. Some addi cts frequentl y change jobs over a peri od of several years i n an attempt
to fi nd a geographi c cure for thei r disease, or to hi de i t from coworkers.
9. Addi cts need to be near thei r drug source. For a heal th care professi onal, this
means long hours at the hospi tal , even when off duty. For al cohol ics, i t means
call i ng in sick to work. Al cohol ics may di sappear wi thout any expl anati on to bars or
hi di ng pl aces to dri nk secretl y.
10. Addi cts may suddenl y devel op the habi t of l ocki ng themselves in the bathroom or
other rooms whil e they are usi ng drugs.
11. Addicts frequently hi de pi ll s, syringes, or alcohol bottl es around the house.
12. Persons who i nject drugs may l eave bl oody swabs and syri nges containi ng bl ood-
ti nged l i qui d i n conspi cuous places.
13. Addi cts may di spl ay evi dence of withdrawal , especi all y diaphoresi s (sweati ng) and
tremors.
14. Narcoti c addi cts often have pi npoi nt pupi l s.
15. Wei ght l oss and pal e ski n are also common si gns of addi cti on.
16. Addi cts may be seen i njecti ng drugs.
17. Tragi cal l y, some addi cts are found comatose or dead before any of these si gns
have been recogni zed by others.
WHAT TO LOOK FOR INSIDE THE HOSPITAL
1. Addi cts si gn out ever-i ncreasi ng quanti ti es of narcoti cs.
2. Addicts frequently have unusual changes i n behavi or, such as wi de mood swings
and peri ods of depressi on, anger, and irritabi l ity al ternating wi th periods of
euphori a.
3. Charti ng becomes increasi ngl y sl oppy and unreadabl e.
4. Addicts often si gn out narcoti cs i n inappropri atel y hi gh doses for the operation
bei ng performed.
5. They refuse l unch and coffee reli ef.
6. Addicts l i ke to work al one i n order to use anestheti c techni ques wi thout narcoti cs,
fal si fy records, and di vert drugs for personal use.
7. They vol unteer for extra cases, often where l arge amounts of narcoti cs are
avai labl e (e.g., cardiac cases).
8. They frequentl y rel ieve others.
9. They' re often at the hospi tal when off duty, stayi ng cl ose to thei r drug suppl y to
prevent withdrawal .
10. They vol unteer frequentl y for extra cal l .
11. They' re often difficult to fi nd between cases, taki ng short naps after usi ng.
12. Addicted anesthesi a personnel may i nsi st on personal l y admini steri ng narcoti cs i n
the recovery room.
13. Addi cts make frequent requests for bathroom rel i ef. This i s usual ly where they use
drugs.
14. Addicts may wear long-sl eeved gowns to hide needl e tracks and al so to combat the
subjecti ve feel ing of col d they experi ence when usi ng narcotics.
15. Narcoti c addi cts often have pi npoi nt pupi l s.
16. An addi ct' s patients may come into the recovery room compl aini ng of pai n out of
proporti on to the amount of narcoti c charted on the anesthesia records.
17. Wei ght l oss and pal e ski n are also common si gns of addi cti on.
18. Addi cts may be seen i njecti ng drugs.
19. Untreated addi cts are found comatose.
20. Undetected addi cts are found dead.
Adapted from Farl ey WJ, Arnol d WP: Vi deotape: Unmasking addi cti on: Chemi cal
Dependency i n Anesthesi ology. Produced by Davi ds Producti ons, Parsi ppany, NJ, funded
by Janssen Pharmaceuti ca, Pi scataway, New Jersey, 1991.

In i ts end stage, substance dependence i s often a fatal i ll ness. Al exander et al
14
cal cul ated a
rel ati ve risk of 2.75 for drug-rel ated deaths among anesthesi ol ogi sts compared to interni sts. In
thei r study of substance abuse i n anesthesi ol ogists, Ward et al
104
reported that among the 334
confi rmed drug abusers, 27 di ed of drug overdose and i n another 3, abuse was discovered at
death. Gravenstei n et al
105
reported 7 deaths among 44 confi rmed drug abusers. Menk et al
106

found 14 drug-rel ated deaths among the 79 drug abusers who had been reenrol l ed in
anesthesiol ogy resi dencies after treatment.
In addi tion to heal th hazards, there are si gni fi cant legal and medi col egal consi derations that may
affect chemi cal l y dependent physi cians.
96
Laws and regul ations vary by state but they detai l the
necessary steps for handli ng the drug-abusi ng physi ci an. In many states discipl i nary acti on and
crimi nal penal ties can be i mposed on physi ci ans who knowi ngl y fail to report an i mpai red
coll eague. Di sci pl inary action taken agai nst an i mpai red physi ci an must also be reported to the
Nati onal Practi ti oner Data Bank to be in compli ance wi th federal l aw. State medi cal soci eties often
have well ness commi ttees, and when chemi cal l y dependent physi cians seek treatment through
this venue, the legal impact may be mi ti gated.
Debate conti nues regardi ng the issue of compul sory random drug testing of physi cians.
107

Preempl oyment and/or random drug screeni ng i s al ready wel l establ i shed i n various i ndustries,
especial ly those with hi gh publ i c heal th profi l es (nuclear, aviation, mi l itary). Many chai rs of
academic anesthesiology programs have indicated a wil l ingness to ini ti ate a program of random
drug screening of thei r staff.
100
Al though random drug testi ng is an establ i shed element of most
reentry contracts for recovering anesthesi ologists, seri ous questi ons remai n about the legali ty of
thi s approach and i ts effecti veness in preventi ng substance abuse. Because fentanyl and sufentani l
are the drugs abused by many chemicall y dependent anesthesi ologists and because routine drug
screens do not detect these agents, tests that effectively identi fy thei r use are expensi ve and
have l imited avail abil i ty.
When there i s suffi cient data to i dentify an anesthesiol ogi st as havi ng chemi cal dependence, an
interventi on shoul d be conducted by an experi enced i ndi vi dual . The purpose of the i ntervention is
to demonstrate to the anesthesi ol ogi st that they have the disease and to i mmedi atel y have them
enter a faci l ity for eval uati on and treatment. Treatment usual ly begins wi th i npatient therapy
progressi ng to outpati ent sessi ons. The fami l y i s acti vely i nvol ved wi th treatment, and the
i ndi vi dual begi ns associ ati on with Alcoholi cs Anonymous (AA) or Narcoti cs Anonymous (NA).
Controversy remai ns about the ul ti mate career path of the anesthesi ol ogi st in recovery from
chemi cal dependency. Wi thi n the general popul ati on, the reci divism rate approaches 60% for
pati ents who have been treated for drug dependency. However, physi cians are hi ghl y moti vated
and better rehabi l i tati on rates mi ght be expected. Reports by Tal bott et al
97
and Ward et al
104

provi ded early opti mi sm that i n many cases anesthesi ologists coul d be successful l y rehabil i tated
and safely returned to their practices. In a study that examined rel apse i n addi cted physi ci ans,
Repri nted wi th permi ssi on from Ameri can Soci ety of Anesthesi ol ogists: Task Force on
Chemical Dependence of the Committee on Occupational Health of Operati ng Room
Personnel : Chemical Dependence i n Anesthesi ol ogi sts: What You Need to Know When You
Need to Know It. Park Ri dge, Il l inoi s, Ameri can Soci ety of Anesthesiol ogi sts, 1998.
P.94
the rate of rel apse among anesthesi ol ogi sts was 40% and that of control physi ci ans was 44%.
108

Sustai ned recovery for longer than 2 years occurred i n 81% and 86%, respecti vel y. Although
these data suggested that the outcome for recoveri ng anesthesiol ogi sts was simi lar to other
physi ci ans, a study by Menk and col leagues
106
drew a different concl usion. Among 79 opi oi d-
dependent anesthesi ol ogy resi dents, there was a 66% (52 of 79) fail ure rate for successful
rehabi li tati on and return to practi ce. Even more di scouragi ng, there were 14 sui ci de or overdose
deaths among the 79 returni ng trainees. Thei r conclusi on was that redi rection into another
special ty i s the safer course after rehabil i tation of narcoti c-dependent resi dents.
Because of the contradi ctory data, no uni versal recommendations can be made about reentry i nto
the practi ce of anesthesi a after treatment. The American Board of Anesthesi ol ogy has establ i shed
a pol icy for candi dates wi th a hi story of alcohol i sm or il l egal use of drugs (Tabl e 4-7). To reenter
practi ce, the recoveri ng physi ci an must quali fy for a val i d l icense to practice medi cine and must
be recredenti al ed at their medi cal faci li ty. This must be done i n compl i ance wi th thei r state l aws
and regul ati ons that detai l the ci rcumstances under whi ch a recovering physi cian can return to
practi ce. Federal laws, such as the Americans wi th Di sabi l iti es Act, i mpose addi ti onal
consi derati ons. Addi ti onall y, a careful ly worded contract i s an i mportant fi rst step i n the reentry
process to defi ne the obl i gati ons of the physi ci an and the department.
96, 109
There shoul d al so be
regul ar meeti ngs with the departmental supervi sor to monitor the return process. It i s al so
general ly recommended that the returni ng anesthesiol ogi st not take ni ght or weekend cal l or
handl e opi oids wi thout di rect supervisi on for at l east the fi rst 3 months. Despi te al l of these
precauti ons, the potenti al for rel apse must be anti ci pated.
Guidel i nes from physi cian treatment centers may be helpful to assist i n the deci si ons surrounding
reentry.
93
Indi vi duals who, in most si tuati ons, can successfull y return to the
TABLE 4-7 Policy Statement of the American Board of Anesthesiology (ABA)
The Ameri cans with Disabil i ti es Act (ADA) protects indi vi duals wi th a hi story of al cohol
abuse or substance abuse who are not currentl y abusi ng al cohol or usi ng drugs il l egal l y.
The ABA supports the intent of the ADA.
The ABA wi ll admi t qual ified appl i cants and candi dates wi th a hi story of alcohol abuse to
its exami nati on system and to exami nati on i f, in response to i ts inqui ries, the ABA
recei ves acceptabl e documentati on that they do not currently pose a di rect threat to the
heal th and safety of others.
The ABA wi ll admi t qual ified appl icants and candidates wi th a hi story of i ll egal use of
drugs to i ts exami nation system and to exami nation if, i n response to its i nquiri es, the
ABA recei ves acceptable documentati on that they are not currentl y engaged i n the i l l egal
use of drugs.
After a candidate wi th a hi story of alcohol abuse or i ll egal use of drugs satisfi es the
examinati on requi rements for certi fi cation, the ABA wi ll determine whether i t shoul d
defer awarding i ts certi fi cation to the candi date for a peri od of ti me to avoi d certi fyi ng a
candi date who poses a direct threat to the heal th and safety of others. If the ABA
determi nes that deferral of the candi date' s certificati on i s appropri ate because the
candi date does currentl y pose a threat to the heal th and safety of others, the ABA will
assess the speci fi c circumstances of the candi date' s hi story of al cohol abuse or i l l egal
use of drugs to determine when the candi date should wri te the Board to request i ssuance
of its certi fi cati on.
Repri nted wi th permi ssion from Booklet of Information, Board Pol i ci es 6.01: Al cohol and
Substance Abuse. Ral eigh, North Carol i na, Ameri can Board of Anesthesi ol ogy, March
2004.

practi ce of anesthesiol ogy immedi atel y after treatment (Category I) accept and understand thei r
di sease and have no evi dence of accompanyi ng psychiatri c disorders. They have strong support
from their family, demonstrate a bal anced li festyle, are commi tted to thei r recovery contract, and
bond wi th AA or NA. Thei r anesthesi ol ogy department and hospi tal must be supporti ve of thei r
return, and the i ndi vi dual must have a sponsor that supports thei r return to anesthesi ology.
Category II i ncl udes those i ndi vi dual s who coul d possi bl y return to anesthesi ol ogy wi thi n a few
years. They must have no or minimal denial regardi ng thei r di sease and have no other psychi atric
di agnoses. Their recovery ski ll s are conti nual l y i mproving and they are i nvol ved, but not
necessari ly bonded, wi th AA/NA. Although thei r fami ly situation may be characterized as
dysfuncti onal , there should be tangi bl e evi dence of improvement.
Indi vi dual s who should not return to anesthesi ol ogy and woul d best be redi rected i nto another
medical speci al ty are i ncl uded i n Category III. These i ndi vi dual s may have had a hi story of
prol onged i ntravenous substance use and have experi enced rel apses and pri or treatment fai l ures.
Their di sease remai ns active, and they have coexisting severe psychi atri c diagnoses. Often, these
i ndi vi dual s entered anesthesiol ogy wi th an expectati on of bei ng able to readi ly obtain drugs.
Impairment
Substance abuse probably accounts for the majori ty of the cases of impai rment among physi ci ans.
(An i mpaired physi cian is defi ned as one whose performance as a professional person and as a
practi ti oner of the heal ing arts is i mpai red because of alcohol i sm, drug abuse, mental i l lness,
senil i ty, or disabl i ng di sease.
110
) Other factors that may lead to impai rment i ncl ude physical or
mental i l lness and deterioration associ ated wi th agi ng. Some authoriti es incl ude unwi ll i ngness or
inabi l ity to keep up wi th current l i terature and techni ques as a form of i mpai rment.
Data regardi ng the preval ence of these di sabl i ng di sorders are more diffi cult to obtain than are
those on drug abuse. Physici ans are admi tted to psychi atri c faci l i ti es for organi c psychoses,
personal i ty disorders, schizophreni a, neuroses, and affecti ve, di sorders, parti cul arl y depressi on.
It i s not surprisi ng that depression shoul d fi gure promi nentl y among the personal i ty
characteri sti cs of emoti onal l y i mpai red physici ans. One survey noted that approxi mately 30% of
medical interns were cl i ni cal l y depressed.
111
Indeed, when exaggerated, many of the personality
trai ts that ensure success i n the physi cian' s worl d, such as sel f-sacri fi ce, competiti veness,
achi evement orientation, deni al of feel i ngs, and i ntell ectual i zati on of emotions, may also serve as
ri sk factors for depressi on. Several studi es on alcoholi c physi cians have provi ded some i nsight into
this l i nk between achievement ori entati on and emotional di sturbance. In one study, more than hal f
of the al cohol i c physi ci ans graduated i n the upper one thi rd of thei r medi cal school class, 23%
were i n the upper one tenth, and onl y 5% were in the lower one third of their class.
112
Similarly, a
report on alcohol use i n medical school demonstrated better fi rst-year grades and higher scores on
Part I National Board of Medi cal Examiners tests among those students i denti fi ed as al cohol
abusers.
113
Al cohol abuse is l i kely a mani festation of psychol ogical di sturbance resulti ng from
excessive degrees of stress among some students who are most determined to have fl awless
records.
It can be di ffi cul t to appropri atel y respond to the probl ems imposed by the i mpai red or unsafe
anesthesiol ogi st.
114
Fortunatel y, most state legi slatures and medi cal societi es have formal
protocol s that address the i mpaired physi ci an. These programs are usuall y therapeutic and
nonpuni ti ve i n nature and provi de for a rel ati vel y nonthreatening environment for i ntervention for
the impai red physi cian. The l i cense suspensi on power of the State Board of Medi cal Examiners is
exercised onl y i n cases in which a real ri sk to the publ i c welfare exi sts and the i nvol ved physi ci an
is unwi l li ng to vol untari l y suspend practi ce and accept assistance. Management protocol s for
deal i ng wi th the i mpai red physi ci an are covered i n a seri es of articl es by Canavan.
115

The Aging Anesthesiologist
Littl e research has been di rected toward the chall enges faced by ol der anesthesi ol ogi sts.
43
Thi s i s
P.95
in contrast to the si tuati on i n most other i ndustries where stri ct attenti on i s paid to the
competence and wel l -bei ng of ol der workers. For exampl e, commerci al pi l ots are required to take
regul ar medical exami nati ons and conform to pol i ci es regardi ng hours of work.
There are no age-specific condi ti ons pl aced on state medi cal li censure or on the practi ce of
anesthesiol ogy. In most cases, the deci sion to li mit practice or reti re remai ns at the di screti on of
the i ndi vi dual anesthesi ol ogi st based on hi s or her sel f-eval uation. Since 2000, dipl omates of the
Ameri can Board of Anesthesi ol ogists have time-li mi ted certi fi cati on and must successful l y
compl ete the Mai ntenance of Certificati on i n Anesthesi ol ogy program every 10 years to document
conti nui ng quali fi cati ons and to mai ntai n certi fi cati on.
As a resul t of a number of demographi c factors, i ncluding the smal l er residency class si zes
observed during the mid 1990s, the mean age of the anesthesi ol ogy workforce i s increasi ng. The
greatest number (30%) of anesthesi ol ogi sts are between age 45 and 54 years of age, and 56% are
age 45 and ol der (up from 49% 10 years ago).
15

Several physi ol ogic changes frequentl y associated wi th aging have the potenti al of i mpacti ng on
an i ndi vi dual' s abil i ty to practice anesthesi ol ogy. Potenti al sources of i mpai rment i ncluding
decrements in hearing, vi si on, short-term memory, strength, and endurance may often be
compensated by other advantages conferred by ol der age, i ncl udi ng the experi ence acqui red by a
l i fel ong practi ce of the speci al ty.
One area of parti cul ar di fficul ty for anesthesi ol ogists i s maintai ni ng the stami na requi red for l ong
work shi fts and ni ght cal l . Superi mposed on a propensi ty to sl eep di sturbance, the demands of
ni ght cal l and associ ated sleep deprivati on are parti cularly di ffi cul t for older anesthesi ol ogi sts.
Ni ght call i s consi dered one of the most stressful aspects of practi ce and i s often ci ted as a reason
for reti rement among older anesthesi ol ogi sts.
Aging among anesthesi ologi sts rai ses i nteresting l egal i ssues. A number of federal l aws potential ly
impact the aging anesthesi ol ogist's and hi s or her col l eagues' deci si ons whether to conti nue to
work and under what arrangements. These i nclude the Age Di scri minati on Act, Ti tl e VII of the Ci vi l
Ri ghts Act (Equal Pay Act), the Medical and Famil y Leave Act, the Fair Labor Standards Act, and
the Empl oyee Reti rement Income Security Act (ERISA). An anesthesi ol ogi st' s decisi on to retire
must fi t wi thin the compl ex framework of federal and state l aws and regul ati ons. Anesthesi ol ogi sts
tend to reti re at a younger age than do many other special ists.
116

Mortality Among Anesthesiologists
It i s debatabl e whether anesthesiol ogi sts are subject to premature death compared to other
physi ci ans. Early studies of anesthesi ol ogi sts i n the United States
13
and studi es conducted in
Europe
117
have demonstrated death rates among anesthesi ol ogists less than that seen i n thei r
control groups. However, contrary results have been reported i n other studi es both from the
Uni ted States
14
and Europe.
118
As an exampl e, data

from Alexander et al
14
demonstrated a signi fi cant di fference i n the mean age at death among
anesthesiol ogi sts, 66.5 14.7 years, compared to thei r control group (interni sts), 69.0 14.5
years. In a subsequent study, Katz
15
concl uded that there was no stati sti cal di fference in age-
specific mortal ity among anesthesi ol ogists, interni sts, and other physi cians when ages of the
living members of the physi ci an groups were consi dered i n the analyses.
Suicide
Perhaps one of the most al arming of the potential occupati onal hazards for anesthesi ol ogists i s a
frequentl y ci ted excess rate of sui ci de. It has been wel l establ i shed that among physici ans in
general , the rate of sui cide ranks disproportionately hi gh as a cause of death.
119
Earl y reports
si ngl ed out anesthesi ol ogists as being particularl y vul nerable. However, this conclusi on has been
questi oned as the result of the methodol ogi cal di ffi cul ti es i n col l ecti ng accurate data on sui ci de
and the frequent fai l ure to adequatel y correct for confoundi ng vari abl es in the study populations.
P.96
Why might there be a hi gh rate of sui cide among anesthesi ol ogists? A parti al expl anati on l i es with
the hi gh degree of stress that i s an i ntegral part of the job. The rel ati onshi p between general i zed
stress and sui cide i s not direct. But, i n susceptibl e people, feel i ngs of i nabi li ty to cope resulti ng
from overwhelming stress can gi ve way to despair and sui ci de ideati on.
Extensive personali ty profil es col lected from suici de-suscepti bl e indi vi duals i ndi cate characteristics
such as hi gh anxiety, insecuri ty, l ow sel f-esteem, i mpulsi veness, and poor self-control . It is
di sturbi ng to note that in Reeve' s study of personali ty trai ts of anesthesiol ogi sts,
120
some 20%
mani fested psychol ogi cal profi l es that refl ected a predi sposi ti on to behavi oral di si ntegrati on and
attempted suici de when pl aced under extremes of stress. Thi s study rai ses the di scomforti ng
noti on that premorbi d personal i ty characteri sti cs exi st before entering speci alty training and are
not bei ng identi fi ed i n the admissions process.
One speci fi c type of stress, that resul ti ng from a malpracti ce lawsui t, may have a di rect causati ve
association wi th sui ci de among physi ci ans in general and anesthesi ol ogi sts i n particul ar.
Newspaper reports have descri bed the emoti onal deterioration and ul timate sui cide of experi enced
physi ci ans who have become i nvol ved i n a mal practi ce sui t. One study reported that 4 of 185
anesthesiol ogi sts bei ng sued for medical mal practice attempted or commi tted sui ci de.
121

Substance abuse among anesthesia personnel i s another potential contributor to the i ncreased
sui ci de rate. Indi vi dual s wi th chemi cal dependence, who are not i denti fi ed and are i n the end
stages of the di sease, may di e of drug overdose, a cause of death that may be di ffi cul t to
di sti ngui sh from sui cide. Physi cians who are i mpai red from chemi cal dependence and whose
pri vi leges to practi ce medi ci ne are revoked are also at heightened ri sk for attempting sui ci de.
Crawshaw et al
122
reported ei ght successful and two near-mi ss sui cide attempts among 43
physi ci ans pl aced on probati on for drug-rel ated di sabi l i ty.
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> Tabl e of Contents > Secti on I - Introducti on to Anesthesi a Practi ce > Chapter 5 - Professi onal Li abi l i ty,
Qual i ty Improvement, and Anestheti c Ri sk
Chapter 5
Professional Liability, Quality Improvement, and
Anesthetic Risk
Karen L. Posner
Frederick W. Cheney Jr.
Donald A. Kroll
KEY POINTS
In anesthesi a, as i n other areas of li fe, everything does not al ways go as pl anned. Undesi rabl e
outcomes occur regardl ess of the quali ty of care provi ded. The l egal aspects of Ameri can medi cal
practi ce have become increasi ngl y important as the publi c has turned to the courts for economic
Medi cal mal practi ce refers to the legal concept of professi onal negl igence. The
patient-pl aintiff must prove that the anesthesi ol ogi st owed the pati ent a duty,
fai l ed to ful fi ll thi s duty, that the anesthesi ologi st' s actions caused an i njury,
and that the injury resulted from a breach i n the standard of anesthesia care.
The court establ ishes the standard of care i n a particul ar case by the testi mony
of expert wi tnesses. The standard of care may al so be determined from
publ ished sources such as hospi tal pol ici es, textbooks, and standards adopted
by the Ameri can Soci ety of Anesthesiol ogi sts.
Ri sk management programs are broadl y ori ented toward reduci ng the l iabi li ty
exposure of the organi zation. Risk management programs complement quality
improvement programs i n mi ni mi zi ng li abil i ty exposure whi l e maxi mi zi ng quali ty
of patient care.
Quality improvement programs are general l y gui ded by the requi rements of the
Joint Commi ssion on Accreditati on of Heal thcare Organi zations (JCAHO). Qual i ty
improvement programs focus on i mproving the structure, process, and outcome
of care.
Conti nuous qual ity improvement (CQI) is a systems approach to i dentifying and
i mprovi ng qual i ty of care.
Anestheti c mortali ty has decreased recentl y but acci dental deaths and di sabl i ng
compl i cati ons sti l l occur.
redress when thei r expectati ons of medi cal treatment are not met. Payers such as Medi care are
increasi ngl y depending on accreditati on through bodi es such as the Joi nt Commission on
Accredi tati on of Healthcare Organizations (JCAHO) to ensure that mechani sms are i n pl ace to
del i ver quali ty care to al l pati ents. An anesthesi a ri sk management program can work i n
conjunction with a program for quali ty i mprovement to mi ni mi ze the l iabi li ty risk of practi ce whi l e
assuri ng the hi ghest qual i ty of care for patients.
Thi s chapter provi des background for the practi tioner about how the legal system handl es
malpractice cl ai ms and the role of ri sk management activity in minimi zi ng and managing l iabi li ty
exposure. An i ntroducti on to the concepts of qual i ty i mprovement (formerl y call ed qual i ty
assurance) extends the discussion to the broader arena of qual ity of care in anesthesi a practi ce.
Fi nal ly, there is a di scussi on of anestheti c mortali ty and some anestheti c compl i cations frequentl y
associated wi th mal practi ce li tigation.
PROFESSIONAL LIABILITY
Thi s secti on addresses the basi c concepts of medical li abil i ty. A more detail ed di scussi on of the
steps of the l awsuit process and appropri ate actions for physi cians to take when sued i s avai l abl e
from the Ameri can Soci ety of Anesthesi ol ogi sts (ASA).
1

Tor t Syst em
Although physi cians may become involved in the criminal l aw system in a professional capaci ty,
they more commonly become involved in the l egal system of ci vi l l aws. Ci vil l aw i s broadly divided
into contract law and tort l aw. A tort may be l oosel y defi ned as a ci vi l wrongdoi ng; negl i gence i s
one type of tort. Mal practi ce actual l y refers to any professi onal mi sconduct but its use i n l egal
terms typicall y refers to professional negl igence.
To be successful in a mal practi ce suit, the pati entpl aintiff must prove four thi ngs:
1. Duty: that the anesthesi ol ogi st owed the pati ent a duty;
2. Breach of duty: that the anesthesiol ogi st fai l ed to ful fi ll his or her duty;

3. Causation: that a reasonabl y cl ose causal rel ati on exists between the anesthesi ol ogist' s acts
and the resultant i njury; and
4. Damages: that actual damage resul ted because of a breach of the standard of care.
Fai lure to prove any one of these four el ements wi ll resul t i n a deci si on for the defendant
anesthesiol ogi st.
Duty
As a physici an, the anesthesiol ogi st establ i shes a duty to the pati ent when a doctorpatient
rel ati onship exists. When the patient i s seen preoperati vel y, and the anesthesi ologist agrees to
provi de anesthesi a care for the pati ent, a duty to the patient has been establi shed. In the most
general terms, the duty the anesthesiologi st owes to the pati ent is to adhere to the standard of
care for the treatment of the pati ent. Because it i s vi rtual ly i mpossi ble to deli neate speci fi c
standards for al l aspects of medical practi ce and al l eventual iti es, the courts have created the
concept of the reasonable and prudent physi cian. For al l speci alti es, there i s a nati onal standard
whi ch has di splaced the l ocal standard.
There are certai n general duti es that all physici ans have to thei r pati ents, and breachi ng these
duties may al so serve as the basi s for a l awsuit. One of these general duti es is that of obtaini ng
informed consent for a procedure. Consent may be wri tten, verbal , or i mpl i ed. Oral consent is just
as val i d, al bei t harder to prove years after the fact, as wri tten consent. Impl i ed consent for
anesthesia care may be present i n ci rcumstances i n whi ch the patient is unconsci ous or unable, for
P.100
any reason, to give hi s or her consent, but where it i s presumed that any reasonable and prudent
pati ent woul d gi ve consent.
Although there are excepti ons to the requi rement that consent be obtained, anesthesi ol ogists
should be sure to obtain consent whenever possi bl e. Fai lure to do so coul d, i n theory, expose the
anesthesiol ogi st to possi bl e prosecuti on for battery.
The requi rement that the consent be informed is somewhat more opaque. The guidel i ne i s
determi ni ng whether the pati ent recei ved a fai r and reasonabl e account of the proposed
procedures and the ri sks inherent in these procedures. The duty to disclose ri sks i s not l i mi tless,
but i t does extend to those risks that are reasonabl y l i kel y i n any pati ent under the circumstances
and to those that are reasonabl y l i kel y i n parti cul ar pati ents because of thei r conditi on. For
exampl e, i t woul d be prudent to i nform the patient of possibl e sore throat or dental damage
associated wi th tracheal i ntubati on, but not about an unli kel y compl i cation such as vocal cord
paral ysi s.
Breach of Duty
In a malpracti ce acti on, expert wi tnesses wi l l revi ew the medical records of the case and
determi ne whether the anesthesi ol ogi st acted in a reasonabl e and prudent manner i n the specific
si tuati on and ful fi ll ed his or her duty to the pati ent. If they fi nd that the anesthesiol ogi st ei ther
di d somethi ng that shoul d not have been done or fai l ed to do somethi ng that shoul d have been
done, then the duty to adhere to the standard of care has been breached. Therefore, the second
requi rement for a successful sui t wi ll have been met.
Causation
Judges and juri es are i nterested i n determi ni ng whether the breach of duty was the proxi mate
cause of the i njury. If the odds are better than even that the breach of duty l ed, however
ci rcuitously, to the i njury, thi s requi rement i s met.
There are two common tests empl oyed to establi sh causati on. The fi rst is the but for test, and the
second i s the substantial factor test. If the i njury woul d not have occurred but for the acti on of
the defendant-anesthesiol ogi st, or i f the act of the anesthesi ol ogist was a substantial factor in the
injury despi te other causes, then proxi mate cause i s establi shed.
Although the burden of proof of causation ordinari ly fal ls on the pati ent-pl aintiff, i t may, under
special circumstances, be shifted to the physi ci an-defendant under the doctri ne of res i psa
loqui tur (l i teral l y, the thing speaks for i tsel f). Applying thi s doctri ne requi res proving that:
1. the injury is of a kind that typically woul d not occur i n the absence of negli gence,
2. the injury must be caused by something under the exclusive control of the anesthesiol ogi st,
3. the injury must not be attri butable to any contri buti on on the part of the pati ent,
4. the evi dence for the explanation of events must be more accessi ble to the anesthesi ologi st
than to the patient.
Because anesthesiologi sts render patients i nsensi ble to thei r surroundi ngs and unabl e to protect
themsel ves from i njury, thi s doctri ne may be invoked i n anesthesia mal practice cases. Al l that
needs to be proved is that the injury typi cal l y would not occur in the absence of negl igence. At
this point, the anesthesi ol ogist i s put i n the positi on of havi ng to prove that he or she was not
negli gent.
Damages
The l aw al l ows for three different types of damages. General damages are those such as pai n and
sufferi ng that di rectl y resul t from the injury. Speci al damages are those actual damages that are a
consequence of the injury, such as medi cal expenses, l ost income, and funeral expenses. Puni tive
damages are i ntended to punish the physi cian for negli gence that was reckl ess, wanton,
fraudulent, or wi l lful . Puni ti ve damages are exceedi ngl y rare in medi cal mal practice cases. More
li kel y i n the case of gross negl igence is a loss of the l icense to practi ce anesthesia. In extreme
cases, criminal charges may be brought against the physi ci an. Determini ng the dol lar amount of
damages i s the job of the jury, and the determi nati on i s usuall y based on some assessment of the
pl aintiff' s condi ti on versus the condi ti on he or she woul d have been in had there been no
negl i gence. Pl ai nti ffs' attorneys general l y charge a percentage of the damages and wi l l , therefore,
seek to maximize the award gi ven.
Standard of Care
Because medical malpractice usual l y i nvol ves i ssues beyond the comprehensi on of l ay jurors
and judges, the court establ i shes the standard of care in a particul ar case by the testi mony
of expert wi tnesses. These wi tnesses di ffer from factual wi tnesses mai nl y i n that they may gi ve
opi ni ons. The trial court judge has sol e discreti on in determining whether a witness may be
quali fi ed as an expert. Al though any l icensed physi ci an may be an expert, i nformation wil l be
sought regardi ng the wi tness' s educati on and trai ni ng, the nature and scope of the person' s
practi ce, memberships and affiliations, and publ i cati ons. The purpose i n gatheri ng this i nformati on
is not onl y to establi sh the quali fi cations of the wi tness to provi de expert testi mony, but al so to
determi ne the wei ght to be given to that testi mony by the jury. In many cases the success of a
sui t depends pri mari l y on the stature and beli evabi li ty of the expert wi tnesses.
In certai n ci rcumstances, the standard of care may al so be determi ned from publi shed soci etal
gui del i nes, wri tten pol ici es of a hospi tal or department, or textbooks and monographs. Some
medical speci al ty soci eti es have careful l y avoided appl yi ng the term standards to thei r
gui del i nes i n the hope that no bi ndi ng behavi or or mandatory practi ces have been created. In
1986 the ASA, for the first ti me, publ i shed Standards for Basic Intra-Operative Monitori ng (now
enti tled Standards for Basi c Anesthetic Moni toring). These standards have been

updated several times si nce thei r ini ti al adoption and are more bi ndi ng than gui deli nes. The
essenti al di fference between standards and gui del i nes i s that guidel i nes should be adhered to and
standards must be adhered to. Currentl y, the ASA al so publ i shes standards on preanesthesi a care
and postanesthesi a care, as wel l as guidel i nes for a vari ety of anesthesi a-rel ated activiti es.
2

Causes of Suits
Si nce 1985, the pri nci pal cause of sui ts agai nst anesthesi ol ogi sts i s pati ent i njury. The ASA
Commi ttee on Professi onal Li abil i ty has conducted a nati onwi de anal ysis of mal practi ce clai ms
against anesthesiol ogi sts.
3, 4
The leadi ng i njuries i n mal practice clai ms i n the 1990s were death
(22%), nerve damage (21%), and brai n damage (10%). The causes of death and permanent brai n
damage were predomi nantl y problems in airway management, such as i nadequate venti lation,
di fficul t i ntubation, premature extubati on, and mul tifactorial and other cardi ovascul ar events such
as arrhythmi a, stroke, and myocardi al infarction. Nerve damage, especi al l y to the ulnar nerve,
often occurs despite apparentl y adequate posi tioni ng.
5, 6
Spinal cord injury was the most common
cause of nerve damage cl ai ms agai nst anesthesi ol ogi sts i n the 1990s.
5
Chroni c pai n management
is an i ncreasi ng source of mal practice clai ms agai nst anesthesi ol ogi sts.
7

Because death and brai n damage are hi gh-cost i njuries, anesthesi a practi ce is cl early a hi gh-ri sk
endeavor. The anesthesi ol ogi st is l i kely to be the target of a l aw sui t i f an untoward outcome
occurs because the physi cianpatient rel ati onship is usuall y tenuous at best. That is the patient
rarel y chooses the anesthesiologi st, the preoperati ve visi t i s brief, and the anesthesi ol ogi st who
sees the pati ent preoperati vely may not actual l y anestheti ze the patient. Communi cation between
anesthesiol ogi sts and surgeons about compl icati ons i s often l acking and the tendency i s for the
surgeon to bl ame anesthesia.
Supervisi on of nurse anesthetists i s another endeavor that puts the anesthesi ol ogi st in a hi gh-ri sk
category. The more nurse anesthetists supervi sed by any one anesthesi ologist, the greater the
P.101
exposure to the possibi l ity of pati ent i njury. Anesthesiologi sts are l i abl e not onl y for the nurse
anesthetists they employ but al so for those they supervi se who are empl oyed by the hospi tal .
Because anesthesiologi sts are i nvol ved i n the care of pati ents undergoing hi gh-ri sk surgical
procedures, they are often sued along wi th the surgeon in the case of an adverse outcome. This
may occur even i f the outcome was in no way rel ated to the anestheti c care.
What to Do When Sued
A l awsuit begi ns when the patientpl aintiff' s attorney fil es a compl aint and demand for jury tri al
with the court. The anesthesi ol ogi st is then served with the compl aint and a summons requi ri ng an
answer to the complaint. Unti l thi s happens, no l awsui t has been fi led. Insurance carriers must be
noti fi ed i mmedi atel y after the receipt of the compl ai nt. The anesthesi ologi st wi ll need assistance
in answeri ng the complai nt, and there i s a ti me l i mi t placed on the response.
Speci fi c actions at this poi nt i nclude the fol lowi ng:
1. Do not di scuss the case wi th anyone, incl uding col l eagues who may have been involved,
operating room personnel , or fri ends.
2. Never alter any records.
3. Gather together al l pertinent records, i ncl udi ng a copy of the anestheti c record, bi ll i ng
statements, and correspondence concerni ng the case.
4. Make notes recordi ng al l events recall ed about the case.
5. Cooperate fully with the attorney provi ded by the insurer.
The fi rst task the anesthesi ol ogist must perform with an attorney is to prepare an answer to the
compl ai nt. The complai nt contai ns certai n facts and all egati ons wi th which the defense may either
agree or di sagree. Defense attorneys rely on the frank and totall y candi d observati ons of the
physi ci an i n prepari ng an answer to the compl ai nt. Physici ans shoul d be wi l li ng to educate their
attorneys about the medi cal facts of the case, al though most medi cal malpracti ce attorneys wi l l be
knowl edgeabl e and medi cal l y sophi sti cated.
The next phase of the malpracti ce sui t i s cal led di scovery. The purpose of discovery is the
gathering of facts and cl arificati on of i ssues in advance of the tri al . Another purpose of discovery
is to assess or harass the defendant to determine how good a wi tness he or she wi l l make. This
occurs at several poi nts i n the di scovery process, and by several mechanisms.
In al l l ikeli hood the anesthesi ologist wi l l receive a wri tten interrogatory, which wi ll request factual
information. In consul tati on with the defense attorney, the i nterrogatory shoul d be answered i n
wri ting, because carel essl y or i nadvertentl y misstated facts can become troublesome l ater.
Depositi ons are a second mechanism of di scovery. The defendantanesthesiol ogi st wi l l be deposed
as a fact wi tness, and deposi ti ons wi ll be obtai ned from other anesthesi ol ogists who wi l l act as
expert wi tnesses. The defendantanesthesiol ogi st may be asked to suggest other anesthesi ologi sts
who woul d provi de expert revi ew of the medi cal records. A nati onall y recognized expert i n the
area i n questi on who i s not a personal fri end but agrees wi th the defense posi ti on may be very
val uabl e.
The pl ai nti ff' s attorney, not the defense attorney, wil l depose the anesthesi ol ogi st. Most often, the
depositi on wi l l occur at a pl ace and ti me conveni ent for the anesthesi ol ogist, typicall y in the
defense attorney' s offi ce. Despi te the apparent i nformali ty of the deposi tion, the anesthesi ologist
must be constantl y aware that what is said duri ng the deposi ti on carries as much wei ght as what
would be sai d i n court. It i s important to be factual l y prepared for the deposi ti on. A revi ew of
personal notes, the anestheti c record, and the medi cal record i s necessary. The physici an shoul d
dress conservati vely and professi onall y because appearance and image are very i mportant. The
opposi tion is assessing the physici an to see how he or she wi ll appear to a jury. Answer only the
questi on asked, and do not volunteer i nformation. Occasi onal l y, physi cians wi l l be asked leading
questi ons that are impossibl e to answer without quali fi cati ons. In thi s case, the physici an may
quali fy hi s or her answer but shoul d avoi d gi vi ng lengthy opini on answers.
There wi l l be deposi ti ons from expert wi tnesses, both for the plai ntiff and for the defense. The
anesthesiol ogi st should work with hi s or her attorney to suggest questi ons and rebuttal s. The
better educated the attorney is about the medical facts, the reasons the anesthesi ol ogi st di d what
was done, and the al ternati ve approaches, the better abl e the attorney wi l l be to conduct these
expert deposi ti ons.
If there i s some merit i n the case but the damages are minimal , or if proof of i nnocence wi l l be
di ffi cul t, there wi l l probabl y be a settl ement offer. There i s a high cost incurred by both pl ai nti ffs
and defendants i n pursui ng a mal practi ce cl aim up through a jury tri al . Unl ess there is a strong
probabi l ity of a l arge dol lar award, reputabl e pl ai nti ffs' attorneys are not li kel y to pursue the
cl ai m. Thus, even if physi cians bel ieve that they are total l y i nnocent of any wrongdoi ng, they
should not be offended or angered about settli ng of the case: this i s sol ely a matter of money, not
medi ci ne.
If a settl ement is not reached duri ng the di scovery phase, a trial wi ll occur. Only about 1 in 20
malpractice cases ever reaches the point of a jury trial . It usuall y becomes clear

duri ng di scovery whether the sui t has a sol id chance of being successful l y prosecuted. Onl y those
cases i n whi ch both si des feel they can win, and whi ch are li kel y to have si gni fi cant financi al
impact, wi l l proceed to tri al .
The di scussi on of deposi ti on testi mony al so appl ies to testimony i n court, but there are a few
addi ti onal poi nts to consider duri ng the trial . The members of the jury wi ll not be as sophi sti cated
medicall y as the attorneys who deposed the anesthesi ol ogi st duri ng di scovery. A tendency to
overuse speci fi c medi cal terms shoul d be corrected by learni ng to expl ai n answers i n l ay terms for
the benefi t of the jury. Do not underesti mate the i ntel l i gence of the jury, however, because
talking down to them wi ll create an unfavorabl e impression. If the answer to a question is not
known, avoi d guessi ng. If specific facts cannot be remembered, say so. Nobody expects total
recal l of events that may have occurred years before.
The defendantphysi ci an shoul d be present duri ng the enti re trial , even when not testifying, and
should dress conservati vely, neatly, and professi onall y. Displ ays of anger, remorse, reli ef, or
hosti li ty wi l l hurt the physi cian in court. When gi vi ng testi mony, the anesthesi ologi st must give
cl ear answers to al l questi ons asked. The physi ci an shoul d be abl e to gi ve his or her testimony
without using notes or documents. When it i s necessary to refer to the medi cal record, i t wi l l be
admitted into evi dence. The anesthesi ol ogist's goal is to convince the jury that he or she behaved
in thi s case as any other competent and prudent anesthesi ol ogi st woul d have behaved.
It i s important to keep i n mi nd that proof in a mal practi ce case means onl y more l i kely than not.
The pati entpl aintiff must prove the four elements of negl igence, not to absolute certai nty, but
only to a probabil i ty greater than 50%. On the posi tive si de, thi s means that the defendant
anesthesiol ogi st must onl y show that hi s or her actions were, more l ikely than not, wi thi n an
acceptable standard of care.
RISK MANAGEMENT AND QUALITY IMPROVEMENT
Ri sk management and qual i ty improvement programs work hand i n hand in mi nimizing
li abi l i ty exposure whi le maximi zi ng qual i ty of pati ent care. Al though the functi ons of these
programs vary from one i nstituti on to another, they overl ap i n thei r focus on pati ent safety. They
can general l y be di sti ngui shed by their basi c di fference i n ori entati on. A hospi tal risk management
program i s broadly ori ented toward reduci ng the li abil i ty exposure of the organi zati on. Thi s
incl udes not onl y professi onal l i abi l ity (and therefore pati ent safety) but al so contracts, empl oyee
safety, publi c safety, and any other l iabi li ty exposure of the i nstituti on. Quali ty i mprovement
programs have as thei r main goal the continuous mai ntenance and improvement of the qual ity of
patient care. These programs may be broader i n thei r pati ent safety focus than strictly ri sk
P.102
management.
Ri sk Management
Those aspects of ri sk management that are most di rectly rel evant to the l iabi li ty exposure of the
anesthesiol ogi st i ncl ude preventi on of pati ent injury, adherence to standards of care,
documentation, and pati ent rel ati ons.
The key factors i n the preventi on of pati ent i njury are vi gi l ance, up-to-date knowl edge, and
adequate moni toring.
8
Physi ol ogic monitori ng of cardi opul monary functi on, combi ned with
moni tori ng of equi pment functi on, mi ght be expected to reduce anestheti c i njury to a mi nimum.
Thi s was the rati onale for the adopti on of the ASA Standards for Basi c Anestheti c Monitori ng.
2

The ASA websi te shoul d be reviewed yearl y for any changes i n ASA Standards of Practi ce. It woul d
al so be reasonabl e to revi ew the ASA Guidel i nes and Statements publ i shed on the ASA websi te. It
shoul d be noted that, al though membershi p i n the ASA i s not requi red for the practi ce of
anesthesi ol ogy, expert witnesses wil l , wi th virtual certai nty, hol d any practi ti oner to the ASA
standards. It is also possi ble that, as a risk management strategy, a professi onal li abi l i ty insurer
or hospital may hold an i ndi vi dual anesthesi ol ogist to standards hi gher than those promul gated by
the ASA.
Another ri sk management tool i s the use of checkl i sts pri or to each case, or at least dai l y, i n an
attempt to reduce equi pment-rel ated mi shaps.
9, 10, 11
A regular schedule of equi pment mai ntenance
shoul d be establ i shed as wel l as procedures to fol l ow whenever equi pment mal function is
suspected of contributi ng to pati ent i njury. If equipment mal functi on i s suspected to have
contri buted to a compl i cation, the devi ce should be i mpounded and exami ned concurrentl y by the
representati ves of the hospi tal , the anesthesi ologi st, and the manufacturer.
Although i t may seem obvi ous, qual ified anesthesia personnel should be i n continuous attendance
duri ng the conduct of al l anestheti cs. The onl y excepti ons shoul d be those that l ay peopl e (i.e.,
judge and jury) can understand, such as radi ati on hazards or an unexpected l i fe-threatening
emergency elsewhere. Even then, provisi ons shoul d be made for moni tori ng the pati ent
adequately. Adequate supervi sion of nurse anestheti sts and residents i s al so important, as i s good
communi cati on wi th surgeons when adverse anestheti c outcomes occur.
Informed consent shoul d be documented with a general consent, whi ch shoul d i nclude a statement
to the effect that, I understand that all anestheti cs i nvol ve ri sks of compl i cations, seri ous i njury,
or, rarel y, death from both known and unknown causes. In addi tion, there should be a note i n the
patient' s record that the ri sks of anesthesia and al ternatives were di scussed, and that the pati ent
accepted the proposed anestheti c plan. A bri ef documentati on i n the record that the common
compl i cati ons of the proposed techni que were di scussed i s helpful . If i t i s necessary to change the
agreed-on anesthesi a plan si gni fi cantl y after the pati ent i s premedi cated or anesthetized, the
reasons for the change shoul d be documented in the record.
Good records can form a strong defense i f they are adequate, however records can be di sastrous i f
inadequate. The anesthesia record itself shoul d be as accurate, complete, and as neat as possi ble.
The use of automated anesthesi a records may be helpful i n the defense of mal practi ce cases.
12
In
addi ti on to documenti ng vital si gns every 5 mi nutes, special attention should be pai d to ensure
that the patient' s ASA cl assi fi cation, the moni tors util i zed, fluids admi ni stered, and doses and
ti mes of al l admi ni stered drugs are accuratel y charted. Because the pri ncipal causes of hypoxi c
brai n damage and death duri ng anesthesi a are related to venti l ati on and/or oxygenation, al l
respiratory vari abl es that are moni tored shoul d be documented accuratel y. It i s i mportant to note
when there i s a change of anesthesi a personnel duri ng the conduct of a case. Sl oppy, i naccurate
anesthesia records, when enlarged and placed before a jury, can be damaging to the defense.
If a criti cal i ncident occurs duri ng the conduct of an anestheti c, the anesthesi ol ogist shoul d
document, i n narrative form, what happened, whi ch drugs were used, the time sequence, and who
was present. Thi s shoul d be documented i n the pati ent' s progress notes, as catastrophic i ntra-
anesthetic event cannot be summari zed adequatel y i n a smal l amount of space on the usual
anesthesia record. The criti cal i ncident note shoul d be wri tten as soon as possibl e. The report
should be as consistent as possi bl e wi th concurrent records, such as the anesthesi a, operati ng
room, recovery room, and cardi ac arrest records. If si gni fi cant

inconsi stenci es exist, they should be expl ai ned. Records shoul d never be al tered after the fact. If
an error i s made in record keeping, a l ine shoul d be drawn through the error, l eavi ng i t l egi bl e,
and the correction should be ini ti al ed and ti med. Li ti gati on i s a l engthy process, and a court
appearance to explai n the i nci dent to a jury may be years away, when memori es have faded.
If anestheti c compl i cati ons occur, the anesthesiol ogi st should be honest wi th both the pati ent and
famil y about the cause. Whenever an anestheti c compl i cation becomes apparent postoperati vel y,
appropri ate consul tati on shoul d be obtai ned qui ckl y, and the departmental or insti tutional ri sk
management group shoul d be notified. If the compl i cation i s apt to l ead to prol onged
hospi tal izati on or permanent i njury, the li abil i ty insurance carri er shoul d be noti fi ed. The pati ent
should be foll owed closel y whi l e in the hospi tal , wi th tel ephone fol l ow-up, i f i ndicated, after
di scharge. Al so, the anesthesi ol ogist and surgeon shoul d be consi stent in thei r explanations to the
patient or the pati ent's famil y as to the cause of any compli cati on.
Jehovah's Witnesses and Other Treatment Obligations
It i s important to recogni ze that pati ents have wel l -establ i shed ri ghts, and that among these i s
the ri ght to refuse speci fic treatments because of rel i gious bel iefs. In the case of Jehovah' s
Wi tnesses, the treatment refused is the administration of blood or bl ood products. Thi s i s a central
part of their reli gi ous bel i efs, which hold that the fai thful wi l l be forbidden the pl easures of the
afterl i fe i f they recei ve bl ood or bl ood products. Thus, for them to recei ve a transfusi on i s a
mortal si n, and many Jehovah's Wi tnesses woul d actual ly rather die in grace than l i ve wi th no
possi bi li ty of salvati on. Anesthesi ologi sts recogni ze and respect these bel i efs but are al so
cogni zant that these convi cti ons may confl i ct wi th the physi ci ans' personal, rel igi ous, or ethical
codes.
Mi nor chi ldren of Jehovah's Wi tness parents represent a speci al group for considerati on. Al though
the U.S. Supreme Court has uphel d the ri ght of an adul t to become a martyr by refusi ng
treatments based on rel i gious convictions, no court has extended to parents the ri ght to martyr
thei r chi ldren.
13
Obtaining a proper court order is of cri ti cal i mportance i n the care of a mi nor
chil d of Jehovah' s Wi tness parents when the parents refuse to authori ze a bl ood transfusi on.
As a general rule, physi ci ans are not obli gated to treat al l pati ents who apply for treatment i n
el ecti ve si tuati ons. It i s wel l wi thin the ri ghts of a physi cian to decli ne to care for any patient who
wishes to pl ace burdensome constrai nts on the physici an or to unacceptably l imit the physi ci an' s
abi li ty to provi de opti mal care. When presented wi th the opportunity to provi de elective care for a
Jehovah' s Wi tness, the physi ci an may decl i ne to provi de any care or may li mi t, by mutual consent
with the pati ent, his or her obl i gati on to adhere to the pati ent' s rel igi ous bel iefs. If such an
agreement i s reached, i t must be documented cl earl y i n the medi cal record, and it i s desi rabl e to
have the pati ent co-si gn the note. Not al l Jehovah' s Witnesses have i dentical bel i efs regardi ng
bl ood transfusi ons or which methods of blood preservation or sequestration wi ll be al lowed. Some
patients wil l not al l ow any bl ood that has left the body to be rei nfused, yet others wi ll accept
autotransfusi on i f thei r blood remai ns i n constant contact wi th the body (via tubi ng). Therefore, it
is important to reach a cl ear understanding of which techni ques for bl ood preservation are to be
used and to document thi s pl an i n the record.
Emergency medi cal care i mposes greater constrai nts on the treati ng physi cian, as there is no
opportuni ty to decl i ne the care of a pati ent wi th an immediatel y l i fe-threatening conditi on. If the
patient is an adult and i s conscious and mentall y competent, he or she has the ri ght to refuse
bl ood transfusi on. The excepti ons to pati ents' ri ghts i n thi s regard include pregnant women and
adults who are the sol e support of mi nor chi ldren. In these ci rcumstances, the i nterests of the
fetus in survi vi ng may supersede the ri ghts of the mother, as may the i nterests of the state in not
bei ng obl i gated to provi de for the wel fare of dependent chil dren.
13
In ei ther case, obtai ning a
court order i s the best pl an i f ti me permi ts. If the probl em concerns bl ood products and there i s
i nsuffi ci ent ti me to obtai n a court order, pregnant women should be given a transfusi on to save
P.103
the li fe of the fetus, but parents of mi nor chi l dren shoul d not receive transfusi ons agai nst their
wishes unl ess the dependency of the chi ldren i s obvi ous.
When the patient is a minor, i t is i mportant to ascertai n the true wi shes of the parents. Some
parents know that a court order can be obtained and vi ew thi s as a reli ef from the onerous burden
of havi ng to deci de whether they are wi l li ng to l et their chi l d di e. However, some parents are
adamant that blood not be given, and there have been cases i n whi ch chi l dren have been
ostraci zed by thei r parents and rel i gi ous communi ty for havi ng received a court-ordered
transfusion. Reachi ng an understanding about the consequences for the chi ld who receives a
court-ordered transfusi on i s therefore vi tal for the determi nation of what risks wi l l be taken before
orderi ng a transfusion.
The procedure for obtai ni ng a court order may vary, dependi ng on the speci fi c state l aws.
Typicall y, an order may be obtai ned over the telephone. Thi s cal l ini ti ates the i ssue of a wri tten
order, whi ch wi l l arri ve several days later. Although not a total l y automati c procedure, i t woul d be
very rare for a judge to deny this order for a minor.
National Practitioner Data Bank
It i s usual ly the obli gati on of the hospi tal ri sk management department to make reports and
inqui ri es to the Nati onal Practi ti oner Data Bank (NPDB), a nati onwi de i nformati on system that
theoreti cal ly woul d all ow l i censi ng boards and hospi tal s a means of detecting adverse i nformati on
about physi cians.
14
Si mpl y movi ng i nto another state woul d no l onger provi de safe haven for
incompetent physi cians.
The NPDB requi res i nput from fi ve sources: (1) medi cal mal practi ce payments, (2) l i cense actions
by medi cal boards, (3) professi onal revi ew or cl i ni cal privil ege acti ons taken by hospi tal s and
other health care entiti es (i ncl udi ng professi onal soci eties), (4) acti ons taken by the Drug
Enforcement Agency (DEA), and (5) Medi care/Medi cai d exclusi ons. There has been a great deal of
effort to establish a mi nimum reporting doll ar val ue bel ow whi ch no report i s necessary, but to
date, any payment made on behal f of a physi ci an i n response to a wri tten complai nt or cl ai m must
be reported. Settl ements made by cancel lation of bi ll s or settl ements made on verbal compl ai nts
are not consi dered a reportabl e payment.
Once a report has been submi tted, the physi ci an i s noti fi ed and has 60 days from the date the
data bank processed the report to di spute the i nput. At this ti me, the reporting enti ty may correct
the form or voi d i t. Fai li ng that, the physi ci an has the option of putting a bri ef statement i n the
fi l e or appeal i ng to the U.S. Secretary of Health and Human Servi ces, who may al so either correct
or voi d the form. Once i t i s entered, there i s no means of purgi ng the form. A practi ti oner may
make a query about hi s or her fil e at any ti me. The exi stence of the NPDB reporti ng requi rements
has made physi ci ans rel uctant to all ow settl ement of nui sance sui ts because i t wi ll cause their
names to be added to the data bank.
QUALITY IMPROVEMENT IN ANESTHESIA PRACTICE
Qual i ty is a concept that has conti nued to el ude preci se defi niti on i n medi cal practi ce.
However, it i s general ly accepted that attention to qual ity wi ll i mprove pati ent safety and
sati sfacti on

with anesthesi a care. The fi el d of qual ity assurance or qual ity improvement is conti nuall y
evol vi ng, as i s the terminol ogy used to descri be such efforts. The term quali ty assurance has
gone out of fashion, being repl aced by qual i ty i mprovement in an effort to emphasi ze a change
in underl yi ng phi losophy. Al though quali ty i mprovement programs i n anesthesi a are general l y
gui ded by requi rements of the JCAHO, they are basi cal ly ori ented toward i mprovement of the
structure, process, and outcome of heal th care del i very programs. An understandi ng of the
fundamental pri nci pl es of quali ty i mprovement may clari fy the relationshi p between the conti nual l y
evol vi ng JCAHO requirements and mandated qual i ty improvement activiti es.
P.104
St r uct ur e, P r ocess, and Out come: The Bui l di ng Bl ocks of
Qual i t y
Al though qual i ty of care i s di ffi cul t to defi ne, i t i s general l y accepted that i t i s composed of three
components: structure, process, and outcome.
15
Structure refers to the setti ng i n whi ch care was
provi ded, for example, personnel and faci l iti es used to provide heal th care services and the
manner i n whi ch they are organi zed. This i ncl udes the qual i ficati ons and l i censi ng of personnel ,
rati o of practi tioners to pati ents, standards for the facil i ti es and equi pment used to provi de care,
and the organi zati onal structure withi n which care is del ivered. The process of care includes the
sequence and coordi nati on of patient care activi ties, that i s, what was actuall y done. Was a
preanestheti c evaluati on performed and documented? Was the patient conti nuousl y attended and
moni tored throughout the anestheti c? Outcome of care refers to changes i n health status of the
patient fol l owing the del ivery of medi cal care. A qual i ty i mprovement program focuses on
measuri ng and i mprovi ng these basic components of care.
Conti nuous qual ity improvement (CQI) takes a systems approach to identi fying and i mprovi ng
quali ty of care.
16, 17
The operator i s just one part of a compl ex system. An important
underlying premi se i s that poor resul ts may be a resul t of ei ther random or systematic error.
Random errors are i nherentl y di ffi cul t to prevent and programs focused i n thi s di recti on are
mi sguided. System errors, however, shoul d be control l abl e and strategi es to mini mize them should
be wi thin reach. CQI is basi cal l y the process of conti nual l y eval uati ng anesthesi a practi ce to
identi fy systemati c probl ems (opportuni ti es for i mprovement) and i mpl ementi ng strategies to
prevent thei r occurrence.
A CQI program may focus on undesirabl e outcomes as a way to identi fy opportuni ti es for
improvement in the structure and process of care. The focus i s not on bl ame but rather on
identi fi cation of the causes of undesi rabl e outcomes. Instead of asking whi ch practi tioners have
the hi ghest pati ent mortali ty rates, a CQI program may focus on the relationshi p between the
process of care and pati ent mortal ity. What proporti on of deaths was rel ated to the pati ent's
di sease process or debi l i tated condi tion? Are these patients bei ng appropri ately evaluated for
anesthesia and surgery? Were there any controllable causes, such as a l ack of hands duri ng
resusci tati on? The latter may lead to a modificati on of personnel resources (structure) or
assi gnments (process) to be sure that adequate personnel are avail able at al l times.
Formal l y, the process of CQI involves the identification of opportuni ti es for i mprovement through
the conti nual assessment of i mportant aspects of care. Peer review and i nput are cri ti cal to this
process. It i s a process that is i nsti tuted from the bottom up, by those who are actual ly involved
i n the process to be i mproved, rather than from the top down by admi ni strators. Identi fi cati on of
opportuni ti es for i mprovement may be carri ed out by vari ous means, from brai nstorming sessi ons
focusing on a systematic evaluation of care acti vi ti es to the careful measurement of i ndi cators of
quali ty (such as morbi di ty and mortal ity). In any event, once areas are identi fi ed for
improvement, their current status i s measured and documented. Thi s may i nvol ve measurement of
outcomes, such as delayed recovery from anesthesi a or peri pheral nerve injury. The process of
care l eading to these probl ems is then analyzed. If a change is i dentified that shoul d l ead to
improvement, it i s impl emented. After an appropri ate ti me period, the status i s then measured
again to determi ne whether improvement actual l y resul ted. Attenti on may then be di rected to
conti nui ng to i mprove thi s process or turni ng to a di fferent process to target for improvement.
An extensi on of the CQI method i s total qual ity management (TQM). A TQM program woul d extend
beyond pati ent care to appl y CQI methods to al l aspects of the pati ent care deli very system. This
would include such thi ngs as bi ll i ng and housekeeping, for exampl e. With the expectati on of
conti nui ng changes in the structure and financi ng of heal th care in the Uni ted States, CQI
programs i n anesthesi a can be i ncorporated into TQM of the enti re hospi tal system to mai ntain the
quali ty of pati ent care as practi ce changes are i mpl emented i n response to a changi ng
envi ronment.
Difficulty of Outcome Measurement in Anesthesia
Improvement i n qual ity of care is often measured by a reducti on i n the rate of adverse outcomes.
However, adverse outcomes are rel ati vel y rare i n anesthesi a maki ng measurement of i mprovement
di fficul t. For exampl e, i f an insti tution lowers i ts mortal i ty rate of surgery pati ents from 1 in 1,000
to 0.5 in 1,000, thi s difference may not be statisticall y si gni fi cant. Many adverse outcomes i n
anesthesia are even more rare.
To compl ement outcome measurement, anesthesi a CQI programs can focus on cri ti cal i nci dents,
senti nel events, and human errors. Cri tical inci dents are events that cause, or had the potenti al to
cause, pati ent i njury i f not noti ced and corrected i n a ti mel y manner. For example, a parti al
di sconnect of the breathing ci rcui t may be corrected before patient i njury occurs, yet has the
potential for causi ng hypoxi c brai n i njury or death. Cri tical inci dents are more common than
adverse outcomes. Measurement of the occurrence rate of i mportant cri tical inci dents may serve
as a proxy measure for rare outcomes i n anesthesi a i n a CQI program designed to i mprove pati ent
safety and prevent i njury.
Sentinel events are singl e, isolated events that may i ndi cate a systemi c probl em. JCAHO has a
specific definition of senti nel events that wi l l be discussed later. In general , a sentinel event may
be a si gni fi cant or alarming cri tical inci dent that di d not resul t i n pati ent injury, such as a syri nge
swap and administration of a potential ly lethal dose of medi cation that was noted and treated
promptl y, avoi di ng catastrophe. Or a senti nel event may be an unexpected signi fi cant pati ent
injury such as intraoperative death. In either case, a CQI program may i nvestigate senti nel events
in an attempt to uncover systemi c probl ems i n the del i very of care that can be corrected. For
example, a syri nge swap may be anal yzed for confusing or uncl ear l abel i ng of medi cati ons or
unnecessary medicati ons routi nel y stocked on the anesthesi a cart, setti ng the scene for
uni ntended mi x-up. In the case of death, al l aspects of the patient' s hospi tal course from sel ecti on
for surgery to anestheti c management may be anal yzed to determi ne i f si mi l ar deaths can be
prevented by a change i n the care del i very system.
Human error has garnered much attenti on si nce a government report that 98,000 Ameri cans may
di e annual ly from medi cal errors i n hospi tal s.
18
Human errors are i nevitable yet potential ly
preventabl e by appropri ate system safeguards.

Errors of pl anni ng involve use of a wrong plan to achi eve an ai m.
19
Errors of executi on are the
fai l ure of a planned acti on to be compl eted as i ntended.
19
Modern anesthesia equi pment is
desi gned with safeguards such as al arm systems to detect errors that coul d l ead to pati ent injury.
Other anesthesi a care processes are al so amenabl e to human factors desi gn pri nci ples, such as
col or codi ng of drug l abel s. A qual i ty i mprovement program may i denti fy human errors and
insti tute safety systems to aid in error preventi on.
JCAHO Requirements for Quality Improvement
JCAHO requi rements for quali ty i mprovement activi ti es are updated on an annual basi s. In
general , a hospi tal must adopt a method for systematicall y assessing and i mprovi ng i mportant
functi ons and processes of care and thei r outcomes in a cycli cal fashi on. The general outli ne for
this CQI cycle is the desi gn of a process or function, measurement of performance, assessment of
performance measures through statistical anal ysi s or comparison with other data sources, and
improvement of the process or functi on. Then the cycle repeats. JCAHO provides specifi c
standards that must be met, with exampl es of appropri ate measures of performance. The goal of
this cycl e of desi gn, measurement, assessment, and i mprovement of performance of i mportant
functi ons and processes i s to i mprove pati ent safety and qual i ty of care.
Anesthesi a care is one i mportant function of the care of pati ents moni tored by JCAHO. It i s
important that pol i ci es and procedures for admini stration of anesthesi a be consi stent i n al l
locations withi n the organi zati on.
In 2004, JCAHO adopted pati ent safety goals for accredi ted organi zati ons. These i nclude i mproved
accuracy of patient i denti fi cation, improved effecti veness of communicati on among caregi vers,
el i mi nation of wrong si te/wrong pati ent/wrong procedure surgery, i mproved safety of infusi on
pumps, and i mproved effecti veness of cli nical alarm systems. JCAHO al so requi res all senti nel
P.105
events (any unexpected occurrences i nvol vi ng death or seri ous physi cal or psychologi cal i njury or
ri sk thereof) to undergo Root Cause Analysi s.
20
A Root Cause Anal ysi s i s typi cal ly faci l itated by
the hospi tal and incl udes everyone i nvol ved i n the care of the affected pati ent in reconstructi ng
the events to i denti fy system process flaws that faci l itated medi cal error. Any surgery on the
wrong pati ent or wrong body part i s i ncluded in thi s pol i cy. JCAHO publi shes a Senti nel Event Alert
so heal th care organi zati ons can learn from the experi ences of others and prevent future medical
errors.
Measuring Quality: Approaches to Data Collection
There are vari ous methods in use for col l ection of CQI data in anesthesi a. These include
retrospecti ve records revi ew as wel l as sel f-reporting by provi ders of care. Checkl i sts to report
adverse events or outcomes are someti mes used. Important consi derations i ncl ude compl iance
with reporti ng requirements, standardizati on of defi ni ti ons, and appropri ate sampl i ng.
Retrospective records review usual ly i nvol ves a random sampl e of anesthesi a records. The actual
revi ew may be done by an anesthesi a provi der or by a trai ned medi cal records special ist. Expli cit
definiti ons of qual ity indi cators woul d be provi ded, such as hypotensi on = bl ood pressure <80%
of basel ine for 5 mi nutes or more. Such indicators of possi bl e qual i ty problems and opportuni ti es
for i mprovement are restricted to data that are normal l y i ncl uded i n the anesthesi a record for
every pati ent. Records revi ew i s an especi al l y appropri ate techni que for gatheri ng data on
adequacy of documentation. An asset of automated anesthesia records i s that they can be
programmed to screen al l records for qual i ty i ndi cators.
For col lecti on of data on events or outcomes that may not normal ly be charted, a sel f-reporting
system may be used. This i s an especi all y good mechani sm for tracking cri tical i nci dents and
senti nel events. For example, a syri nge swap that was noted and corrected before drug
administrati on i s a cri ti cal i nci dent that would not normal l y be i ncl uded i n an anestheti c record but
coul d be reported by an anesthesia provider i n a self-report system. Many sel f-report systems
provi de a checkli st of events and outcomes that is compl eted by the provi der for each anestheti c.
Other systems provide general gui deli nes of cri ti cal i nci dent reporti ng without specifi c check-off
items.
21, 22
The rel evant cli ni cal i nformation is then obtained from the practiti oner by quali ty
improvement personnel .
Whatever system is used, it i s i mportant that i t be i n compl iance wi th current JCAHO standards.
Standardi zed definiti ons must be provided. In general , defi ni tions that take into account the
context of care (patient status, type of anestheti c) whi le maintai ni ng expli cit cri teri a for i ncl usi on
in the CQI system wi ll most cl earl y refl ect qual i ty issues (rather than, for exampl e, compl i cations
rel ated purel y to patient physi cal conditi on). For exampl e, bl ood l oss and repl acement of 8 uni ts
would be consi dered excessi ve and i ndi cati ve of a probl em duri ng a knee arthroscopy but woul d be
consi dered mi nimal duri ng a li ver transpl ant. A stri ct defi ni tion of excessive blood loss = >5
uni ts woul d i denti fy both cases as qual ity issues where i t woul d onl y be appropri ate for the
arthroscopy. Contextual i zati on of defi ni tions wil l hel p avoid the frustrati on of providers when
presented wi th data that otherwi se may be irrel evant to i mprovi ng the process of anesthesi a care.
Peer Review
Peer review, which refers to the revi ew of cases by members of one's special ty, i s an integral part
of qual i ty i mprovement programs. Peer revi ew is commonl y integrated i nto a quali ty i mprovement
program i n the context of the morbidi ty and mortal i ty conference. This provides a forum for
review of case management by all members of the department, i ntegrati ng an educati onal
component i nto the qual i ty improvement process as di fferi ng knowl edge bases and cl i ni cal
experi ences are shared. Peer review can provi de a mechani sm to anal yze the structure and
process of care and opportuni ties for improvement.
Peer review can al so be incorporated i nto the analysi s of cri ti cal incidents, senti nel events, and
trends i n measured outcomes of care. Peer revi ew has the di sti nct advantage of credi bil i ty and an
aura of fai rness i n a democrati c system. Although personal bias i n cl ini cal care may be recognized,
adherence to the reasonable man pri nci pl e provides a basi s for anal ysi s that refl ects generall y
accepted pri nci pl es of care. It provi des a basi s for analysis of trends and i nci dents, suggesti ng
hypotheses for their causes and changes in the system that might i mprove the structure, process,
and outcome of care.
However, peer review i s subject to bias that may not be recogni zed by the parti cipants. Thi s i s a
tendency of anesthesi ologists to judge care as l ess than appropriate if severe pati ent i njury
occurs.
23
In a study of anesthesiol ogi sts presented wi th identi cal case scenari os with differi ng
outcomes, they were more li kel y to judge the care as appropriate if the i njury was temporary and
to judge care as l ess than appropri ate i f the i njury was permanent. In conducti ng peer revi ew for
a CQI system, this tendency toward assessments bi ased by case outcome shoul d be recogni zed
and resi sted. Careful attenti on to the process of care and opportuni ti es for i mprovement shoul d be
made regardl ess of the extent of pati ent injury. Cri tical incidents resulti ng i n no i njury shoul d be
as careful l y anal yzed for opportuniti es for i mprovement i n the structure and process of care as
inci dents wi th adverse outcomes.

Even though anesthesiol ogi sts may be bi ased in their assessment of case management by
outcome, they exhi bi t onl y moderate l evel s of general agreement i n their assessments.
24, 25
When
revi ewi ng i denti cal case histories, di fferent anesthesi ologists may not al ways agree on whether
the care was appropriate. Al though thi s di sagreement may be because of di fferences i n
i ndi vi dual l y hel d standards and practices, i t must be recogni zed i n any analysi s of case
management for a CQI program. Incorporati on of mul ti pl e anesthesi ol ogi sts i nto the process of
case revi ew wil l compensate for thi s l ack of agreement. Al though a consensus may not be reached,
deci si ons wi l l not be subject to the vari abil i ty of i ndi vi dual judgments. Incorporati on of mul ti pl e
peer reviewers wi l l compensate for di fferences in assessments and strengthen the process by
improvi ng reli abil i ty.
25

The Future of Quality Improvement: A Multidisciplinary Focus
JCAHO is moving toward a focus on the pati ent' s hospi tal course i n a mul ti di scipl i nary emphasis
rather than departmental qual i ty i mprovement programs. The shi ft i n emphasi s i s toward an
anal ysi s of the entirety of each pati ent's care as the process to be i mproved. Each department' s
role is just one part of this process, and the care provi ded by vari ous departments i s often not the
rel evant unit of anal ysis. This shi ft i n focus may requi re movement from departmental reli ance on
standi ng commi ttees to i ncreased use of ad hoc study groups. Comparison of outcomes of care
across i nsti tuti ons, wi th adjustments for case mi x, has long been the goal but has proven to be
di fficul t to impl ement.
MORTALITY AND MAJOR MORBIDITY RELATED TO ANESTHESIA
Esti mates of anesthesia-rel ated morbi di ty and mortal ity are diffi cult to quanti fy. Not only are
there di ffi cul ti es obtaini ng data on compl i cations, but different methodol ogi es yi eld different
estimates of anesthesi a ri sk. Studi es differ in thei r definiti ons of compl i cations, l ength of foll ow-
up, and especi al l y i n approaches to evaluati on of the contri buti on of anesthesi a care to pati ent
outcomes. A comprehensive revi ew of anesthesia compl i cations i s beyond the scope of this
chapter. A sampli ng of studi es of anesthesi a mortal i ty and morbidi ty wil l be presented to provi de
hi stori cal perspecti ve pl us a l imi ted overvi ew of rel ati vel y recent fi ndi ngs.
Earl y studi es estimated the anesthesia-rel ated mortali ty rate as 1 per 1,560 anestheti cs.
26

More recent studies usi ng data from the 1990s estimate the anesthesia-rel ated death rate i n
the Uni ted States to be <1 per 10,000 anestheti cs.
27, 28
Some exampl es of modern esti mates of
anesthesia-rel ated death from throughout the worl d are provi ded in Tabl e 5-1. Di fferences i n
estimates may be infl uenced by di fferent reporti ng methods, defi ni tions, anesthesi a practi ces,
patient population, as wel l as actual di fferences in underl yi ng compl icati on rates.

Nevertheless, i t is generall y accepted that anesthesi a safety has i mproved over the past 50+
years.
P.106
P.107
TABLE 5-1 Recent Estimates of Anesthesia-Related Death
REFERENCE COUNTRY TIME
PERIOD
DATA
SOURCES/METHODS
RATE OF DEATH
Newl and et
al .
27
USA 1989
1999
Cardi ac arrests wi thi n 24
hrs of surgery (n =
72,959 anestheti cs) i n a
teaching hospital
Death rel ated to
anesthesia-
attri butabl e
peri operative
cardi ac arrest =
0.55/10,000
anesthetics
Lagasse
28
USA (a)
1992
1994
(b)
1995
1999
(a) suburban teachi ng
hospi tal (n = 115 deaths;
n = 37,924 anestheti cs)
(b) urban teaching
hospi tal (n = 232 deaths;
n = 146,548 anestheti cs)
Anesthesi a-
rel ated death =
(a) 0.79/10,000
anesthetics;
(b) 0.75/10,000
anesthetics
Arbous et
al .
37
Hol l and 1995
1997
All deaths wi thin 24 hrs
or pati ents who remained
uni ntenti onal l y comatose
24 hrs postanesthesia (n
= 811 i n 869,483
anesthetics)64 hospi tal s
Anesthesi a-
rel ated death =
1.4/10,000
anesthetics
Eagl e,
Davis
38
Western
Austral i a
1990
1995
Deaths wi thi n 48 hrs or
deaths i n whi ch
anesthesia was
consi dered a contributing
factor (n = 500 deaths)
Anesthesi a-
rel ated death =
1/40,000
anesthetics
Davis, ed.
39
Austral i a 1994
1996
Deaths reported to the
committee (n =
8,500,000 anestheti cs)
Anesthesi a-
rel ated death =
0.16/10,000
anesthetics
Irita et
al .
40
Japan 1999
2002
Deaths as a resul t of li fe-
threatening events i n the
operating room (n =
3,855,384 anestheti cs) i n
trai ni ng hospi tal s
Death total l y
attri butabl e to
anesthetic
management =
0.1/10,000
anesthetics
Kawashima
et al .
41
Japan 1994
1998
Questionnai res to traini ng
hospi tal s (n = 2,363,038
anesthetics)
Death total l y
attri butabl e to
anesthesia =
Other compl i cations rel ated to anesthesia that have recei ved rel ati vel y recent attenti on i ncl ude
postoperative nerve i njury, awareness and recal l , eye i njuries and vi sual defi ci ts, and dental
injury. Ulnar neuropathy i s one of the most common nerve i njuries l eadi ng to anesthesi a
malpractice cl ai ms in the Uni ted States.
5
The i nci dence of ul nar neuropathy has been esti mated
between 3.7 and 50 per 10,000 pati ents (Tabl e 5-2). Lower extremity neuropathy fol l owing
surgery i n the li thotomy positi on was observed i n 2.7/10,000 pati ents (Tabl e 5-2).
29
Awareness
with recall after general anesthesi a has been esti mated to occur in 15 to 40 per 10,000
patients.
30, 31, 32

0.21/10,000
anesthetics
Bi boulet et
al .
42
France 1989
1995
ASA 14 pati ents
undergoi ng anesthesi a (n
= 101,769 anesthetics)
cardi ac arrest wi thin 12
hrs postanesthesia (n =
24)
Anesthesi a-
rel ated death =
0.6/10,000
anesthetics
Morray et
al .
43
USA 1994
1997
Pedi atric patients from 63
hospi tal s (n = 1,089,200
anesthetics)
Anesthesi a-
rel ated death =
0.36/10,000
anesthetics
TABLE 5-2 Rates of Selected Anesthesia Complications
COMPLICATION REFERENCE COUNTRY TIME
PERIOD
SPECIFIC
COMPLICATION
RESULTS
Nerve i njury Warner et
al .
44
USA 1995 Ulnar
neuropathy in
adults
fol l owing
noncardiac
surgery
0.5%
Warner et
al .
45
USA 1957
1991
Persistent
ul nar
neuropathy
fol l owing
di agnosti c or
noncardiac
procedures
wi th
anesthesia
1/2,729
patients
Alvine et
al .
46
USA 1980
1981
Ulnar
neuropathy
after general
anesthesia
0.26%
Warner et
al .
29
USA 1957
1991
Lower
extremi ty
motor
neuropathy
fol l owing
surgery i n
li thotomy
positi on
1/3,608
procedures
Awareness and
recal l
Sandi n et
al .
30
Sweden 1997
1998
Awareness and
recal l
associated
wi th general
anesthesia
18/11,785
procedures
Lui et al .
31
Great
Bri tai n
1990 Awareness
wi th recal l i n
adults
fol l owing
surgery
0.2%
Ranta et
al .
32
Fi nl and 1994
1995
Awareness in
patients >12
yrs old having
general
anesthesia
0.4%
Eye i njuries
and vi sual
changes
Warner et
al .
34
USA 1999 New onset
bl urred vi si on
lasti ng 3
days
4.2%
Warner et
al .
35
USA 1986
1998
New onset
visual l oss or
visual changes
lasti ng >30
days after
noncardiac
surgery
1/125,234
patients
Roth et
al .
33
USA 1988
1992
Eye i njury
after
0.056%
Eye i njuries are a risk of anesthesi a, incl uding corneal abrasi ons as wel l as more rare
compl i cati ons such as bl indness from i schemic opti c neuropathy or central reti nal artery occl usi on
(Tabl e 5-2). Eye i njury after nonocul ar surgery was observed i n 5.6/10,000 pati ents.
33
New onset
bl urred vi si on has been observed in 4.2% of patients (Tabl e 5-2).
34
New onset visual l oss or
changes l asti ng more than 30 days after noncardi ac surgery were observed in 1/125,234
patients.
35

Damage to teeth or dentures is perhaps the most common injury leadi ng to anesthesi a malpractice
cl ai ms. Dental i njury complai nts are usual l y resol ved by a hospital ri sk management department.
Dental i njuri es requiri ng interventi on were observed i n 1/4537 pati ents.
36

Unl i ke studies of anesthesia mortal ity, most studi es of nonfatal compl i cations do not attempt to
assess the relationshi p between the compl i cation and anesthesi a care. Many of these
compl i cati ons are known ri sks of anesthesi a. Such ri sks vary accordi ng to the speci fi c surgi cal and
anesthesia pl an as wel l as the patient' s physical characteri sti cs. Ri sk management and qual ity
improvement programs general l y focus on l ocal experience with postoperative compl i cations i n
targeting emphasi s areas for i mprovement.
References
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> Tabl e of Contents > Secti on II - Basi c Pri nci pl es of Anesthesi a Practi ce > Chapter 6 - Cel l ul ar and Mol ecul ar
Mechani sms of Anesthesi a
Chapter 6
Cellular and Molecular Mechanisms of Anesthesia
Alex S. Evers
C. Michael Crowder
KEY POINTS
The i ntroduction of general anestheti cs i nto cl i ni cal practice 150 years ago stands as one of
the seminal i nnovati ons of medi ci ne. Thi s si ngle di scovery facil i tated the devel opment of
modern surgery and spawned the special ty of anesthesi ol ogy. Despi te the importance of general
Despi te the importance of general anestheti cs, the molecul ar mechani sms
responsi bl e for anesthetic acti ons remai n one of the unsol ved mysteries of
pharmacol ogy.
The spinal cord i s probably the site at whi ch anestheti cs act to i nhi bi t
purposeful responses to noxious sti mulation (end poi nt for measurements of
equal potency, MAC).
Inhalational anestheti cs can depress the exci tabi l ity of thalami c neurons,
potential ly resul ting i n the loss of consciousness.
Synaptic function is considered a li kel y subcel lul ar si te of general anestheti c
acti on. Nevertheless, the effects of anestheti cs on synapti c functi on di ffer
among vari ous anestheti c agents, neurotransmitters, and neuronal preparati ons.
Ion channel s (especi all y GABA
A
receptors) are a l ikel y molecul ar targets of
anesthetic acti on.
Direct anestheti cprotei n-bi nding i nteracti ons may be responsibl e for anestheti c
effects on i on channels i n the central nervous system (CNS) (stereoselectivity i s
the strongest argument i n favor of thi s mechani sm).
Geneti c techni ques provi de the most rel i abl e and versati l e methods for changing
the structure of putative anestheti c targets.
The uni tary theory of anesthesi a i s i ncorrect and there are several mol ecul ar
mechani sms (anesthetics act vi a sel ecti ve effects on speci fi c mol ecular targets).
anesthetics and despite over 100 years of acti ve research, the mol ecular mechani sms responsibl e
for anestheti c acti on remai n one of the unsol ved mysteri es of pharmacology.
Why have mechani sms of anesthesi a been so di ffi cul t to elucidate? Anestheti cs, as a cl ass of
drugs, are chal l engi ng to study for three major reasons:
1. Anesthesi a, by defi niti on, i s a change in the responses of an intact ani mal to external
stimul i . Maki ng a defi ni ti ve l i nk between anestheti c effects observed i n vi tro and the
anesthetic state observed and defi ned i n vi vo has proven di ffi cul t.

2. No structureacti vi ty relationshi ps are apparent among anestheti cs; a wi de vari ety of
structurall y unrel ated compounds, ranging from steroi ds to el emental xenon, are capable of
producing cli nical anesthesia. Thi s suggests that there are mul tipl e mol ecul ar mechani sms
that can produce cl i ni cal anesthesi a.
3. Anestheti cs work at very high concentrati ons in compari son to drugs, neurotransmi tters, and
hormones that act at specific receptors. Thi s impl ies that if anestheti cs do act by bi ndi ng to
specific receptor si tes, they must bi nd wi th very low affinity and probabl y stay bound to the
receptor for very short periods of ti me. Low-affinity binding i s much more diffi cult to
observe and characteri ze than hi gh-affinity binding.
Despi te these di fficul ties, mol ecul ar and geneti c tools are now avai l abl e that should al l ow for
major i nsi ghts into anestheti c mechani sms i n the next decade. The aim of thi s chapter i s to
provi de a conceptual framework for the reader to catal og current knowl edge and i ntegrate future
developments about mechani sms of anesthesi a. Five speci fi c questi ons wi ll be addressed i n thi s
chapter:
1. What i s anesthesi a and how do we measure i t?
2. What i s the anatomi c site of anestheti c acti on i n the central nervous system?
3. What are the cel l ul ar neurophysiologi c mechani sms of anesthesi a (e.g., effects on synapti c
functi on versus effects on acti on potenti al generati on) and what anesthetic effects on i on
channel s and other neuronal protei ns underli e these mechani sms?
4. What are the molecul ar targets of anestheti cs?
5. How are the mol ecul ar and cel lular effects of anesthetics l inked to the behavioral effects of
anesthetics observed i n vivo?
WHAT IS ANESTHESIA?
General anesthesi a can broadl y be defi ned as a drug-i nduced reversibl e depression of the central
nervous system resul ti ng in the l oss of response to and percepti on of all external stimul i .
Unfortunatel y, such a broad defi ni ti on i s i nadequate for two reasons. Fi rst, the defi ni tion is not
actual l y broad enough. Anesthesia i s not si mpl y a deafferented state; amnesi a and
unconsci ousness are i mportant aspects of the anesthetic state. Second, the defi ni ti on i s too broad,
as all general anesthetics do not produce equal depressi on of al l sensory modali ties. For exampl e,
barbiturates are considered to be anesthetics, but they are not particularl y effecti ve anal gesi cs.
These confli cti ng probl ems wi th defi ni tion can be bypassed by a more practi cal descri pti on of the
anesthetic state as a coll ecti on of component changes i n behavi or or percepti on. The
components of the anesthetic state i nclude unconsciousness, amnesi a, anal gesia, i mmobi l ity, and
attenuati on of autonomi c responses to noxi ous sti mulation.
Regardl ess of whi ch defi niti on of anesthesi a is used, essenti al to anesthesi a are drug-induced
changes i n behavi or or percepti on. As such, anesthesi a can onl y be defi ned and measured i n the
P.112
intact organism. Changes i n behavi or such as unconsci ousness or amnesia can be i ntuiti vely
understood i n hi gher organi sms such as mammal s, but become i ncreasingly di ffi cul t to defi ne as
one descends the phyl ogeneti c tree. Thus, whil e anestheti cs have effects on organi sms rangi ng
from worms
1
to man, i t is diffi cult to map wi th certainty the effects of anestheti cs observed i n
lower organi sms to any of our behavioral defi ni tions of anesthesia. This contri butes to the
di fficul ty of using simple organisms as models i n which to study the molecul ar mechani sms of
anesthesia. Si mil arl y, any cell ul ar or mol ecular effects of anestheti cs observed i n hi gher
organisms can be extremel y di ffi cul t to l i nk wi th the constel l ation of behavi ors that consti tute the
anesthetic state. The absence of a simpl e and conci se defi ni ti on of anesthesia i s clearl y one of the
stumbli ng blocks to el uci dati ng the mechani sms of anesthesi a at a mol ecular and cel l ul ar l evel .
HOW IS ANESTHESIA MEASURED?
To study the pharmacology of anesthetic acti on, quanti tati ve measurements of anesthetic potency
are absolutel y essential . To thi s end, Eger and col l eagues have defi ned the concept of MAC, or
mi ni mum al veol ar concentrati on. MAC i s defi ned as the alveol ar parti al pressure of a gas at whi ch
50% of humans do not respond to a surgi cal incisi on.
2
In ani mal s, MAC i s defi ned as the alveol ar
parti al pressure of a gas at whi ch 50% of animal s do not respond to a noxious sti mul us, such as
tail cl amp,
3
or at whi ch they l ose their righti ng reflex. The use of MAC as a measure of anesthetic
potency has two major advantages. Fi rst, i t is an extremel y reproduci ble measurement that i s
remarkabl y constant over a wi de range of speci es.
2
Second, the use of end-ti dal gas concentrati on
provi des an index of the free concentration of drug requi red to produce anesthesi a si nce the
end-ti dal gas concentrati on i s in equi l ibri um wi th the free concentrati on in pl asma. The MAC
concept has several i mportant l i mi tations, particul arl y when tryi ng to rel ate MAC val ues to
anesthetic potency observed i n vi tro. First, the end point in a MAC determi nati on i s quantal: a
subject i s either anestheti zed or unanestheti zed; it cannot be partial ly anestheti zed. Furthermore,
MAC represents the average response of a whol e population of subjects rather than the response
of a si ngl e subject. The quantal nature of the MAC measurement makes it very di fficul t to compare
MAC measurements to concentrati on-response curves obtai ned i n vi tro, where the graded response
of a si ngle preparati on i s measured as a functi on of anesthetic concentrati on. The second
limitation of MAC measurements is that they can only be directly appl i ed to anestheti c gases.
Parenteral anesthetics (barbiturates, neurosteroi ds, propofol ) cannot be assigned a MAC val ue,
maki ng i t diffi cult to compare the potency of parenteral and volatil e anestheti cs. A MAC equi valent
for parenteral anestheti cs i s the free concentrati on of the drug i n pl asma requi red to prevent
response to a noxi ous sti mulus in 50% of subjects; thi s value has been estimated for several
parenteral anesthetics.
4
A thi rd li mitati on of MAC is that i t i s highly dependent on the anestheti c
end poi nt used to defi ne i t. For example, if l oss of response to a verbal command is used as an
anesthetic end poi nt, the MAC val ues obtai ned (MAC
awake
) wil l be much l ower than cl assi c MAC
val ues based on response to a noxious sti mul us. Indeed, each behavi oral component of the
anesthetic state wi l l li kel y have a different MAC val ue. Despi te i ts li mitati ons, MAC remains the
most robust measurement and the standard for determi ni ng the potency of vol ati l e anestheti cs.
The foregoi ng di scussi on of MAC bri ngs forth an i mportant and somewhat controversial question.
What drug concentration should be measured when determi ni ng anesthetic potency? When
measuri ng potency of i ntravenous anestheti cs, the answer to this questi on i s rel ati vely simple.
One woul d l ike to rel ate the free concentrati on of the drug at i ts si te of action (the biophase) to
the drug' s effect. It i s, of course, not practical to measure the drug' s concentrati on in the
extracel lul ar fl ui d of the brain, so free concentration in plasma i s used as an approximati on of the
bi ophase concentration. Thi s al l ows one to compare the concentration of drug required to produce
anesthesia i n humans to the concentrati ons requi red to produce specific effects in vi tro. Wi th the
vol ati l e anestheti cs, potency i s defi ned by MAC, whi ch i s measured i n units of

parti al pressure. Because the parti al pressure of a dissol ved gas is di rectly proporti onal to the free
concentration of that gas i n a l i qui d, alveol ar parti al pressures are accurate reporters of the free
anesthetic concentrati ons i n pl asma and i n brain tissue.
P.113
WHERE IN THE CENTRAL NERVOUS SYSTEM DO ANESTHETICS
WORK?
In pri nci pl e, general anesthesi a could resul t from interrupti on of nervous system activity at myri ad
l evel s. Pl ausi bl e targets i ncl ude peripheral sensory receptors, spi nal cord, brai nstem, and cerebral
cortex. Of these potenti al sites, onl y peripheral sensory receptors can be eli minated as an
important si te of anesthetic acti on. Animal studi es have shown that fluori nated volatil e anestheti cs
have no effect on cutaneous mechanosensors in cats
5
and can even sensi tize nociceptors in
monkeys.
6
Furthermore, sel ecti ve perfusi on studies i n dogs have shown that MAC for isoflurane is
unaffected by the presence or absence of isofl urane at the si te of noxi ous sti mulati on, provi ded
that the central nervous system is perfused wi th bl ood contai ning i sofl urane.
7

Spi nal Cor d
Clearl y, anestheti c actions on the spi nal cord cannot produce either amnesi a or
unconsci ousness. However, several li nes of evi dence indi cate that the spi nal cord is probabl y
the si te at whi ch anestheti cs act to i nhi bit purposeful responses to noxi ous sti mulation. Thi s is, of
course, the end poi nt used i n most measurements of anestheti c potency. Rampi l and col l eagues
have shown that MAC values for fl uorinated vol ati le anesthetics are unaffected i n the rat by ei ther
decerebrati on
8
or cervical spi nal cord transecti on.
9
Antogni ni and col l eagues have used the
strategy of i sol ati ng the cerebral ci rculation of goats to expl ore the contri buti on of brai n and
spi nal cord to the determi nati on of MAC. They found that when i sofl urane i s admi ni stered onl y to
the brai n, MAC is 2.9%, whereas when i t i s administered to the enti re body, MAC i s 1.2%.
10

Surpri si ngly, when i sofl urane was preferenti al l y admini stered to the body and not to the brai n,
isoflurane MAC was reduced to 0.8%.
11
The acti ons of volatil e anestheti cs in the spinal cord are
mediated, at l east i n part, by di rect effects on the excitabil i ty of spi nal motor neurons. Thi s
concl usion has been substanti ated by experi ments i n rats,
12
goats,
13
and humans,
14
showing that
vol ati l e anestheti cs depress the ampl i tude of the F wave in evoked potenti al measurements (F-
wave ampl itude correlates with motor neuron excitabil i ty). These provocati ve resul ts suggest not
only that anesthetic actions at the spinal cord underli e the determinati on of MAC, but also that
anesthetic acti ons on the brai n may actual l y sensi ti ze the cord to noxious sti muli . The pl ausi bi li ty
of the spi nal cord as a locus for anesthetic immobi li zati on i s also supported by several
el ectrophysiol ogi cal studi es showi ng inhi bi ti on of exci tatory synapti c transmi ssi on i n the spi nal
cord.
15, 16, 17, 18

Ret i cul ar Act i vat i ng Syst em
The reti cul ar acti vati ng system, a di ffuse col lection of brainstem neurons i nvol ved i n arousal
behavior, has l ong been specul ated to be a si te of general anestheti c action on consci ousness.
Evidence to support this notion came from early whol e ani mal experi ments showi ng that el ectrical
stimul ati on of the reticular activati ng system could induce arousal behavior in anestheti zed
animal s.
19
A rol e for the brai nstem i n anestheti c acti on i s also supported by studi es examini ng
somatosensory evoked potenti al s. General ly, these studies show that anestheti cs produce
i ncreased l atency and decreased ampl itude of corti cal potenti al s, i ndi cating that anestheti cs
inhi bit i nformati on transfer through the brai nstem.
20
In contrast, studi es usi ng brai nstem audi tory
evoked potential s have shown vari able effects rangi ng from depression to enhancement of
information transfer through the reti cul ar formati on.
21, 22, 23
Whi le there i s evi dence that the
reticul ar formati on of the brai nstem i s a l ocus for anesthetic effects, it cannot be the onl y
anatomic si te of anestheti c acti on for two reasons. First, as di scussed earl ier, the brai nstem i s not
even requi red for anesthetics to i nhi bit responsi veness to noxi ous sti mul i. Second, the reticular
formation can be largel y abl ated wi thout el iminati ng awareness.
24

Wi thi n the reticular formation is a set of ponti ne noradrenergi c neurons cal l ed the l ocus coerul eus
(LC). The LC i nnervates a number of targets in basal forebrai n and cortex i ncluding a set of
GABAergi c hypothal ami c neurons cal led the ventrol ateral preoptic nucleus (VLPO). The VLPO i n
turn i nnervates the tuberomammi ll ary nucl eus (TMN). The LC-VLPO-TMN pathway has been shown
to be cri ti cal for non-REM sl eep. Gi ven that EEG patterns under anesthesia and non-REM sl eep are
qui te si mi l ar, thi s pathway i s a parti cul arly good candi date for a si te of anestheti c action. Using
stereotacti c techni ques, Maze and col l eagues tested this hypothesi s by measuri ng whether
appl i cati on of a GABAergi c antagoni st di rectly onto the TMN al tered the efficacy of anestheti cs.
25

Indeed, discrete appl i cation of the GABAergic antagoni st gabazi ne onto the TMN markedl y reduced
the durati on of sedation produced by systemi cal l y admi ni stered propofol or pentobarbi tal . Thi s
effect i s unli kel y to be a consequence of a nonspeci fi c i ncrease in arousal state because
systemi cal ly admi ni stered gabazi ne di d not antagoni ze the potency of ketamine whereas i t di d
antagoni ze propofol and pentobarbi tal i n a manner simil ar to appl i cation directl y onto the TMN.
Thi s resul t strongl y impli cates the TMN as a si te for the sedative action of GABAergi c anestheti cs
li ke propofol and barbi turates.
Cer ebr al Cor t ex
The cerebral cortex i s the major si te for integrati on, storage, and retri eval of i nformati on. As
such, i t is a l i kely site at whi ch anestheti cs mi ght i nterfere wi th compl ex functi ons l ike
memory and awareness. Anestheti cs cl earl y al ter corti cal el ectri cal acti vi ty, as evi denced by the
changes i n surface EEG patterns recorded duri ng anesthesia. Anestheti c effects on patterns of
corti cal electri cal acti vi ty vary widely among anestheti cs,
26
provi ding an i niti al suggesti on that al l
anesthetics are not l i kely to act through i dentical mechani sms. More detai led i n vi tro
el ectrophysiol ogi cal studi es examining anestheti c effects on different corti cal regi ons support the
noti on that anestheti cs can differenti all y al ter neuronal functi on i n vari ous corti cal preparati ons.
For exampl e, volatil e anestheti cs have been shown to inhi bi t exci tatory transmi ssi on at some
synapses i n the ol factory cortex
27
but not at others.
28
Si mi larl y, whereas vol ati l e anestheti cs
inhi bit exci tatory transmission in the dentate gyrus of the hi ppocampus,
29
these same drugs can
actual l y enhance excitatory transmissi on at other synapses i n the hi ppocampus.
30
Anestheti cs al so
produce a vari ety of effects on inhi bi tory transmi ssi on i n the cortex. A variety of parenteral and
inhalational anestheti cs have been shown to enhance i nhibi tory transmi ssion i n ol factory cortex
28

and i n the hi ppocampus.
31
Conversel y, vol ati l e anestheti cs have also been reported to depress
inhi bitory transmi ssi on i n hi ppocampus.
32
One area of the brai n that has been postul ated as a
potential site of anestheti c acti on is the thal amus. The thalamus i s

important i n rel aying sensory modal iti es and motor informati on to the cortex via thal amocorti cal
pathways. A devel opi ng body of evidence i ndicates that inhalational anestheti cs can depress the
exci tabi l ity of thal ami c neurons, thus bl ocking thalamocorti cal communicati on potenti all y resul ting
in l oss of consci ousness.
33

Summar y
Anestheti cs are abl e to produce effects on a vari ety of anatomi c structures i n the CNS, i ncl udi ng
spi nal cord, brai nstem, and cerebral cortex. Whereas certai n anestheti c effects may be
attri butabl e to specific anatomic locati ons (e.g., purposeful response to noxi ous sti mul ati on maps
to the spi nal cord), existing evi dence provi des no basi s for a si ngl e anatomi c site responsibl e for
anesthesia. This di fficul ty i n identi fying a si te for anesthesia mi ght pl ausibl y resul t from the
vari ous components of the anestheti c state bei ng produced by anestheti c effects on di fferent
regi ons of the CNS. Nevertheless, despi te the di ffi cul ty in i denti fyi ng a common anatomi c si te for
anesthesia, investi gators have conti nued to l ook for other uni fying princi pl es in anestheti c action.
Speci fi cal ly, attenti on has been focused on i denti fyi ng common cel l ul ar or mol ecular anestheti c
targets that may have a wide anatomic di stributi on, expl ai ni ng the abil i ty of anestheti c to affect
nervous system functi on i n an anatomically diffuse manner.
HOW DO ANESTHETICS INTERFERE WITH THE
ELECTROPHYSIOLOGIC FUNCTION OF THE NERVOUS SYSTEM?
In the simpl est terms anesthetics i nhi bi t or turn off vital central nervous system functi ons. They
must do thi s by acti ng at speci fi c physi ol ogic switches. A great deal of i nvesti gative effort has
been devoted to identi fying these switches. In pri ncipl e, the CNS coul d be swi tched off by several
means:
P.114
1. By depressi ng those neurons or pattern generators that subserve a pacemaker functi on i n
the CNS,
2. By reduci ng overal l neuronal excitabi l i ty; ei ther by changi ng resti ng membrane potenti al or
by i nterferi ng with the processes involved in generating an acti on potenti al,
3. By reduci ng communi cati on between neuronsspecificall y, by ei ther inhi bi ti ng excitatory
synapti c transmi ssi on or enhanci ng i nhi bitory synapti c transmi ssi on.
P at t er n Gener at or s
Information concerning the effects of anestheti cs on pattern-generati ng neuronal ci rcuits i n the
CNS i s l i mi ted, but cli nical concentrati ons of anesthetics are l i kel y to have signi fi cant effects on
these ci rcuits. The si mpl est evidence for thi s i s the observati on that most anestheti cs exert
profound effects on respi ratory rate and rhythm, strongly suggesti ng an effect on respi ratory
pattern generators i n the brai nstem. Invertebrate studies suggest that vol ati le anestheti cs can
sel ecti vely i nhibi t the spontaneous (pacemaker) fi ri ng of specific neurons. As shown i n Fi g. 6-1,
halothane (1.0 MAC) completely i nhibi ts spontaneous action potential generati on by one neuron i n
the ri ght pari etal gangl i on of the great pond snail whi le producing no observable effect on the
firi ng frequency of adjacent neurons.
34

FIGURE 6-1. Selectivity of vol ati l e anestheti c inhi bi ti on of neuronal automati ci ty. Hal othane
(1 MAC) reversibl y i nhi bits the spontaneous firi ng acti vi ty of a neuron from the pari etal
gangli on of Lymnaea stagnali s (A). The same concentrati on of hal othane has no effect on the
Neur onal Exci t abi l i t y
The abil i ty of a neuron to generate an acti on potenti al is determi ned by three parameters: resti ng
membrane potenti al , the threshold potenti al for action potential generati on, and the functi on of
vol tage-gated sodi um channel s. Anesthetics can hyperpolari ze (create a more negati ve resting
membrane potenti al ) both spi nal motor neurons and corti cal neurons,
35, 36
and thi s abi li ty to
hyperpol ari ze neurons correlates with anestheti c potency. In general , the i ncrease i n resti ng
membrane potenti al produced by anestheti cs is smal l i n magni tude and i s unli kel y to have an
effect on axonal propagati on of an acti on potenti al . Small changes i n resti ng potenti al may,
however, inhi bi t the initi ati on of an action potential ei ther at a postsynapti c site or in a
spontaneousl y fi ri ng neuron. Indeed, hyperpol ari zati on i s responsibl e for the i nhibi tion of
spontaneous action potential generati on shown in Fi g. 6-1. Recent evidence al so i ndi cates that
isoflurane hyperpol ari zes thalami c neurons, leadi ng to an i nhibi tion of toni c fi ri ng of action
potential s.
33
There is no evidence indicati ng that anestheti cs al ter the threshold potenti al of a
neuron for action potential generati on.

However, the data i s confl i cti ng on whether the size of the acti on potenti al , once i ni tiated, i s
di mi ni shed by general anestheti cs. A cl assi c paper by Larrabee and Posternak demonstrated that
concentrations of ether and chl oroform that compl etel y bl ock synapti c transmi ssi on i n mammal ian
sympatheti c gangli a have no effect on presynapti c action potential ampl itude.
37
Si mi lar resul ts
have been obtai ned with fl uori nated volatil e anestheti cs in several mammal i an brai n
preparati ons.
27, 29
Thi s dogma that the acti on potenti al is relativel y resi stant to general anesthetics
has been chall enged by more recent reports that volatil e anestheti cs at cli nical concentrations
produce a smal l but si gni fi cant reducti on i n the si ze of the action potential i n mammali an
neurons.
38, 39
In one case, the reducti on i n the acti on potenti al was shown to be ampl i fi ed at the
presynaptic terminal resul ti ng in a large reducti on i n neurotransmi tter rel ease.
39
Thus, whi l e
current data sti l l support the prevai l ing vi ew that neuronal excitabil i ty i s only sli ghtl y affected by
general anestheti cs, thi s small effect may neverthel ess contri bute si gnifi cantly to the cl ini cal
acti ons of vol ati le anesthetics.
Synapt i c Funct i on
Synapti c functi on i s wi del y considered to be the most l i kel y subcellular si te of general
anesthetic acti on. Neurotransmission across both exci tatory and i nhibi tory synapses has been
found to be markedl y al tered by general anestheti cs. General anestheti cs have been shown to
inhi bit excitatory synapti c transmi ssi on i n a vari ety of preparations, i ncl udi ng sympatheti c
gangli a,
37
ol factory cortex,
27
hi ppocampus,
29
and spinal cord.
17
However, not al l excitatory
synapses appear to be equal l y sensi ti ve to anestheti cs; i ndeed, transmission across some
hi ppocampal exci tatory synapses has been shown to be enhanced by inhal ati onal anestheti cs.
30
In
a si mi l ar fashion, general anestheti cs have been shown both to enhance and depress i nhi bi tory
synapti c transmi ssi on i n vari ous preparati ons. In a cl assic paper i n 1975, Ni col l and col l eagues
showed that barbi turates enhanced i nhi bitory synapti c transmi ssi on by prol ongi ng the decay of the
GABAergi c i nhi bi tory postsynapti c current.
40
Enhancement of inhi bi tory transmi ssi on has al so been
observed wi th many other general anestheti cs, i ncl udi ng etomi date,
41
propofol ,
42
inhal ati onal
anesthetics,
28
and neurosteroi ds.
43
Al though anestheti c enhancement of i nhibi tory currents has
recei ved a great deal of attention as a potenti al mechani sm of anesthesi a,
4
it i s i mportant to note
that there is al so a l arge body of experimentati on showi ng that cli ni cal concentrati ons of general
anesthetics can depress i nhi bi tory postsynapti c potenti al s i n the hi ppocampus
32, 44, 45
and in the
firi ng acti vi ty of an adjacent, and apparentl y i dentical, neuron (B). Note that i n (A)
halothane markedly reduces resti ng membrane potenti al i n addi tion to inhi bi ti ng fi ri ng. (From
Franks NP, Li eb WR. Mechani sms of general anesthesi a. Environ Heal th Perspect.
1990;87:204.)
P.115
spi nal cord.
18
Anestheti cs do appear to have preferenti al effects on synapses, but there i s a great
deal of heterogenei ty in the manner i n whi ch anesthetic agents affect different synapses. This i s
not surprisi ng gi ven the l arge vari ati on i n synapti c structure, functi on (i .e., effi cacy), and
chemi stry (neurotransmi tters, modul ators) extant in the nervous system.
P r esynapt i c Ef f ect s
General anestheti cs affect synapti c transmi ssi on both pre- and postsynapti cal l y. However, the
magni tude and even the type of effect vary according to the type of synapse and the parti cul ar
anesthetic. Presynapti cal l y, neurotransmi tter rel ease from gl utamatergi c synapses has consi stentl y
been found to be i nhi bited by cl i ni cal concentrati ons of volatil e anestheti cs. For exampl e, a study
by Perouansky and col l eagues conducted i n mouse hi ppocampal sl i ces showed that hal othane
i nhi bi ted exci tatory postsynaptic potenti als el i ci ted by presynaptic el ectrical sti mul ati on, but not
those el ici ted by di rect appl icati on of gl utamate. Thi s i ndi cates that hal othane must be acti ng to
prevent the rel ease of gl utamate, the major exci tatory neurotransmitter i n the brai n.
46
MacIver
and col leagues extended these observati ons by providi ng evi dence that the i nhi biti on of gl utamate
rel ease from hi ppocampal neurons i s not due to effects at GABAergi c synapses that could
indirectl y decrease transmi tter release from glutamatergi c neurons. Effects of i ntravenous
anesthetics on gl utamate rel ease have al so been demonstrated but the evidence is more l i mi ted
and the effects potential ly i ndi rect.
47, 48
The data for anestheti c effects on i nhibi tory
neurotransmitter release is mixed. Inhi bi ti on,
49
sti mulation,
50, 51
and no effect
52
have been
reported for vol ati l e anestheti c and i ntravenous anesthetic acti on on GABA rel ease. In a brain
synaptosomal preparation where effects on both GABA and gl utamate rel ease could be studied
si multaneously, Hemmi ngs and coworkers found that gl utamate and, to a lesser degree, GABA
rel ease were inhi bi ted by cli ni cal concentrati ons of isofl urane.
53
The mechanism underl yi ng
anesthetic effects on transmi tter rel ease have not been establ ished. The effects of anestheti cs on
neurotransmitter release do not appear to be medi ated by reduced neurotransmitter synthesi s or
storage, but rather by a di rect effect on the process of neurosecreti on. A vari ety of evi dence
argues that at some synapses the majority of the anestheti c effect is upstream of the transmi tter
rel ease machi nery, perhaps on presynapti c sodium channel s (see di scussi on later). However,
geneti c data i n C. el egans shows that the transmi tter rel ease machi nery strongl y infl uences
vol ati l e anestheti c sensi tivity;
54, 55
at present, it i s uncl ear whether these findi ngs represent
speci es di fferences or di fferent aspects of the same mechani sm.
P ost synapt i c Ef f ect s
Anestheti cs al so al ter the postsynaptic response to rel eased neurotransmi tter. The effects of
general anestheti cs on exci tatory neurotransmi tter receptor functi on vary dependi ng on
neurotransmitter type, anestheti c agent, and preparation. Ri chards and Smaje exami ned the
effects of several anesthetic agents on the response of ol factory corti cal neurons to appl i cation of
gl utamate, the major exci tatory neurotransmitter i n the CNS.
56
They found that while
pentobarbi tal , di ethyl ether, methoxyfl urane, and al phaxal one depressed the el ectri cal response to
gl utamate, halothane was wi thout effect. In contrast, when acetyl chol i ne was appl i ed to the same
ol factory corti cal preparation, halothane and methoxyfl urane sti mulated the electri cal response
whereas pentobarbi tal had no effect; only al phaxal one depressed the electri cal response to
acetylchol ine.
57
The effects of anestheti cs on neuronal responses to i nhibi tory neurotransmitters
are more consistent. A wide vari ety of anestheti cs, i ncl udi ng barbi turates, etomi date,
neurosteroids, propofol, and the fl uori nated volatil e anestheti cs, have been shown to enhance the
el ectrical response to exogenousl y appli ed GABA (for a review, see
58
). For exampl e, Fi g. 6-2
il l ustrates the abil i ty of enflurane to i ncrease both the ampli tude and the durati on of the current
el i ci ted by appl icati on of GABA to hippocampal neurons.
59

Summar y
Attempts to i dentify a physiologi c swi tch at which anestheti cs act have suffered from their own
success. Anestheti cs produce a vari ety of effects on many physi ol ogi c processes that mi ght
logicall y contri bute to the anestheti c state, i ncl udi ng neuronal automati city, neuronal exci tabi l ity,
and synapti c functi on. The synapse i s general ly thought to be the most li kel y rel evant site of
anesthetic acti on. Exi sti ng evi dence i ndi cates that even at thi s one si te, anestheti cs produce
vari ous effects, i ncl udi ng presynaptic inhi bi ti on of neurotransmitter release, inhi bi ti on of
exci tatory neurotransmi tter effect, and

enhancement of inhi bi tory neurotransmi tter effect. Furthermore, the effects of anesthetics on
synaptic function differ among various anestheti c agents, neurotransmitters, and neuronal
preparati ons.
ANESTHETIC ACTIONS ON ION CHANNELS
Ion channel s are one l ikely target of anesthetic action. The advent of patch cl amp techniques
in the earl y 1980s made i t possi bl e to di rectly measure the currents from single ion channel
protei ns. It was attracti ve to think that anestheti c effects on a smal l number of i on channel s mi ght
hel p to expl ain the compl ex physi ologi c effects of anestheti cs that we have al ready descri bed.
Accordi ngl y, duri ng the 1980s and 1990s a major effort was directed at descri bi ng the effects of
anesthetics on the vari ous ki nds of ion channel s. The fol l owing section summarizes and di sti ll s thi s
effort. For the purposes of thi s discussi on, i on channel s are catal oged according to the sti muli to
whi ch they respond by opening or cl osi ng (i .e., thei r mechani sm of gati ng).
FIGURE 6-2. Enfl urane potenti ates the abil i ty of GABA to acti vate a chl ori de current i n
cultured rat hi ppocampal cel l s. Thi s potentiation i s rapi dl y reversed by removal of enfl urane
(wash) (Panel A). Enfl urane increases both the ampl itude of the current (Panel B) and the
ti me (
1/2
) i t takes for the current to decay (Panel C). (Reproduced wi th permission from
Jones MV, Brooks PA, Harri son L. Enhancement of -aminobutyri c aci d-acti vated Cl
-
currents
in cul tured rat hi ppocampal neurones by three volatil e anaestheti cs. J Physiol .
1992;449:289.)
P.116
Anest het i c Ef f ect s on Vol t age- Dependent I on Channel s
A vari ety of i on channels can sense a change i n membrane potenti al and respond by either
openi ng or closing thei r pore. These channel s i ncl ude voltage-dependent sodi um, potassi um, and
calci um channel s, all of whi ch share si gnifi cant structural homol ogi es. Vol tage-dependent sodi um
and potassi um channel s are l argel y i nvol ved i n generating and shapi ng acti on potenti als. The
effects of anestheti cs on these channel s have been extensi vel y studi ed by Haydon and col l eagues
in the squi d gi ant axon.
60, 61
These studies show that these invertebrate sodi um channel s and
potassium channel s are remarkabl y i nsensi ti ve to vol atil e anestheti cs. For exampl e, 50% inhi bi ti on
of the peak sodi um channel current required hal othane concentrations 8 times those required to
produce anesthesi a. The del ayed rectifi er potassi um channel was even less sensiti ve, requi ri ng
halothane concentrati ons more than 20 ti mes those required to produce anesthesi a. Simil ar resul ts
have been obtai ned in a mammali an cell l i ne (GH
3
pi tui tary cel l s) where both sodi um and
potassium currents were i nhi bited by halothane onl y at concentrati ons greater than 5 ti mes those
requi red to produce anesthesi a.
62
However, a number of studi es wi th vol ati le anestheti cs have
chal l enged the noti on that vol tage-dependent sodi um channel s are i nsensi ti ve to anestheti cs.
Rehberg and col leagues expressed rat brai n IIA sodi um channel s i n a mammali an cel l li ne and
showed that cl inicall y rel evant concentrati ons of a vari ety of inhal ati onal anestheti cs suppressed
vol tage-el i ci ted sodi um currents.
63
Hemmings and coworkers showed that sodi um fl ux medi ated by
rat brain sodi um channels was si gnifi cantly inhi bi ted by cl i ni cal concentrations of hal othane.
64

Harri s and col l eagues documented the effects of isofl urane on a vari ety of sodi um channel
subtypes and found that several but not al l subtypes are sensiti ve to cl i ni cal concentrati ons.
65

Fi nal ly as descri bed above, in a rat brai nstem neuron Wu and col l eagues found that a small
i nhi bi ti on of sodi um currents by isofl urane resul ted in a l arge i nhibi tion of synapti c activity.
39

Thus, sodium channel activity not only appears to be i nhi bi ted by vol ati l e anesthetics, but thi s
inhi biti on results in a si gnifi cant reducti on i n synapti c functi on, at least at some mammal ian
synapses. Intravenous anestheti cs have also been shown to inhi bit sodium channel s, but the
concentrations for thi s effect are supracli ni cal .
66, 67, 68

Vol tage-dependent cal cium channel s (VDCC) serve to couple electrical acti vi ty to speci fic cel lular
functi ons. In the

nervous system, VDCCs l ocated at presynapti c termi nal s respond to acti on potenti als by opening.
Thi s al l ows calci um to enter the cell , acti vati ng cal ci um-dependent secreti on of neurotransmi tter
into the synapti c cleft. At l east si x types of cal cium channel s (designated L, N, P, Q, R, and T)
have been i denti fi ed on the basis of el ectrophysiologi cal properti es and a l arger number based on
amino acid sequence si mil ari ti es.
69
N-, P-, Q-, and R-type channel s, as wel l as some of the
unti tl ed channels, are preferential ly expressed i n the nervous system and are thought to pl ay a
major rol e i n synapti c transmi ssi on. L-type cal ci um channel s, although expressed i n the brai n,
have been best studied i n their rol e in exci tationcontracti on coupl ing i n cardi ac, skel etal , and
smooth muscl e and are thought to be l ess i mportant i n synapti c transmi ssi on. The effects of
anesthetics on L- and T-type currents have been well characteri zed,
62, 70, 71
and there are some
reports concerning the effects of anestheti cs on N- and P-type currents.
72, 73, 74
As a general rul e,
these studi es have shown that vol ati le anesthetics i nhibi t VDCCs (50% reduction i n current) at
concentrations 2 to 5 times those requi red to produce anesthesi a i n humans, wi th l ess than a 20%
inhi biti on of cal cium current at cl inical concentrations of anesthetics (Fi g. 6-3). However, some
studi es have found VDCCs that are extremel y sensi ti ve to anestheti cs. Takenoshi ta and Stei nbach
reported a T-type cal ci um current i n dorsal root gangli on neurons that was i nhi bi ted by
subanesthetic concentrations of hal othane.
75
Additi onal l y, ffrench-Mul len and col l eagues have
reported a VDCC of unspeci fi ed type i n gui nea pi g hi ppocampus that i s i nhi bi ted by pentobarbi tal
at concentrati ons identi cal to those requi red to produce anesthesi a.
76
Thus, VDCCs coul d wel l
mediate some actions of general anesthetics, but thei r general insensiti vi ty makes them unl i kel y
to be major targets.
P.117
Potassium channel s are the most diverse of the i on channel types and i ncl ude vol tage-gated,
second messenger and li gand-acti vated, and so-call ed i nward rectifyi ng channel s; some channel s
fal l into more than one category. Hi gh concentrations of both vol ati l e anestheti cs and i ntravenous
anesthetics are requi red to significantly affect the functi on of voltage-gated K
+
channel s.
61, 77, 78

Simil arl y, cl assi c i nward recti fyi ng K
+
channel s are relativel y insensiti ve to sevofl urane and
barbiturates.
79, 80, 81
However, some li gand-gated K
+
channel s are reasonabl y sensi tive to volatil e
anesthetics as discussed bel ow.
Summar y
Exi sti ng evidence suggests that most VDCCs are modestl y sensi ti ve or i nsensi ti ve to anestheti cs,
but some reports argue for significant heterogenei ty in the anesthetic sensi ti vi ty of speci fi c
channel types and subtypes. In particular, some sodi um channel subtypes are i nhibi ted by vol ati l e
anesthetics and thi s effect may be responsi bl e in part for a reducti on in neurotransmi tter rel ease
at some synapses. Addi ti onal experi mental data wi l l be requi red to establ i sh whether anestheti c-
sensi ti ve VDCCs are local ized to speci fi c synapses at whi ch anesthetics have been shown to i nhi bi t
neurotransmitter release.
Anest het i c Ef f ect s on Li gand- Gat ed I on Channel s
Fast exci tatory and inhi bi tory neurotransmi ssi on i s medi ated by the acti ons of l i gand-gated i on
channel s. Synapticall y rel eased gl utamate or GABA diffuse across the synapti c cl eft and bi nd to
channel proteins that open as a consequence of neurotransmi tter rel ease. The channel proteins
that bind GABA (GABA
A
receptors) are members of a superfami l y of structural l y rel ated l i gand-
gated i on channel protei ns that i ncl ude ni cotinic acetyl choli ne receptors, gl yci ne receptors, and 5-
FIGURE 6-3. Halothane i nhibi tion of voltage-dependent Ca
2+
, Na
+
, and K
+
currents. The Ca
2+

channel s are L-type channel s from GH
3
cel l s, and the Na
+
and K
+
channels are from the squid
gi ant axon. The closed ci rcl es show the concentrati ons of hal othane requi red to anestheti ze
humans. Note that the Ca
2+
currents are i nhibi ted about 20% by cli ni cal concentrati ons of
halothane whereas the Na
+
and K
+
currents are not i nhibi ted at al l . (Reproduced by
permi ssi on from Franks NP, Li eb WR. Mol ecul ar and cel l ul ar mechanisms of anesthesia.
Nature. 1994;367:607, Macmi ll an Magazi nes Ltd.)
HT
3
receptors.
82
Based on the structure of the ni coti ni c acetyl chol i ne receptor, each l igand-gated
channel is thought to be composed of five nonidenti cal subuni ts. The gl utamate receptors al so
comprise a fami l y, each receptor thought to be a tetrameric protei n composed of structurall y
rel ated subuni ts.
83
The l i gand-gated i on channel s provi de a l ogi cal target for anestheti c acti on
because sel ecti ve effects on these channel s coul d i nhi bit fast exci tatory synapti c transmi ssi on
and/or facilitate fast inhi bi tory synaptic transmission. The effects of anestheti c

agents on l i gand-gated i on channel s are thoroughl y catal oged i n a revi ew by Krasowski and
Harrison.
58
The fol lowi ng section provi des a brief summary of thi s l arge body of work.

Gl ut amat e- Act i vat ed I on Channel s
Gl utamate-acti vated ion channel s have been cl assi fi ed, based on sel ecti ve agoni sts, i nto three
categori es: AMPA receptors, kai nate receptors, and NMDA receptors. Mol ecul ar bi ol ogic studi es
indicate that a large number of structural ly di sti nct glutamate receptor subunits can be used to
form each of the three categori es of gl utamate receptors.
84
Thi s structural heterogenei ty i s
refl ected i n functi onal heterogenei ty withi n each category of gl utamate receptor. AMPA and
kai nate receptors are rel ati vel y nonselective monovalent cati on channel s involved in fast
exci tatory synapti c transmi ssi on, whereas NMDA channel s conduct not only Na
+
and K
+
but al so
Ca
++
and are i nvol ved i n l ong-term modulation of synapti c responses (l ong-term potenti ati on).
Studies from the earl y 1980s i n mouse and rat brai n preparati ons showed that AMPA- and kai nate-
acti vated currents are i nsensi ti ve to cli ni cal concentrati ons of hal othane,
85
enfl urane,
86
and the
neurosteroid al l opregnanolone.
87
In contrast, kainate- and AMPA-acti vated currents were shown to
be sensi tive to barbi turates; i n rat hippocampal neurons, 50 M pentobarbi tal (pentobarbi tal
produces anesthesia at approximatel y 50 M) i nhi bi ted kai nate and AMPA responses by 50%.
87

More recent studies usi ng cl oned and expressed glutamate receptor subuni ts show that
submaxi mal agoni st responses of Gl uR3 (AMPA-type) receptors are i nhi bi ted by fluorinated vol ati le
anesthetics whereas agoni st responses of GluR6 (kainate-type) receptors are enhanced.
88
In
contrast both Gl uR3 and Gl uR6 receptors are i nhi bi ted by pentobarbital . The di recti onal l y opposi te
effects of the vol ati le anestheti cs on different gl utamate receptor subtypes may expl ai n the earl ier
inconcl usive effects observed i n tissue, where mul tipl e subuni t types are expressed. These
opposi te effects have al so been used as a strategy to identi fy cri ti cal si tes on the mol ecul es
invol ved in anestheti c effect. By produci ng Gl uR3/Gl uR6 receptor chi meras (receptors made up of
vari ous combi nations of sections of the Gl uR3 and GluR6 receptors) and screeni ng for vol ati l e
anesthetic effect, speci fi c areas of the protei n requi red for vol ati le anesthetic potenti ati on of
Gl uR6 have been i denti fi ed. Subsequent si te-di rected mutagenesi s studi es have i denti fi ed a
specific gl yci ne resi due (Gl y-819) as criti cal for volatil e anestheti c action on Gl uR6-contai ning
receptors.
89

NMDA-acti vated currents al so appear to be sensi ti ve to a subset of anestheti cs.
El ectrophysi ol ogical studi es show vi rtual l y no effects of cli nical concentrati ons of vol ati l e
anesthetics,
85, 86
neurosteroi ds, or barbi turates
87
on NMDA-acti vated currents. It shoul d be noted
that there is some evi dence from fl ux studi es that vol ati l e anestheti cs may i nhi bi t NMDA-acti vated
channel s. A study i n rat brain mi crovesicl es showed that anestheti c concentrati ons (0.20.3 mM)
of halothane and enfl urane i nhi bi ted NMDA-acti vated cal ci um fl ux by 50%.
90
In contrast, ketami ne
is a potent and sel ecti ve i nhi bitor of NMDA-acti vated currents. Ketami ne stereosel ectively inhi bi ts
NMDA currents by bi ndi ng to the phencycli di ne si te on the NMDA receptor protei n.
91, 92, 93
The
anesthetic effects of ketamine i n i ntact ani mal s show the same stereoselectivity as that i s
observed in vi tro,
94
suggesti ng that the NMDA receptor may be the pri nci pal mol ecul ar target for
the anestheti c actions of ketami ne. Two other recent fi ndi ngs suggest that NMDA receptors may be
an i mportant target for ni trous oxi de and xenon. These studies show that N
2
O
95, 96
and xenon
97
are
potent and selective inhi bi tors of NMDA-acti vated currents. Thi s i s il l ustrated in Fi g. 6-4, showing
that N
2
O i nhi bits NMDA-el i ci ted, but not GABA-el i ci ted, currents i n hi ppocampal neurons.
P.118
GABA- Act i vat ed I on Channel s
GABA i s the most i mportant i nhibi tory neurotransmitter i n the mammal i an central nervous system.
GABA-acti vated ion channel s (GABA
A
receptors) medi ate the postsynapti c response to synapticall y
rel eased GABA by sel ecti vel y al lowi ng chlori de i ons to enter and thereby hyperpolarizing neurons.
GABA
A
receptors are multi subunit proteins consi sti ng of vari ous combi nations of , , , , and
subuni ts, and there are many subtypes of each of these subunits. The functi on of GABA
A
receptors
i s modul ated by a wi de vari ety of pharmacol ogi cal agents incl uding convul sants, anti convul sants,
sedati ves, anxiolyti cs, and anestheti cs.
98
The effects of these various drugs on GABA
A
receptor
functi on vari es across brai n regions and cel l types. The fol lowi ng secti on bri efly reviews the
effects of anestheti cs on GABA
A
receptor function.
Barbi turates, anesthetic steroids, benzodi azepi nes, propofol , etomi date, and the volatil e
anesthetics all modulate GABA
A
receptor function.
59
,
98, 99, 100, 101
These drugs produce three ki nds
of effects on the el ectrophysi ol ogi cal behavi or of the GABA
A
receptor channel s: potentiation, direct
gati ng, and i nhi bi ti on. Potentiation refers to the abi l i ty of anestheti cs to increase markedl y the
current eli ci ted by low concentrations of GABA, but to produce no increase i n the current el i ci ted
by a maxi mal ly effecti ve concentration of GABA.
85, 102
Potenti ati on is i l lustrated i n Fi g. 6-5,
showi ng the effects of hal othane on currents el i ci ted by a range of GABA concentrations i n
FIGURE 6-4. Ni trous oxi de i nhibi ts NMDA-el i ci ted, but not GABA-el i ci ted, currents i n rat
hi ppocampal neurons. (Panel A) 80% N
2
O has no effect on holdi ng current (upper trace),
but i nhi bi ts the current el ici ted by NMDA. (Panel B) N
2
O causes a ri ghtward and downward
shift of the NMDA concentrati on-response curve, indicati ng a mi xed
competiti ve/noncompeti ti ve antagonism. (Panel C) 80% N
2
O has l i ttl e effect on GABA-
el i ci ted currents. In contrast, an equi potent anestheti c concentrati on of pentobarbital
markedl y enhances the GABA-el i ci ted current. (Reproduced wi th permi ssi on from Jevtovi c-
Todorovi c V, Todorovi c SM, Menneri ck S, et al . Ni trous oxi de (laughing gas) i s an NMDA
antagonist, neuroprotectant, and neurotoxin. Nature Medi ci ne. 1998;4:460)
di ssociated corti cal neurons. Anestheti c potenti ation of GABA
A

currents general ly occurs at concentrati ons of anestheti cs withi n the cli ni cal range. Di rect gati ng
refers to the abil i ty of anestheti cs to acti vate GABA
A
channel s i n the absence of GABA. General ly,
di rect gati ng of GABA
A
currents occurs at anestheti c concentrati ons hi gher than those used
cl i ni cal ly, but the concentrati on-response curves for potenti ati on and for direct gating can overl ap.
It i s not known whether di rect gati ng of GABA
A
channel s i s either requi red for or contri butes to the
effects of anestheti cs on GABA-mediated i nhi bi tory synaptic transmission in vi vo. In the case of
anesthetic steroids, strong evidence i ndi cates that potentiation, rather than direct gating of GABA
A

currents, is requi red for produci ng anesthesi a.
103
Anestheti cs can al so i nhi bit GABA-acti vated
currents. Inhi biti on refers to the abi l ity of anestheti cs to prevent GABA from i ni tiating current flow
through GABA
A
channel s and has generall y been observed at hi gh concentrati ons of both GABA and
anesthetic.
104, 105
Inhi bi ti on of GABA
A
channel s may help to expl ain why vol ati le anestheti cs have,
in some cases, been observed to inhi bit rather than faci l itate inhi bi tory synaptic transmission.
32

Effects of anesthetics have al so been observed on the function of single GABA
A
channel s. These
studi es show that barbiturates,
99
propofol ,
101
and volatil e anestheti cs
106
do not al ter the
conductance (rate at which ions traverse the open channel ) of the channel , but that they i ncrease
the frequency with whi ch the channel opens and/or the average length of time that the channel
remai ns open. Col lectivel y, the whol e cell and si ngle channel data are most consi stent with the
idea that cl i ni cal concentrati ons of anesthetics produce a change in the conformati on of GABA
A

receptors that increases the affi nity of the receptor for GABA. Thi s is consistent wi th the abi li ty of
anesthetics to i ncrease the duration of inhi bi tory postsynapti c potenti al s (IPSPs), because hi gher
affinity binding of GABA would sl ow the di ssoci ati on of GABA from postsynapti c GABA
A
channel s. It
would not be expected that anestheti cs would i ncrease the peak ampli tude of a GABAergi c IPSP
because synapticall y rel eased GABA probabl y reaches very hi gh concentrati ons in the synapse.
Higher concentrations of anestheti cs can produce addi ti onal effects, ei ther directl y acti vati ng or
P.119
FIGURE 6-5. The effects of hal othane (Hal ), enfl urane (Enf), and fl uorothyl (HFE) on GABA-
acti vated chl ori de currents in di ssoci ated rat CNS neurons. (Panel A) Cl ini cal concentrati ons
of halothane and enfl urane potenti ate the abi l ity of GABA to el i cit a chl ori de current. The
convul sant fl uorothyl antagoni zes the effects of GABA. (Panel B) GABA causes a
concentration-dependent activati on of a chl oride current. Hal othane shifts the GABA
concentration-response curve to the l eft (increases the apparent affi ni ty of the channel for
GABA) whereas fluorothyl shifts the curve to the right (decreases the apparent affini ty of the
channel for GABA). (Reproduced wi th permi ssi on from Wakamori M, Ikemoto Y, Akaike N.
Effects of two volatil e anestheti cs and a volatil e convul sant on the exci tatory and inhi bi tory
amino acid responses i n dissoci ated CNS neurons of the rat. J Neurophysi ol. 1991;66:2014.)
inhi biti ng GABA
A
channel s. Consi stent wi th these i deas, a study by Banks and Pearce showed that
isoflurane and enfl urane si multaneousl y increased the durati on and decreased the ampl i tude of
GABAergi c i nhi bi tory postsynaptic currents i n hippocampal sl ices.
107

Despi te the si mil ar effects of many anestheti cs on GABA
A
receptor functi on, there i s si gni fi cant
evidence that the various anesthetics do not act by bi ndi ng to a si ngl e common bi ndi ng si te on the
channel protein. Fi rst, even anestheti cs that di rectly activate the channel probabl y do not bi nd to
the GABA bi ndi ng si te. Thi s i s most cl early demonstrated by mol ecular biol ogi c studies i n whi ch
the GABA bi ndi ng si te i s el i mi nated from the channel protei n but pentobarbital can sti ll acti vate
the channel .
108
Di rect radi ol i gand bi ndi ng studies have demonstrated that benzodi azepi nes bi nd to
the GABA
A
receptor at nanomol ar concentrati ons and that other anestheti cs can modulate bindi ng
but do not bi nd di rectl y to the benzodi azepi ne si te.
98, 109
A seri es of more complex studies
examini ng the i nteractions between barbiturates, anestheti c steroi ds, and benzodi azepi nes
indicates that these three classes of drugs cannot be acti ng at the same si tes.
98
The actions of
anesthetics on GABA
A
receptors are further compl i cated by the observati on that steroi d
anesthetics can produce di fferent effects on GABA
A
receptors i n different brain regions.
110
Thi s
suggests the possibi l i ty that the specific subunit composi tion of a GABA
A
receptor may encode
pharmacol ogical sel ecti vi ty. This i s wel l il l ustrated by benzodi azepi ne sensi tivity, whi ch requires
the presence of the
2
subuni t subtype.
111
Si mi larl y, sensi tivity to etomidate has been shown to
requi re the presence of a
2
or
3
subunit.
112
More recentl y, i t has been shown that the presence
of a or subuni t i n a GABA
A
receptor confers insensiti vi ty to the potentiati ng effects of some
anesthetics.
113, 114

Interesti ngl y, GABA
A
receptors composed of -type subunits (referred to as GABA
C
receptors) have
been shown to be inhi bi ted rather than potenti ated by vol ati l e anestheti cs.
115
This property has
been expl oi ted, usi ng mol ecul ar biol ogi c techni ques, by constructing chi meric receptors composed
of part of the receptor coupl ed to part of an , , or gl yci ne receptor subuni t. By screeni ng
these chi meras for anestheti c sensiti vi ty, regi ons of the , , and gl yci ne subunits responsibl e for
anesthetic sensi ti vi ty have been i dentified. Based on the resul ts of these chi meri c studies, si te-
di rected mutagenesi s studi es were performed to i denti fy the speci fi c amino aci ds

responsi bl e for conferri ng anestheti c sensi tivity. These studies reveal ed two cri ti cal ami no aci ds,
near the extracel l ul ar regions of transmembrane domai ns 2 and 3 (TM2, TM3) of the glyci ne and
GABA
A
receptors that are requi red for vol ati le anesthetic potenti ati on of agoni st effect.
116
It i s not
yet cl ear i f these ami no aci ds represent a volati l e anestheti c bindi ng si te, or whether they are
si tes criti cal to transduci ng anesthetic-induced conformational changes in the receptor mol ecul e.
Interesti ngl y, one of the amino aci ds shown to be cri ti cal to volatil e anestheti c effect (TM3 si te)
has al so been shown to be required (in the
2
/
3
subunit) for the potenti ati ng effects of
etomi date.
117
In contrast, the TM2 and TM3 si tes do not appear to be required for the actions of
propofol , barbi turates, or neurosteroi ds.
118
Interesti ngl y, a di sti nct amino aci d i n the TM3 regi on
of the
1
subunit of the GABA
A
receptor has been shown to sel ectively modul ate the abil i ty of
propofol to potenti ate GABA agonist effects.
118
Coll ecti vel y, these mol ecular bi ol ogi c data provi de
strong evidence that there are mul ti pl e unique bi ndi ng si tes for anestheti cs on the GABA
A
receptor
protei n.
Ot her Li gand- Act i vat ed I on Channel s
Other members of the l i gand-gated receptor superfamil y incl ude the ni cotini c acetylchol ine
receptors (muscl e and neuronal types), gl yci ne receptors, and 5-HT
3
receptors. A l arge body of
work has gone into exami ni ng the effects of anestheti cs on ni coti ni c acetyl chol i ne receptors. The
muscle type of ni cotinic receptor has been shown to be i nhi bi ted by anestheti c concentrati ons i n
the cl i ni cal range
119
and to be desensi ti zed by hi gher concentrations of anesthetics.
120
The muscle
ni cotinic receptor i s an i nformati ve model to study because of its abundance and the wealth of
knowl edge about i ts structure. It i s, however, not expressed i n the central nervous system and
hence not involved in the mechani sm of anesthesi a. However, a neuronal type of ni cotini c
receptor, whi ch i s wi del y expressed i n the nervous system, mi ght pl ausi bl y be i nvol ved i n
anesthetic mechanisms. Ol der studi es looki ng at neuronal ni cotinic receptors i n mol l uscan
P.120
neurons
121
and i n bovi ne chromaffi n cel l s
122
indi cate that these channel s are i nhi bited by cl i ni cal
concentrations of vol ati le anesthetics. More recent studi es usi ng cl oned and expressed neuronal
ni cotinic receptor subuni ts have shown a hi gh degree of subuni t and anestheti c sel ecti vi ty.
Acetyl chol i ne-el i ci ted currents are i nhibi ted, i n receptors composed of vari ous combinati ons of
2
,
4
,
2
, and
4
subuni ts, by subanesthetic concentrati ons of halothane
123
or i sofl urane.
124
In
contrast, these receptors are relatively insensiti ve to propofol . Most i nteresti ngl y, receptors
composed of
7
subunits are compl etel y i nsensi ti ve to both i sofl urane and propofol.
124, 125

Subsequent pharmacol ogi cal experiments usi ng selective inhi bi tors of neuronal ni cotini c receptors
led to the concl usi on that these receptors are unl i kely to have a major role in i mmobi li zation by
vol ati l e anestheti cs.
126, 127
However, they might play a role i n the amnestic or hypnoti c effects of
128

Gl yci ne i s an i mportant i nhibi tory neurotransmi tter, parti cularly in the spi nal cord and brai nstem.
The gl ycine receptor i s a member of the li gand-acti vated channel superfami ly that, li ke the GABA
A

receptor, is a chl ori de-sel ecti ve i on channel. A l arge number of studies have shown that cl i ni cal
concentrations of vol ati le anesthetics potenti ate gl yci ne-acti vated currents i n i ntact neurons
85
and
in cloned glyci ne receptors expressed i n oocytes.
129, 130
The vol ati le anestheti cs appear to produce
thei r potenti ati ng effect by increasi ng the affi ni ty of the receptor for gl yci ne.
130
Propofol ,
101

al phaxal one, and pentobarbi tal also potenti ate gl yci ne-acti vated currents, whereas etomi date and
ketami ne do not.
129
Potenti ati on of gl yci ne receptor functi on may contribute to the anestheti c
acti on of vol ati l e anestheti cs and some parenteral anesthetics. 5-HT
3
receptors are al so members
of the geneticall y rel ated superfamil y of li gand-gated receptor channel s. Cl i ni cal concentrati ons of
vol ati l e anestheti cs potenti ate currents acti vated by 5-hydroxytryptami ne i n intact cel l s
131
and i n
cl oned receptors expressed in oocytes.
132
In contrast, thi opental i nhibi ts 5-HT
3
receptor
currents
131
and propofol i s wi thout effect on these receptor channel s.
132
5-HT
3
receptors may pl ay
some rol e i n the anestheti c state produced by vol ati le anestheti cs and may also contribute to
some unpl easant anestheti c si de effects such as nausea and vomi ting.
Summar y
Several li gand-gated i on channel s are modulated by cl inical concentrati ons of anesthetics.
Ketamine, N
2
O, and xenon inhi bi t NMDA-type glutamate receptors, and thi s effect may pl ay a
major rol e i n thei r mechani sm of acti on. A large body of evi dence shows that cl inical
concentrations of many anestheti cs potentiate GABA-acti vated currents i n the central nervous
system. Thi s suggests that GABA
A
receptors are a probabl e mol ecular target of anesthetics. Other
members of the l igand-acti vated ion channel fami l y, including gl ycine receptors, neuronal ni cotinic
receptors, and 5-HT
3
receptors, are al so affected by cl i ni cal concentrati ons of anestheti cs and
remai n pl ausi bl e anestheti c targets.
Anest het i c Ef f ect s on Second Messenger Act i vat ed I on
Channel s
Ion channel s can be activated by l i gands present i n the cytopl asm as wel l as by l i gands present in
the extracel l ul ar space. The i ntracel l ul ar li gands that activate these channel s are general l y
chemi cal second messengers, including cycli c nucleoti des, Ca
2+
or H
+
ions, i nosi tol phosphates,
and ATP. The structure of second messengeracti vated ion channel s i s not as wel l understood as
that of the vol tage- or l igand-acti vated channel s, and there i s l ittle i nformation about anestheti c
effects on these channels.
A potassi um-sel ecti ve channel (referred to as I
K(an)
), found in snail neurons, that has many of the
properties of a second messengeracti vated channel i s activated by cl i ni cal concentrati ons of
121, 133, 134
I
K(AN)
shares many bi ophysical properties wi th a second messenger
acti vated potassi um channel found i n Apl ysi a neurons that i s referred to as the S channel . Recent
work by Yost and col l eagues has shown that the S channel i s al so acti vated by cl inical
concentrations of volatil e anestheti cs.
135
The i mportance of volatil e anestheti c activati on of second
messengeracti vated potassi um channel s in i nvertebrates has now become apparent with the
di scovery of a l arge famil y of so-call ed background potassi um channels in mammal s. These
mammal ian potassi um channel s have a uni que structure wi th two pore-formi ng domai ns i n tandem
pl us four transmembrane segments (2P/4TM; Fi g. 6-6C).
136
TOK1, a member of thi s fami l y, was
first shown by Yost and col l eagues to be acti vated by volati l e anestheti cs.
137
The l aboratory of
Mi chel Lazdunski has studied the effects of a vari ety of vol ati l e anestheti cs on several members of
the 2P/4TM famil y. They found that TREK-1 channel s were activated by cl ini cal concentrati ons of
chloroform, di ethyl ether, halothane, and isofl urane (Fi g. 6-6B). In contrast, cl osel y rel ated TRAAK
channel s were insensiti ve to al l the volatil e anestheti cs, and TASK channel s were activated by
halothane and i soflurane, inhi bited by di ethyl ether, and unaffected by chl oroform. These authors
went on to show that the C-termi nal regi ons of TASK and TREK-1 contained ami no aci ds essenti al
for anestheti c acti ons

on TASK and TREK-1 channel s.
138
More recentl y, TREK-1 but not TASK was found to be activated
by cli nical concentrations of the gaseous anestheticsxenon, ni trous oxi de, and cyclopropane.
139

Thus, activati on of background K
+
channel s i n mammali an vertebrates coul d be an i mportant and
general mechani sm through whi ch i nhalational anestheti cs regulate neuronal resti ng membrane
potential and thereby exci tabi li ty; this effect could plausi bl y be a si gni fi cant contri butor to some
components of the anestheti c state.
One type of second messengeracti vated channel , the cal ci um-dependent potassi um channel s, has
been shown to be i nhi bi ted by cl i ni cal concentrati ons of anesthetics.
140
These l arge conductance
potassium channel s open in response to i ncreases in cytopl asmic Ca
2+
concentrati on and are
important i n modul ati ng the shape and frequency of acti on potentials i n the central nervous
system. Whil e a wi de vari ety of anestheti cs inhi bit channel opening, thi s woul d tend to excite
neurons and i s thus unl ikely to be i mportant i n the depressant effects of anestheti cs. Anestheti c
effects on these channels may contribute to the excitatory effects of l ow concentrati ons of
P.121
FIGURE 6-6. Vol ati l e anestheti cs activate background K
+
channel s. (Panel A) Halothane
reversi bl y hyperpol arizes a pacemaker neuron from Lymnaea stagnali s (the pond snai l ) by
acti vating I
Kan
. (Panel B) Halothane (300 M) acti vates human recombi nant TREK-1 channel s
expressed in COS cell s. The fi gure shows currentvol tage rel ationships wi th reversal potential
(V
r ev
) of -88 mV, indicati ve of a K
+
channel . (Panel C) Predi cted structure of a typi cal
subuni t of the mammal i an background K
+
channel s. Note the four transmembrane spanni ng
segments (i n black) and the two pore-formi ng domai ns (P1 and P2). Some but not al l of
these 2P/4TM K
+
channel s are acti vated by vol atil e anestheti cs. (Panel D) Phyl ogenetic tree
for the 2P/4TM fami l y. (Reproduced wi th permission from Franks NP, Li eb WR. Background K
+

channel s: An important target for anestheti cs? Nature Neurosci . 1999;2:395.)
anesthetics and to the convul sant properti es of some anestheti c agents. Several other potassi um-
sel ecti ve i on channel s are also acti vated by second messengers, incl uding ATP-acti vated channel s
and channel s acti vated by muscari ni c acetyl chol i ne receptors, but the effects of anesthetics on
these channels has not been deli neated.
Summar y
Second messengeracti vated ion channel s are a plausi bl e target for anestheti c acti on. Recent
evidence suggests that members of the 2P/4TM fami l y of background potassium channel s may be
i mportant i n produci ng some components of the anestheti c state.
WHAT IS THE CHEMICAL NATURE OF ANESTHETIC TARGET
SITES?
The Meyer - Over t on Rul e
Almost 100 years ago, Meyer and Overton independentl y observed that the potency of gases as
anesthetics was strongly correl ated wi th thei r sol ubi li ty i n ol i ve oil (Fi g. 6-7).
141, 142
Thi s
observation has si gni fi cantl y infl uenced thi nking about anestheti c mechani sms i n two ways. Fi rst,
because a wi de vari ety of structural l y unrelated compounds obey the Meyer-Overton rule, it has
been reasoned that al l anesthetics are l ikely to act at the same mol ecular si te. Thi s i dea i s
referred to as the Uni tary Theory of Anesthesia. Second, it has been argued that since sol ubi li ty i n
a specific sol vent strongl y correl ates wi th anestheti c potency, the sol vent showi ng the strongest
correlation between anestheti c sol ubi li ty and potency i s l ikel y to most cl osel y mimi c the chemi cal
and physi cal properti es of the anestheti c target si te in the CNS. Based on this reasoni ng, the
anesthetic target site was assumed to be hydrophobi c in nature.
FIGURE 6-7. The Meyer-Overton rule. There is a l i near relationshi p (on a l oglog scal e)
between the oil /gas partiti on coeffi cient and the anestheti c potency (MAC) of a number of
gases. The correl ati on between li pi d sol ubi l ity and MAC extends over a 70,000-fol d di fference
in anestheti c potency. (Reproduced wi th permi ssi on from Tanfi uji Y, Eger EI, Terrell RC.
Some characteri sti cs of an excepti onal l y potent inhal ed anestheti c: thi omethoxyfl urane.
The Meyer-Overton correl ati on suffers from two li mi tati ons: (1) it only appli es to gases and
vol ati l e li quids because ol i ve oil /gas parti ti on coeffi cients cannot be determi ned for l i qui d
anesthetics; (2) oli ve oi l is a poorl y characteri zed mi xture of oi l s. To ci rcumvent these l imi tati ons,
attempts have been made to correlate anesthetic potency wi th water/sol vent parti tion

coeffi ci ents. To date, the octanol /water partiti on coeffi cient best correl ates wi th anesthetic
potency. This correlati on holds for a vari ety of classes of anesthetics and spans a 10,000-fol d
range of anestheti c potencies.
143
The properti es of the sol vent octanol suggest that the anestheti c
si te is l i kely to be amphi pathi c, havi ng both pol ar and nonpol ar characteri sti cs.
Except i ons t o t he Meyer - Over t on Rul e
Hal ogenated compounds exi st that are structurall y si mi l ar to the inhal ed anestheti cs yet are
convul sants rather than anestheti cs.
144
There are also convul sant barbiturates
145
and
neurosteroids.
146
One convul sant compound, fl uorothyl (hexafl uorodiethylether), has been shown
to cause sei zures i n 50% of mice at 0.12 vol%, but to produce anesthesi a at hi gher concentrati ons
(EC
50
= 1.22 vol%).
147
The concentrati on of fluorothyl required to produce anesthesi a is
approxi matel y predi cted by the Meyer-Overton rule. In contrast, several polyhalogenated al kanes
have been i denti fi ed that are convul sants but that do not produce anesthesi a. Based on the oli ve
oi l/gas partiti on coeffi cients of these compounds, anesthesia shoul d have been achi eved wi thin the
range of concentrati ons studied.
148
The end poi nt used to determi ne the anestheti c effect of these
compounds was movement in response to a noxi ous sti mul us (MAC). Interesti ngl y, some of these
pol yhal ogenated compounds do produce amnesi a in ani mal s.
149
These compounds are thus referred
to as noni mmobi l izers rather than as nonanestheti cs. Several pol yhal ogenated al kanes have al so
been i dentified that anestheti ze mice, but only at concentrations 10 ti mes those predicted by thei r
oil/gas partition coeffi ci ents;
148
these compounds are referred to as transi tional compounds. The
noni mmobi li zers and transiti onal compounds have been proposed as a l i tmus test for the
rel evance of anestheti c effects observed i n vi tro to those observed in the whol e ani mal.
In several homologous seri es of anesthetics, anestheti c potency increases wi th i ncreasi ng chai n
length unti l a certai n criti cal chain l ength i s reached. Beyond thi s criti cal chain l ength, compounds
are unabl e to produce anesthesi a, even at the highest attainabl e concentrati ons. In the series of
n-al kanols, for exampl e, anestheti c potency increases from methanol through dodecanol ; al l
longer al kanol s are unabl e to produce anesthesi a.
150
This phenomenon is referred to as the cutoff
effect. Cutoff effects have been descri bed for several homologous seri es of anesthetics i ncl udi ng
n-al kanes, n-al kanols, cycl oal kanemethanol s,
151
and perfl uoroal kanes.
152
Whi le the anestheti c
potency i n each of these homol ogous series of anestheti cs shows a cutoff, a corresponding cutoff
in octanol /water or oi l/gas parti ti on coeffi ci ents has not been demonstrated. Therefore,
compounds above the cutoff represent a deviation from the Meyer-Overton rule.
A fi nal devi ati on from the Meyer-Overton rule is the observation that enanti omers of anesthetics
di ffer i n their potency as anesthetics. Enantiomers (mi rror-image compounds) are a cl ass of
stereoisomers that have identi cal physical properties, i ncl udi ng identi cal sol ubil i ty in sol vents such
as octanol or ol i ve oil . Ani mal studi es wi th the enanti omers of barbiturate anestheti cs,
153, 154

ketami ne,
94
neurosteroi ds,
103
etomi date,
155
and i sofl urane
156
al l show enanti osel ecti ve di fferences
in anestheti c potency. These di fferences i n potency range i n magni tude from a >10-fol d di fference
between the enanti omers of etomidate or the neurosteroi ds to a 60% di fference between the
enantiomers of isoflurane. It i s argued that a major difference in anestheti c potency between a
pai r of enanti omers could only be expl ai ned by a protei n bi ndi ng si te (see Protei n Theori es of
Anesthesi a); thi s appears to be the case for etomi date and the neurosteroi ds. Enanti omeri c pai rs
of anesthetics have al so been used to study anestheti c acti ons on i on channel s. It is argued that i f
an anestheti c effect on an i on channel contri butes to the anesthetic state, the effect on the ion
Anesth Anal g. 1977;56:387.)
P.122
channel shoul d show the same enanti osel ecti vi ty as i s observed in whol e ani mal anestheti c
potency. Earl y studi es showed that the (+)-isomer of isofl urane is 1.5 to 2 times more potent than
the (-)-isomer in eli ci ti ng an anestheti c-acti vated potassi um current, i n potentiating GABA
A

currents, and i n i nhi biti ng the current medi ated by a neuronal ni cotinic acetyl chol i ne
receptor.
105, 121
In contrast, the stereoisomers of i soflurane are equi potent i n thei r effects on a
vol tage-acti vated potassi um current and i n their effects on l i pi d phase-transi tion temperature.
121

Studies wi th the neurosteroids
103
and etomidate
155
show that these anesthetics exert
enantiosel ecti ve effects on GABA
A
currents that paral l el the enantiosel ecti ve effects observed for
anesthetic potency.
The excepti ons to the Meyer-Overton rule do not obvi ate the importance of the rule. They do,
however, indi cate that the properti es of a sol vent such as octanol descri be some, but not al l, of
the properti es of an anestheti c binding site. Compounds that deviate from the Meyer-Overton rule
suggest that anesthetic target site(s) are al so defi ned by other properti es including size and
shape.
In defi ni ng the molecul ar target(s) of anestheti c mol ecules one must be abl e to account both for
the Meyer-Overton rule and for the well -defined excepti ons to thi s rul e. It has someti mes been
suggested that a correct molecul ar mechani sm of anesthesi a shoul d also be able to account for
pressure reversal . Pressure reversal is a phenomenon whereby the concentrati on of a gi ven
anesthetic needed to produce anesthesia i s greatl y increased i f the anestheti c is admi ni stered to
an ani mal under hyperbari c condi tions. The i dea that pressure reversal i s a useful tool for
el uci dati ng mechani sms of anesthesi a i s based on the assumption that pressure reverses the
specific physicochemi cal acti ons of the anestheti c that are responsi bl e for

producing anesthesi a; that i s to say, pressure and anestheti cs act on the same mol ecular targets.
However, recent evi dence suggests that pressure reverses anesthesi a by producing excitati on that
physi ol ogi cal l y counteracts anesthetic depression, rather than by acting as an anestheti c
antagonist at the anestheti c si te of action.
157
Therefore, in the following di scussi on of molecul ar
targets of anesthesi a, pressure reversal wi l l not be further discussed.
Li pi d vs. P r ot ei n Tar get s
Anestheti cs mi ght i nteract with several possi bl e molecul ar targets to produce thei r effects on the
function of i on channel s and other protei ns. Anestheti cs might dissol ve i n the li pi d bil ayer, causi ng
physi cochemi cal changes i n membrane structure that alter the abi l i ty of embedded membrane
protei ns to undergo conformati onal changes important for thei r functi on. Al ternativel y, anestheti cs
coul d bi nd di rectl y to protei ns (ei ther ion channel protei ns or modul atory protei ns), thus either (1)
i nterferi ng wi th bi ndi ng of a l i gand (e.g., a neurotransmitter, a substrate, a second messenger
mol ecul e) or (2) altering the abil i ty of the protei n to undergo conformational changes important
for i ts functi on. The fol l owi ng section summarizes the arguments for and against l i pi d theori es and
protei n theories of anesthesi a.
Li pi d Theor i es of Anest hesi a
The el ucidation of the Meyer-Overton rule suggested that anestheti cs i nteract wi th a hydrophobic
target. To i nvestigators i n the earl y part of the twentieth century, the most l ogi cal hydrophobi c
target was a li pi d. In i ts si mpl est i ncarnati on, the l i pid theory of anesthesi a postul ates that
anesthetics di ssolve in the l i pid bil ayers of bi ological membranes and produce anesthesi a when
they reach a criti cal concentrati on in the membrane. Consi stent wi th thi s hypothesis, the
membrane/gas partiti on coeffici ents of anesthetic gases i n pure l i pid bil ayers correl ate strongl y
with anestheti c potency.
158
Thi s si mpl e theory can account for anestheti cs that obey the Meyer-
Overton rule, but cannot account for anesthetics that devi ate from thi s rule. For exampl e, the
cutoff effect cannot be explained by this theory because compounds above the cutoff can achi eve
membrane concentrati ons equal to those of compounds bel ow the cutoff.
159
Si mi l arl y,
enantiosel ecti vi ty cannot be explai ned by thi s theory. Most importantl y, this si mpl est version of
the l i pi d theory does not expl ai n how the presence of the anestheti c in the membrane is transl ated
P.123
into an effect on the functi on of the embedded protei ns.
Membr ane P er t ur bat i on
More sophi sti cated versi ons of the l i pid theory requi re that the anestheti c molecul es dissol ved i n
the l i pi d bi l ayer cause a change or perturbati on i n one or more physi cal properti es of the
membrane. According to thi s theory, anesthesi a i s a functi on of both the concentrati on of
anesthetic i n the membrane and the effectiveness of that anestheti c as a perturbant. Thi s
potential ly could explai n devi ati ons from the Meyer-Overton rule, because nonanestheti cs coul d
achi eve high concentrati ons in the membrane, but might not be effecti ve perturbants. In
examini ng thi s theory it i s important to defi ne expl ici tl y the perturbati on caused by an anesthetic.
One can then test the rel evance of a speci fi c perturbati on to the mechani sm of anesthesi a by
measuri ng the perturbati on caused by various compounds (anestheti cs and nonanestheti cs) and
correl ati ng perturbati on wi th anesthetic potency. The speci fi c perturbations of membrane structure
that have been proposed to be causal ly rel ated to the anestheti c state are bri efl y expl ored i n the
fol l owing section.
Membrane Expansion
Anestheti cs di ssol ved i n membranes do i ncrease membrane vol ume. Thi s occurs both because the
anesthetic mol ecul es occupy space and, i n pri nci ple, because they produce changes i n l i pid
packi ng and/or protei n fol di ng. The criti cal volume hypothesi s is an attempt to correl ate changes
in membrane vol ume wi th anesthesi a. Thi s hypothesi s predi cts that anesthesia occurs when
anestheti c di ssol ved i n the membrane produces a cri ti cal change in membrane vol ume. Changes in
membrane volume coul d compress ion channel s and thus al ter thei r functi on. Al ternativel y,
increases i n membrane thi ckness coul d alter neuronal exci tabi l ity by changi ng the potenti al
gradient across the pl asma membrane.
160
Several studies have shown that anesthetics can
produce changes in membrane vol ume.
161
However, the amount of expansi on caused by cl i ni cal
concentrations of anesthetics is probabl y very smal l . One study of erythrocyte membranes showed
that hal othane (0.27 mM = 1.0 MAC) expanded the membranes by onl y 0.1%.
162
Another study of
erythrocyte membranes showed that both anestheti cs and nonanestheti cs (l ong-chai n n-al kanols
above the anesthetic cutoff) produced simi lar degrees of membrane expansi on.
163
Whi le cl i ni cal
concentrations of anesthetics cl earl y produce membrane expansion, the smal l magnitude of
anesthetic-induced membrane expansi on, coupled wi th the i nabi li ty of thi s theory to account for
the cutoff effect, makes it unlikely that membrane expansi on i s the correct mechani sm of
anesthesia. A recent study by Cantor revi si ts this topi c.
164
Based on thermodynamic modeling, he
argues that anestheti cs i n biol ogi c membranes preferenti al l y di stribute to the i nterface between
l i pi d and aqueous phases. Thi s distri buti on resul ts in i ncreased lateral pressure, whi ch coul d alter
the functi on of membrane-embedded ion channel s. Hi s cal cul ations al so suggest that
noni mmobi li zers shoul d not show the same interfaci al distri buti on. There i s some experi mental
evidence showi ng that anestheti cs, but not noni mmobi li zers, do preferential ly di stribute to the
li pi d/aqueous i nterface i n a membrane.
165
The rel ati onshi p between these recent observati ons and
anesthetic effects on protein functi on remains to be determined.
Membrane Disordering
Studies usi ng nucl ear magneti c resonance (NMR) spectroscopy
166
and el ectron spi n resonance
(ESR) spectroscopy
167
have shown that a variety of anestheti cs can di sorder the packi ng of
phosphol i pi ds i n l i pi d bi l ayers and i n bi ol ogi cal membranes. The decrease i n membrane order
(often referred to as an increase i n membrane fluidi ty) can, i n pri nci pl e, al ter the functi on of i on
channel s embedded i n the l i pi d bil ayer. The abi li ty of anestheti cs to fl uidi ze l i pi d bi l ayers does
show a modest correl ati on wi th anesthetic potency.
168
Membrane disordering can also account for
the cutoff effect. Studi es on synapti c membranes have shown that anestheti c al kanol s (octanol ,
decanol, dodecanol ) fl ui di ze membranes, whereas nonanesthetic al kanol s have ei ther no effect on
fl ui di ty (tetradecanol ) or a ri gi di fyi ng effect (hexadecanol, octadecanol ) on the membranes.
169

Unfortunatel y, the degree of fl ui di zation produced by cl ini cal concentrati ons of anestheti cs i s qui te
smal l .
168
Whi le it i s uncl ear how much fl ui di zati on woul d be requi red to affect i on channel
functi on, anestheti cs produce changes in membrane fluidi ty that can be mi micked by changes in
temperature of l ess than 1C. Cl earl y, a 1C i ncrease in temperature does not cause anesthesia,
or even increase anestheti c potency. It i s highly unli kel y that changes in the fluidity of bulk
membrane lipid are responsibl e for general anesthesi a.

Lipid Phase Transitions
Another l i pi d perturbati on that has been proposed to account for general anesthesi a i s a change in
l i pi d phase-transi ti on behavi or. In i ts ori ginal version this theory proposed that anestheti cs
promote a transi ti on of the l ipi ds i n neuronal membranes between a sol i d (gel ) phase and a l i qui d-
crystal li ne phase. Indeed, in pure l i pid systems cli ni cal concentrati ons of anestheti cs do decrease
the temperature at which such a transi ti on occurs.
170
A second versi on of thi s theory, the lateral
phase-separati on theory, proposed that anestheti cs prevent phase transiti ons between the li quid-
crystal li ne and the gel phase.
171
Accordi ng to thi s theory, l i qui d-crystal li ne to gel phase transiti on
is requi red for normal i on channel function; i nhi biti on of thi s phase transi tion causes anesthesi a.
There i s l ittle evidence to support the phase-transi tion theories. Anestheti c-induced phase
changes have not been observed i n biol ogi c membranes, li pi d phase transiti ons are not known to
be requi red for normal i on channel functi on, and the changes in phase-transi tion temperature
observed in pure l ipi d systems are less than 1C.
P r ot ei n Theor i es of Anest hesi a
The Meyer-Overton rule coul d also be expl ai ned by the di rect i nteracti on of anestheti cs with
hydrophobi c si tes on protei ns. Three types of hydrophobi c si tes on proteins mi ght i nteract
with anestheti cs:
1. Hydrophobi c amino aci ds comprise the core of water-sol ubl e protei ns. Anestheti cs coul d bi nd
i n hydrophobi c pockets that are fortuitously present i n the protei n core.
2. Hydrophobi c amino aci ds al so form the li ni ng of bi ndi ng si tes for hydrophobi c l i gands. For
example, there are hydrophobi c pockets i n whi ch fatty aci ds ti ghtl y bi nd on protei ns such as
al bumi n and the l owmol ecul ar-weight fatty acidbi ndi ng proteins. Anestheti cs coul d
compete wi th endogenous l i gands for bi ndi ng to such si tes on either water-solubl e or
membrane proteins.
3. Hydrophobi c amino aci ds are major consti tuents of the -hel ices, whi ch form the membrane-
spanning regi ons of membrane protei ns; hydrophobic amino aci d side chai ns form the
protei n surface that faces the membrane l i pid. Anestheti c mol ecules coul d i nteract wi th the
hydrophobi c surface of these membrane proteins, di srupti ng normal li pi dprotei n
interactions and possi bl y directl y affecting protein conformation. Thi s l ast possibi l ity would
invol ve the i nteracti on of many anestheti c mol ecules wi th each membrane protei n molecul e
and woul d probabl y be a nonsel ective i nteracti on between anestheti c molecul es and al l
membrane proteins.
Direct i nteracti ons of anestheti c mol ecules wi th protei ns woul d not only sati sfy the Meyer-Overton
rul e, but woul d also provi de the simpl est expl anati on for compounds that devi ate from thi s rul e.
Any protei n-bi nding site is l i kel y to be defi ned by properties such as si ze and shape i n addi tion to
its sol vent properti es. Li mi tations i n si ze and shape coul d reduce the bi ndi ng affi ni ty of
compounds beyond the cutoff, thus expl ai ni ng their l ack of anestheti c effect. Enanti osel ectivity is
al so most easi l y expl ai ned by a direct bi ndi ng of anestheti c mol ecules to defi ned sites on proteins;
a protei n-bi nding si te of defi ned di mensi ons coul d readi l y distingui sh between enanti omers on the
basis of thei r di fferent shape. Protei n-bi nding sites for anesthetics could al so expl ai n the
convul sant effects of some pol yhal ogenated alkanes. Different compounds bindi ng (i n sl ightl y
di fferent ways) to the same bindi ng pocket can produce di fferent effects on protei n conformati on
and hence on protei n functi on. For exampl e, there are three kinds of compounds that can bind at
the benzodi azepi ne bi ndi ng si te on the GABA
A
channel : agoni sts, which potentiate GABA effects
P.124
and produce sedati on and anxi olysi s; inverse-agoni sts, which promote channel cl osure and
produce convul sant effects; and antagonists, which produce no effect on thei r own but can
competiti vel y bl ock the effects of agoni sts and i nverse-agoni sts. By analogy, pol yhal ogenated
al kanes could be inverse-agoni sts, bi ndi ng at the same protei n si tes at which hal ogenated al kane
anesthetics are agoni sts. The evidence for direct i nteractions between anesthetics and proteins i s
briefly reviewed in the foll owing secti on.
Evi dence f or Anest het i c Bi ndi ng t o P r ot ei ns
One of the i ni ti al approaches to probi ng anestheti c interactions wi th proteins was to observe the
effects of anestheti cs on the function of a protei n and to try to make i nferences about bi ndi ng
from the functi onal behavi or. It is enti rel y reasonabl e to assume that direct anestheticprotei n
interactions are responsi bl e for functi onal effects of anestheti cs on puri fi ed water-sol ubl e protei ns
because no l i pid or membrane i s present i n the preparations studi ed. Firefl y l uci ferase is a water-
solubl e, li ght-emitting protei n, which is i nhi bi ted by a wi de vari ety of anestheti c molecul es.
Numerous studi es have extensi vel y characteri zed anestheti c i nhibi tion of firefly luciferase activity
and have revealed the following:
172, 173

1. Anestheti cs i nhi bit firefl y l uci ferase activity at concentrati ons very simil ar to those requi red
to produce cl inical anesthesi a.
2. The potency of anestheti cs as inhi bi tors of fi refl y l uci ferase activity correlates strongl y wi th
thei r potency as anestheti cs, in keepi ng wi th the Meyer-Overton rule.
3. Hal othane i nhi bi ti on of l uci ferase acti vi ty i s competiti ve wi th respect to the substrate D-
luci ferin.
4. Inhi biti on of fi refly l uciferase acti vi ty shows a cutoff i n anestheti c potency for both n-
al kanes and n-al kanols.
Based on these studi es it can be i nferred that a wi de variety of anestheti cs can bi nd in the
luciferin-binding pocket of firefl y l uci ferase. The fact that anestheti c inhi bi ti on of l uci ferase
acti vi ty i s consi stent with the Meyer-Overton rule, occurs at cli ni cal anesthetic concentrati ons, and
explai ns the cutoff effect suggests that the l uciferi n-bi nding pocket may have physi cal and
chemi cal characteri sti cs si mil ar to those of a putati ve anesthetic bi ndi ng si te i n the CNS.
More di rect approaches to study anestheti c bi ndi ng to proteins have included NMR spectroscopy
and photoaffi ni ty l abel i ng. Based on earl y studi es by Wishni a and Pinder, it was suspected that
anesthetics could bind to several fatty acidbi nding proteins, including -l actogl obul i n and bovi ne
serum al bumi n (BSA).
174, 175

19
F-NMR spectroscopi c studi es confi rmed
176
thi s, and demonstrated
that i sofl urane bi nds to approximatel y three saturabl e bi ndi ng si tes on BSA. Isoflurane binding i s
el i mi nated by co-incubati on wi th olei c aci d, suggesting that isoflurane binds to the fatty aci d
bi nding sites on albumi n. Other anestheti cs, incl uding hal othane, methoxyflurane, sevofl urane,
and octanol , compete wi th i sofl urane for binding to BSA.
177
The studi es with BSA provi de direct
evidence that a vari ety of anestheti cs can compete for binding to the same si te on a protei n.
Usi ng thi s BSA model , i t was subsequently shown that anestheti c bindi ng si tes could be identi fi ed
and characteri zed usi ng a photoaffi ni ty l abel i ng techni que. The anestheti c hal othane contai ns a
carbonbromi ne bond. Thi s bond can be broken by ul travi ol et l i ght generati ng a free radi cal . That
free radi cal al lows the anesthetic to permanentl y (coval entl y) l abel the anestheti c binding site.
Eckenhoff and col l eagues used
14
C-labeled halothane to photoaffi ni ty-label anestheti c binding

si tes on BSA
178
and obtai ned results vi rtual ly i dentical to those obtained usi ng NMR spectroscopy.
Eckenhoff subsequentl y has i denti fied the speci fi c amino acids that are photoaffinity-labeled by
[
14
C] hal othane.
179
NMR and photoaffi ni ty-l abeli ng techni ques have al so been appl i ed to several
other protei ns. For exampl e, saturabl e bi ndi ng of hal othane to the l uciferi n-bi nding site on firefl y
luci ferase has been directl y confi rmed usi ng NMR and photoaffi ni ty-labeli ng techniques.
180
Both
NMR and photoaffi ni ty-labeli ng techniques are al so bei ng appl i ed to membrane proteins. At the
P.125
current time these techniques can onl y be appl i ed to purified protei ns avail able i n rel ati vel y l arge
quantity. The muscl e-type ni cotini c acetylchol ine receptor i s one of the few membrane proteins
that can be purified i n l arge quanti ty. Eckenhoff has used photoaffi ni ty l abel ing to show that
halothane bi nds to this protei n. The pattern of photoaffi ni ty l abel i ng i s compl ex, suggesti ng
mul tipl e bi ndi ng si tes.
181
Most recentl y, Mi l ler and col l eagues have devel oped a general anesthetic
that i s an analog of octanol and functions as a photoaffi ni ty l abel . Thi s compound, 3-
di azyri nyl octanol, al so bi nds to speci fi c si tes on the ni coti ni c acetylchol i ne receptor.
182

Al though NMR and photoaffi ni ty techni ques can provide extensi ve informati on about anesthetic
bi nding sites on proteins, they cannot reveal the detai ls of the three-di mensional structure of
these si tes. X-ray di ffraction crystal l ography can provide thi s ki nd of three-di mensional detai l and
has been used to study anestheti c interactions with a smal l number of protei ns. To date, it has
been difficult to crystallize membrane protei ns; thus, these studies have been l i mi ted to water-
solubl e protei ns. In 1965, Schoenborn and col l eagues first used x-ray di ffracti on techni ques to
examine the i nteracti ons of several anestheti cs with crystal li ne myogl obi n.
183, 184
These studies
demonstrated that at a partial pressure of 2.5 atm (xenon MAC = 1 atm), a si ngl e mol ecule of
xenon bi nds to a speci fi c pocket in the hydrophobi c core of the myogl obi n mol ecule. The
anesthetics cyclopropane and di chl oromethane al so bi nd i n thi s pocket, but larger anestheti cs do
not. It shoul d be noted that xenon occupi es a smal l empty space i n the hydrophobic core of
myoglobi n and that even di chl oromethane i s a ti ght fit i n this space. These data provi ded a cl ear
demonstrati on that anesthetic mol ecul es can bi nd in the hydrophobi c core of a water-solubl e
protei n and that the si ze of the hydrophobic bi ndi ng pocket can account for a cutoff in the si ze of
anesthetic mol ecul es that can bi nd i n that pocket. However, myogl obin cannot bind most
anesthetic mol ecul es (because of their si ze) and i s therefore not a good model for the actual
anesthetic bi ndi ng si te(s) i n the central nervous system.
X-ray di ffracti on has al so been used to demonstrate that a si ngl e molecul e of hal othane bi nds i n a
hydrophobi c pocket deep wi thi n the enzyme adenyl ate ki nase.
185
Halothane bi ndi ng was local i zed
to the bi ndi ng si te for the adenine moiety of AMP (adeni ne monophosphate), a substrate for
adenylate ki nase. Consistent wi th thi s fi ndi ng, hal othane was found to inhi bi t adenylate ki nase in
a manner that is competi tive wi th respect to AMP. Unfortunatel y, halothane bi ndi ng to adenyl ate
kinase onl y occurs at concentrati ons wel l beyond the cl inicall y useful range. More recentl y, fi refl y
luci ferase has been crystal li zed i n the presence and absence of the anestheti c bromoform. X-ray
di ffracti on studi es of these crystals showed that the anestheti c does bi nd in the l uci feri n-bi nding
pocket, as had been i nferred from functi onal studi es. Interesti ngl y, two mol ecul es of bromoform
bi nd i n the luciferi n pocketone that i s l ikel y to compete di rectly wi th l uci feri n for bindi ng and
one that i s not.
186
The bi ndi ng data wi th fi refl y l uci ferase and adenyl ate ki nase are of parti cul ar
interest because they demonstrate that anestheti cs can bi nd to endogenous l i gand bi ndi ng si tes
and that thi s bi ndi ng strongl y correlates wi th anestheti c inhi bi ti on of protei n function. The same
group has al so crystal l i zed human serum al bumi n i n the presence of ei ther propofol or hal othane.
The x-ray crystall ographi c data demonstrate bi ndi ng of both anestheti cs to preformed pockets that
had been shown previ ousl y to bi nd fatty aci ds.
187
Given that both of these anesthetics bi nd to
serum al bumi n at cl i ni cal concentrati ons, these data give the best i nsi ght yet i nto the structure of
an anestheti c bi ndi ng pocket.
A recent approach to study anesthetic i nteracti ons wi th protei ns has been to empl oy si te-di rected
mutagenesi s of candi date anestheti c targets, coupl ed with molecul ar model i ng to make predictions
about the l ocati on and structure of anesthetic bindi ng sites. For exampl e, Harri s, Trudel l , and
coll eagues have used this approach to predict the l ocati on and structure of the al cohol bi ndi ng si te
on GABA
A
and gl yci ne receptors.
188
A rel ated approach has been to devel op model protei ns to
define the structural requi rements for an anestheti c bi ndi ng si te. Usi ng thi s approach, Johansson
has shown that a four-hel ix bundle with a hydrophobic core can bi nd vol ati l e anestheti cs at
concentrations (K
D
) si mi l ar to those required to produce anesthesi a.
189

Summar y
Unequivocal evidence from studi es using water-solubl e protei ns demonstrates that anesthetics can
bi nd to hydrophobi c pockets on proteins. Functional and bi ndi ng studi es wi th fi refl y l uci ferase
demonstrate that anestheti cs can bi nd to a protein site at cl i ni cal ly rel evant concentrati ons i n a
manner that can account for the Meyer-Overton rule and devi ati ons from it. Evi dence that direct
anestheticprotei n-bi nding i nteracti ons may be responsi bl e for anesthetic effects on i on channel s
in the CNS remai ns i ndi rect; stereosel ecti vi ty currentl y offers the strongest indirect argument.
Overal l , current evidence strongl y indicates protein rather than li pi d as the molecul ar target for
anesthetic acti on. Whil e the l ong-standi ng controversy between l i pid and protein theori es of
anesthesia may be behi nd us, numerous unanswered questi ons remain about the detail s of
anestheticprotei n interacti ons i ncl udi ng:
1. What i s the stoi chiometry of anestheti c bi ndi ng to a protei n? (i .e., Do many anestheti c
mol ecul es interact wi th a si ngl e protei n molecul e or only a few?)
2. Do anesthetics compete wi th endogenous l i gands for bindi ng to hydrophobi c pockets on
protei n targets or do they bi nd to fortuitous cavi ties in the protei n?
3. Do al l anestheti cs bi nd to the same pocket on a protei n or are there mul tipl e hydrophobi c
pockets for di fferent anestheti cs?
4. How many protei ns have hydrophobi c pockets i n which anesthetics can bind at cl i ni cal ly used
concentrations?
HOW ARE THE EFFECTS OF ANESTHETICS ON MOLECULAR
TARGETS LINKED TO ANESTHESIA IN THE INTACT ORGANISM?
The previous secti ons have descri bed how anestheti cs affect the functi on of a number of i on
channel s and signal i ng protei ns, probably vi a di rect anestheti cprotei n i nteractions. It i s uncl ear
whi ch, i f any, of these effects of anestheti cs on protei n functi on are necessary and/or suffi ci ent to
produce anesthesi a in an

intact organism. A number of approaches have been empl oyed to try to li nk anestheti c effects
observed at a mol ecular level to anesthesi a in i ntact ani mals. These approaches and thei r pi tfall s
are bri efl y expl ored i n the fol l owi ng section.
P har macol ogi cal Appr oaches
An experi mental paradi gm frequently used to study anestheti c mechani sms i s to admi ni ster a drug
thought to act specificall y at a putati ve anestheti c target (e.g., a receptor agonist or antagoni st,
an i on channel activator or antagoni st), then determi ne whether the drug has ei ther i ncreased or
decreased the ani mal 's sensi ti vi ty to a gi ven anestheti c. The underlying assumpti on i s that i f a
change in anestheti c sensiti vi ty i s observed, then the anestheti c is l i kely to act vi a an action on
the speci fi c target of the admini stered drug. Thi s is a l argel y fl awed strategy that has nonetheless
produced a huge li terature. The drugs used to modul ate anestheti c sensiti vi ty usual ly have thei r
own di rect effects on central nervous system exci tabi li ty and thus indirectl y affect anestheti c
requi rements. For exampl e, whil e
2
-adrenergi c agonists decrease hal othane MAC,
190
they are
profound CNS depressants i n their own ri ght and produce anesthesi a by mechanisms distinct from
those used by volatil e anestheti cs. Thus, the MAC-spari ng effects of
2
-agoni sts provi de l i ttl e
insi ght i nto how halothane works. A more useful pharmacol ogi cal strategy woul d be to i denti fy
drugs that have no effect on CNS exci tabi li ty but prevent the effects of given anestheti cs.
Currentl y, however, there are no such anestheti c antagoni sts. Devel opment of speci fi c antagoni sts
for anestheti c agents would provi de a major tool for l i nking anestheti c effects at the molecul ar
level to anesthesi a i n the i ntact organi sm, and mi ght also be of si gnifi cant cl i ni cal uti l ity.
An al ternati ve pharmacol ogical approach i s to devel op li tmus tests for the relevance of
anesthetic effects observed i n vitro. One such test takes advantage of compounds that are
nonanestheti c despi te the predi cti ons of the Meyer-Overton rule. It i s argued that a si te affected
by these nonanestheti c compounds i s unli kel y to be rel evant to the production of anesthesi a.
148
A
P.126
si mi l ar argument uses stereosel ecti vi ty as the di scriminator and argues that a si te that does not
show the same stereoselecti vi ty as that observed for whol e ani mal anesthesi a is unli kel y to be
rel evant to the producti on of anesthesi a.
191
Al though these tests may be useful , they are very
dependent on the assumption that anesthesia i s produced vi a drug acti on at a si ngl e si te. For
example, a nonanestheti c mi ght depress CNS excitabil i ty vi a its acti ons on an i mportant anestheti c
target site whi l e simul taneousl y producing counterbalanci ng exci tatory effects at a second si te. In
this case the li tmus test would incorrectl y el i mi nate the anestheti c si te as i rrel evant to whole
animal anesthesi a. This exampl e i s qui te plausi ble given the convul sant effects of many of the
nonanestheti c pol yhal ogenated hydrocarbons. Another sort of l itmus test i s to selecti vel y
antagonize the putati ve anestheti c target so that this target i s no longer functional . If anestheti c
effects are mediated through thi s target, i nacti vation of the target by the antagonist shoul d result
in anestheti c resistance. Using thi s logi c, the MAC-spari ng effects of GABA
A
and gl yci ne receptor
antagonists were used to argue that both GABA
A
and gl yci ne receptors medi ate some but not al l of
the immobil i zi ng effects of vol ati le anesthetics i n rodents.
192, 193
Thi s same group used the l ack of
effect of neuronal nicoti ni c antagoni sts on isofl urane MAC to concl ude that these receptors had no
role i n volatil e anestheti c immobil i zati on.
127
As wi th many pharmacologi cal resul ts, the i ssues of
specifici ty and efficacy of the antagoni sts prevent these experi ments from bei ng defi ni ti ve.
Nevertheless, these resul ts are consi stent with the fi ndi ngs that vol ati l e anestheti cs affect the
functi on of a l arge number of i mportant neuronal protei ns and no one target i s li kel y to medi ate
al l of the effects of these drugs.
Genet i c Appr oaches
An al ternati ve approach to study the rel ati onshi p between anestheti c effects observed i n vi tro
and whol e ani mal anesthesi a i s to al ter the structure of putative anestheti c targets and
determine how this affects whole ani mal anestheti c sensi tivity. Geneti c techni ques provi de the
most rel i abl e and versati le methods for changi ng the structure of putative anestheti c targets.
Toward this end, a vari ety of approaches have been taken that can be methodol ogi cal l y
categori zed as sel ecti ve breedi ng, forward geneti cs, and reverse geneti cs. Sel ecti ve breedi ng
makes use of exi sti ng geneti c vari ance among strains that are presumabl y because of differences
in multi ple genes and attempts to breed and sel ect for enhanced differences i n the trai t of
interestin thi s case general anestheti c sensi tivity. Kobli n and col l eagues have successful l y used
this strategy to breed two strai ns of mi ce (HI and LO) that differ in thei r sensi ti vi ty to N
2
O by
al most 1.0 atm.
194
A simi lar strategy has been used to breed mice that have differenti al sensi tivity
to the hypnotic effects of the benzodi azepi ne, di azepam. The two strai ns of mi ce (DR and DS)
show some modest, but consi stent, differences i n thei r sensiti vi ty to vol ati le anesthetics.
195
Both
sets of strai ns have differences i n sensi tiviti es to drugs other than general anestheti cs;
196
thus, i t
seems l i kel y that the genetic differences i n these strains may be more general di fferences i n brai n
functi on/exci tabi li ty rather than specific di fferences in an anesthetic target. Neverthel ess, the
HI/LO and DS/DR strains demonstrated that in principl e genes control l ing anestheti c sensi tivity,
perhaps encodi ng anestheti c targets, could be di scovered. These strai ns have not l ed as yet to the
identi fi cation of the responsibl e geneti c l oci . Even under the best of circumstances, mappi ng genes
to the point of their i dentificati on i n mi ce is exceedingl y di ffi cul t, ti me-consumi ng, and expensi ve.
In the parti cular cases of mapping the anestheti c sensi tivity loci i n these strai ns, the task i s made
even more di ffi cul t because the phenotype bei ng mapped requi res speci al testi ng and there i s
overlap i n anestheti c sensi tivity between the strai ns. Further, at least for the HI/LO strai ns,
mul tipl e geneti c loci are contributi ng to the di fferences i n anestheti c sensi tivity.
196
Mul ti pl e l oci
are much more compl ex to i dentify because typi cal l y the contri buti on of each to the phenotype is
smal l and therefore easi l y l ost i n the envi ronmental noi se. Forward geneti cs refers to the cl assical
approach of starti ng from a phenotype of i nterest, for exampl e, al tered anesthetic sensi ti vi ty, and
moving forward ul ti matel y to identi fy the gene of interest. Strictly speaki ng, sel ecti ve breeding
i s one form of forward geneti cs although i t rarel y proceeds al l the way to i denti ficati on of the
genes responsi bl e for the phenotype. More commonl y, forward genetics involves inducing random
mutati ons throughout the genome of a pool of animal s, then i denti fyi ng the rare i ndi vi dual that
carri es a mutati on produci ng the phenotype of i nterest. Thi s approach requi res screening through
large numbers of ani mals and can be effecti vel y accompl i shed only i n l ower organisms with a large
number of offspri ng and short generation ti mes. This typi cal ly means invertebrate model s such as
the frui t fly or nematode.
The fi rst true forward genetic screen for mutants with al tered general anestheti c sensiti vi ty was
performed i n the nematode C. el egans by Phi l Morgan and Margaret Sedensky.
197, 198
They
screened for al tered sensi tivity to supracl ini cal concentrati ons of hal othane. High hal othane
concentrations were used because they are requi red to immobi li ze C. el egans. The first mutant
isol ated had a three-fol d reducti on i n its EC
50
for halothane. Interesti ngly, thi s mutant was
hypersensi tive to chl oroform, methoxyflurane, and thi omethoxyfl urane but not

to l ess l i pophi l i c anesthetics such as isofl urane and enflurane.
198
Thi s sel ecti ve hypersensiti vi ty
argues that a generali zed nervous system dysfuncti on is unli kel y to account for the hal othane
hypersensi tivity. The mutati on was geneticall y mapped and found to be a l oss-of-functi on all ele of
the unc-79 gene, whi ch encodes a neuronal protein that is most si mil ar i n amino aci d sequence to
a l arge human protein encoded by a gene on chromosome 14.
199
The cel lular functi on of either the
C. el egans or human protei n is unknown. To attempt to understand the functi on of unc-79, a
search for mutati ons that return the hal othane hypersensiti vi ty of the unc-79 mutants toward
normal l evels was undertaken. Mutati ons in genes encoding stomatin-li ke protei ns, an i ntegral
membrane protein fi rst identi fi ed i n erythrocytes, were found to suppress unc-79.
200
Geneti c
evidence suggested that the C. el egans stomati ns might control hal othane sensi ti vi ty by regulati ng
the functi on of a mechanical l y gated sodi um channel .
201
Addi ti onal mutant screens i denti fi ed a
gene, cal l ed gas-1, which encodes a hi ghl y conserved mi tochondrial protein functi oni ng i n the
el ectron transport chai n.
202
gas-1 mutants were hypersensiti ve to al l halogenated volati l e
anesthetics tested. The mechani sti c rel ati onshi p between gas-1 and unc-79 and i ts suppressors
genes is unclear.
Cli nical concentrations of vol ati le anesthetics do not immobi li ze C. el egans, but they do produce
behavioral effects including l oss of coordi nated movement.
203
Crowder and col l eagues have
screened for mutants that are resi stant to anestheti c-induced uncoordi nati on and found that
mutati ons i n a set of genes encodi ng protei ns regul ati ng neurotransmitter release control
anesthetic sensi tivity. The gene wi th the l argest effect encoded syntaxi n 1A, a neuronal protei n
hi ghl y conserved from C. el egans to humans and essenti al for fusion of neurotransmi tter vesi cl es
with the presynapti c membrane.
54
Importantl y some syntaxi n mutati ons produced hypersensiti vi ty
to volatil e anestheti cs whi l e others conferred resi stance. These all eli c di fferences i n anestheti c
sensi ti vi ty coul d not be accounted for by effects on the process of transmitter release itself;
54, 55

rather, the genetic data argued that syntaxi n i nteracts wi th a protein cri tical for vol ati l e
anesthetic acti on, perhaps an anestheti c target. Thi s putative target has not yet been identi fi ed.
In Drosophila, cli ni cal concentrati ons of volatil e anestheti cs disrupt negati ve geotaxi s behavi or
and response to a noxi ous li ght or heat sti mul us.
204, 205, 206
Using one or more of these anestheti cs
effects, Nash and col l eagues performed a forward genetic screen for hal othane resi stance. Several
har (halothane resi stance) mutants were isol ated. One set of mutants, har38 and har85, was
found to have mutations i n a gene encodi ng a putati ve cati on channel with predi cted structural
si mi l ariti es to both sodi um and calci um channel s.
207
Interesti ngl y, halothane was shown to reduce
gl utamatergi c transmi ssi on at the Drosophi l a larval neuromuscul ar juncti on, most li kel y by
inhi biti ng gl utamate rel ease, and the har38 and har85 mutants were resistant to thi s presumed
presynaptic hal othane action.
208
As the identi fi cation of the syntaxi n mutants suggested i n C.
el egans, thi s resul t suggests that i nhi biti on of exci tatory neurotransmi tter rel ease may be a
consequenti al acti on of vol ati le anestheti cs in di srupti ng behavior in Drosophila.
At anesthetic concentrati ons 1.5- to 2-fold higher than MAC, volatil e anestheti cs abl ate response
of Drosophila to touch.
209
Using thi s anestheti c end poi nt, Gamo and col l eagues have extensively
screened for Drosophila mutants wi th altered sensi tivity to di ethyl ether. Mutated genes i n two of
the strai ns have been i dentified. A partial -loss-of-functi on mutation in the subuni t of the major
neuronal sodium channel medi ati ng action potential s (para) was one of the mutants. This para Na
+

channel mutant had about a 50% reduction in i ts ether EC
50
.
210, 211
A mutation i n the Drosophila
calreticul i n gene was al so found to produce si mi l ar hypersensi ti vi ty to ether.
212
Interesti ngl y, this
calreticul i n mutant was mi l dly resi stant to i sofl urane and normal l y sensiti ve to halothane.
P.127
Cal reti cul in is a highly conserved protei n l ocali zed to the endopl asmi c reti cul um of al l cell types
and is i nvol ved in Ca
2+
bufferi ng and protei n fol di ng i n the ER.
213
Because of this broad rol e i n
cel lul ar functi on, calreti cul in' s role in anestheti c sensi tivity coul d be i ndi rect.
As with al l model organi sms, a cri ti cal question to ask i s how do the anestheti c mechani sms
impli cated i n nematode and fruit fl y rel ate to mechani sms of anesthesi a i n humans? Even i f a
si mi l ar gene exists in humans, the evol uti onary divergence of the mol ecul es and the very di fferent
nervous systems makes the relevance questi on i mpossi ble to answer without addi ti onal
experi ments. Thus, a more practi cal question i s whi ch of the i mpl i cated invertebrate genes
deserves a potential ly more arduous and expensi ve exami nati on i n a vertebrate speci es? A few
criteri a seem reasonabl e. Fi rst, i s the gene involved i n a process known to be affected by general
anesthetics i n vertebrates? Certai nl y, the genes in C. el egans and Drosophila encodi ng protei ns
regul ati ng neurotransmi tter rel ease and the sodium channel fi t thi s criteri on. Whil e mi tochondrial
el ectron transport has general l y not been impli cated i n vertebrate anestheti c acti on, a case report
of four chil dren who are hypersensi ti ve to sevofl urane by processed EEG cri teri a and found to
carry defects in the same mi tochondrial protein complex impli cated i n C. el egans is an intri gui ng
observation that woul d l i kel y not have been made wi thout the work in C. el egans.
214
Second, is
the gene conserved i n vertebrates and does it function in the nervous system? In thi s regard, both
the mi tochondrial protei n and syntaxi n 1A are very highly conserved and both function in the
nervous system with syntaxin 1A expressed excl usi vel y i n neurons; however, for each of these
protei ns one must expl ai n the eni gma of neuron-subtype-specific effects of anesthetics by a
protei n that functions i n al l neurons. A third cri terion is anestheti c concentrati on. Do the genes
regul ate sensi ti vi ty to cl i ni cal concentrati ons of anestheti cs? However, i n thi s case, some l ati tude
shoul d be gi ven for the possi bi l i ty that the binding sites on the anesthetic targets are parti al l y
di verged and therefore the affinity of the target coul d be reduced. Certai nl y, experi ments wi th
GABA
A
receptors and model anestheti c binding proteins have shown that si ngl e ami no aci d changes
can drasti cal l y alter anestheti c potency or affini ty.
116
,
215, 216, 217, 218
Thus, anestheti c concentration
criteri a shoul d not be used to exclude mechani sms as i s reasonabl y done in more cl osel y related
species such as rodents; rather, the correct concentrati on nei ther rul es in or out the mechani sm
i n questi on but si mpl y makes i t more pl ausi ble. Fi nal ly, one shoul d keep i n mi nd that even if a
parti cul ar anestheti c mechani sm identi fi ed i n i nvertebrates i s operant in humans, i t may not be
the only mechanism of anesthetic action in humans and indeed i t may not even be i nvolved i n
anesthesia at al l but rather i n anestheti c si de effects in other ti ssues such as myocardium or
vascul ar smooth muscl e. Thus, invertebrate genetics shoul d be vi ewed as a means to pose novel
hypotheses, some of which may be compel l ing enough to test in vertebrates.
Reverse genetics refers to al tering the sequence of a known gene and then observi ng the effects
of this mutati on on the process of interest. In other words, reverse geneti cs moves from gene to
phenotype as opposed to cl assi cal forward geneti cs that starts wi th a phenotype and then
proceeds to identi fy the responsi ble gene(s). Reverse geneti cs i s used typi cal ly to test a wel l -
establ i shed hypothesi s, al though occasional ly surpri sing phenotypes produce novel hypotheses.
Whil e reverse geneti cs i s empl oyed i n both i nvertebrate and vertebrate models, i n terms of
anesthetic sensi ti vi ty, reverse geneti cs has been most i nstructi ve i n mi ce.
The GABA
A
receptor has been extensi vely studied using reverse genetic techni ques.
219
The genes
encodi ng for vari ous subuni ts of the GABA
A
receptor have been mutated so that they are either
nonfuncti onal

(gene knockouts) or so that they have al tered ami no acids that mi ght produce al tered functi on
(gene knocki ns). Knockouts of two subuni ts of the GABA
A
receptor have been tested for thei r
anesthetic sensi ti vi ty. Lack of the 1 subunit was not found to al ter sensi tivity of the ani mal to
the hypnoti c effects of pentobarbi tal .
220
Si mi l arl y, 6 subunit knockout mice were normall y
sensi ti ve to hal othane and enflurane.
221
Knocki n mouse strai ns have been generated for several of
the -subuni ts, pri maril y for exami ni ng benzodi azepine action. The l oss of various aspects of
benzodiazepi ne acti on i n these strai ns demonstrated that the 1 subunit medi ates the sedative
and amnesti c acti ons, and i s parti all y requi red for i ts anti convulsant properti es. Simil arl y, the 2
subuni t was found to be essential for anxiol ysis by diazepam, and 3 and 5 knockin strains were
P.128
parti all y resi stant to i ts myorel axant effects. However, none of these -subuni t knocki n strai ns
have been reported to be abnormal l y sensi ti ve to any compl ete general anestheti cs. In contrast,
knockout of the 3 subuni t produced mi ce with a markedl y decreased sensiti vi ty to the hypnoti c
acti on of both mi dazol am and etomi date and a mi ldl y decreased sensiti vi ty to hal othane and
enfl urane i n tail cl amp response assays.
222
The i nterpretation of these data was compl icated by a
vari ety of behavioral and neurological abnormal iti es i n these mi ce that suggested the possibi l ity of
an i ndi rect effect of the mutation on anestheti c sensiti vi ty.
In vi tro electrophysi ol ogical experi ments had shown that a specific 3 subunit point mutation, 3
(N265M), bl ocked the acti on of etomi date and propofol on the GABA
A
receptor wi thout greatl y
al teri ng receptor functi on i n the absence of drug;
117, 223
thi s resul t suggested a means to
ci rcumvent the problems produced by knocking out 3. Thus, a mouse 3(N265M) knockin strai n
was generated and found to be i nsensi ti ve to the immobil i zi ng effects of etomidate and
propofol .
224
However, the 3(N265M) mice were not completely resi stant to the l oss-of-ri ghting
refl ex by etomi date and propofol , i ndi cati ng that other targets medi ated thi s behavi oral effect.
Vol ati le anesthetic sensi tivity was modestly reduced i n the 3(N265M) mice suggesti ng that the 3
subuni t may play some rol e i n their acti on. A si mi lar approach was taken to show that the 2
subuni t i s cri ti cal for the sedating but not anesthetic acti on of etomi date.
225, 226
Fi nal l y, strains
carryi ng a knockout mutati on of the subuni t of the GABA
A
receptor were found to have a shorter
duration of neurosteroi d-induced l oss-of-ri ghting refl ex, whereas their sensi tivity was normal to
other i ntravenous and vol ati l e anestheti cs.
227
Thus, the subuni t may play a relatively speci fi c
role i n neurosteroi d acti on.
Summar y
Overal l , geneti c studi es provi de a powerful tool for determi ni ng whi ch genes and gene products
are important in produci ng anesthesia i n an i ntact organi sm. Forward geneti cs has the potenti al to
identi fy anestheti c mechani sms/targets that may not have been impli cated by vertebrate
bi ochemi cal and el ectrophysi ological studi es that are biased toward abundant i on channels.
However, parti cul arl y for invertebrate geneti cs, the geneti cal l y i dentified mechani sms may not be
operant i n humans or may be operant i n a di fferent physi ol ogical context. Reverse geneti cs has
strengths and weaknesses compl ementary to those of forward geneti cs. Reverse geneti cs rarel y
generates novel hypotheses or fundamental breakthroughs, but i t can confi rm defi ni ti vel y the i n
vi vo rol e of a gene product. Indeed, the demonstrati on that the action of the general anestheti cs
etomi date and propofol can be blocked by a si ngl e mi ssense mutati on i n a subuni t of the GABA
A

receptor i s at the same ti me not surprisi ng and yet one of the most important resul ts thus far i n
anesthetic mechanism research.
CONCLUSION
In thi s chapter evidence has been reviewed concerni ng the anatomi c, physi ol ogi c, and
mol ecul ar l oci of anestheti c acti on. It i s clear that all anesthetic acti ons cannot be local ized
to a speci fi c anatomi c si te in the central nervous system; indeed, some evi dence suggests that
di fferent components of the anestheti c state may be mediated by acti ons at disparate anatomi c
si tes. The acti ons of anesthetics also cannot be local i zed to a speci fic physiol ogi c process. Whil e
there i s consensus that anestheti cs ul timately affect synaptic function as opposed to i ntri nsi c
neuronal excitabil i ty, the effects of anestheti cs are dependent on the agent and synapse studi ed
and can affect presynapti c and/or postsynaptic function. At a mol ecul ar level , anesthetics show
some sel ectivity, but sti l l affect the functi on of multi ple i on channel s and si gnal i ng protei ns.
Although i t is l i kely that these effects are medi ated vi a direct protei nanesthetic i nteracti ons, i t
appears that there are numerous protei ns that can

di rectl y i nteract with anestheti cs. Al l of these data suggest that the uni tary theory of anesthesia i s
incorrect and that there are at l east several molecul ar mechani sms of anesthesi a.
In keepi ng with the idea that anesthesi a can be produced i n a vari ety of ways, Pancrazi o and
Lynch have suggested that di fferent anestheti c targets may mediate different components of the
anesthetic state.
228
As il l ustrated i n Fi g. 6-8, they suggest that the anal gesi c effects of opi ates,
P.129
2
-agoni sts, and vol ati l e anestheti cs are medi ated via inhi bi ti on of cal ci um currents and/or
acti vation of potassi um currents. Sedati on and amnesi a, they propose, are medi ated by
potentiation or activati on of GABA
A
receptors. In thi s model , anesthetic states can al so be
produced by total l y i ndependent mechanisms such as the inhi bi tion of gl utamate receptors by
ketamine. Although there may be many more important anestheti c targets than those suggested
by Pancrazi o and Lynch, thei r proposal il l ustrates the i dea that different molecul ar targets may
mediate the various components of the anestheti c state, and that vol ati l e anestheti cs are
compl ete anesthetics because they can interact wi th several of these mol ecular targets.
Although the preci se molecul ar interactions responsi bl e for produci ng anesthesia have not been
ful l y el uci dated, i t has become cl ear that anestheti cs do act via selective effects on specific
mol ecul ar targets. The technol ogic revoluti ons i n mol ecul ar bi ol ogy, geneti cs, and cel l physi ology
make i t l i kel y that the next decade wi l l provi de the answers to the century-ol d pharmacol ogi cal
puzzle of the molecul ar mechani sm of anesthesi a.
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to volatil e anestheti cs in Caenorhabdi ti s elegans. Proc Natl Acad Sci USA 95:8761, 1998
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control anestheti c sensi tivity i n Caenorhabdi ti s elegans. Geneti cs 153:1673, 1999
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to volatil e anestheti cs in the nematode Caenorhabdi ti s elegans. Anesthesiology 90:545, 1999
203. Crowder CM, Shebester LD, Schedl T: Behavi oral effects of vol atil e anestheti cs in
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> Tabl e of Contents > Secti on II - Basi c Pri nci pl es of Anesthesi a Practi ce > Chapter 7 - Genomi c Basi s of
Peri operati ve Medi ci ne
Chapter 7
Genomic Basis of Perioperative Medicine
Mihai V. Podgoreanu
Joseph P. Mathew
KEY POINTS
Functi onal genomi cs empl oys large-scal e experi mental methodol ogies and
stati sti cal analyses to investi gate the regul ation of gene expressi on i n response
to physi ol ogi cal , pharmacol ogi cal , and pathol ogical changes.
Most of geneti c di versi ty i n the population i s attri butable to wi despread DNA
sequence vari ati ons (pol ymorphi sms).
Speci fi c genotypes are associated wi th a vari ety of organ-specific perioperative
adverse outcomes, i ncluding neurocogni tive dysfuncti on, renal compromise, vein
graft restenosi s, postoperati ve thrombotic compl icati ons, vascular reacti vi ty,
severe sepsi s, transplant rejecti on, and death.
Ri sk strati fi cati on based on cl i ni cal , procedural , and bi ol ogical markers expl ai ns
only a smal l part of the variabi li ty in i nci dence of peri operati ve compl icati ons.
Speci fi c genotypes may i mprove prediction of adverse peri operati ve outcomes i n
otherwi se healthy i ndi vi dual s.
Several genes predi cti ve of perioperative vascular response have been
identi fi ed.
Variabi li ty i n the reported i nci dence of both early and l ate neurol ogi cal defi cits
remai ns poorl y expl ai ned by procedural ri sk factors, suggesti ng that
environmental (operative) and geneti c factors may i nteract to determi ne di sease
onset, progression, and recovery.
Geneti cs pol ymorphi sms are associ ated wi th acute renal i njury fol lowi ng
coronary artery bypass graft (CABG) surgery.
Geneti c vari ants in the reni nangiotensi n pathway and i n proinflammatory
cytoki ne genes have been associ ated with respi ratory compli cati ons post-
cardi opul monary bypass.

GENETIC BASIS OF DISEASE
Human bi ol ogi cal di versi ty i nvol ves i nteri ndi vi dual vari abi l i ty in morphology, behavior,
physi ol ogy, devel opment, suscepti bil i ty to disease, response to stressful sti mul i and drug
therapy (i.e., phenotypes). Thi s phenotypic variation is determined, at least in part, by differences
i n the speci fi c geneti c makeup (i .e., genotype) of an indi vi dual. In 2003, the fi fti eth anni versary of
Watson and Cri ck' s descripti on of the DNA doubl e heli x structure al so marked the compl etion of
the Human Genome Project.
1
Thi s major accompl i shment provides the di sci pl i ne of genomi cs with
basic resources to study the functi ons and i nteracti ons of al l genes in a systematic fashi on,
incl udi ng their i nteracti on with envi ronmental factors, and transl ate the findi ngs i nto cl i ni cal and
soci etal benefits. Functi onal genomi cs empl oy l arge-scal e experi mental methodol ogi es and
stati sti cal analyses to investi gate the regul ati on of gene expression in response to physiol ogi cal ,
pharmacol ogical, and pathol ogi cal changes. It al so uses geneti c information from cl i ni cal studi es to
examine the impact of geneti c vari abi l ity on disease characteri zati on and outcome.
2
To i ntegrate
this new generati on of geneti c resul ts into cl ini cal practi ce, peri operati ve physici ans need to
understand the patterns of human genome vari ati on, the methods of popul ati on-based genetic
investi gati on, and the pri nci ples of gene and protei n expressi on anal ysi s.
Over vi ew of Human Genet i c Var i at i on
Although the human DNA sequence i s 99.9% identi cal between i ndi vi dual s, the vari ati ons may
greatl y affect a person' s disease ri sk. In el uci dati ng the geneti c basi s of disease, much of
what has been i nvestigated to date has focused on rare geneti c vari ants (mutati ons) responsi bl e
The term pharmacogenomics descri bes how i nheri ted vari ati ons in genes
modul ati ng drug acti ons are related to interi ndi vi dual vari abi l ity in drug
response. Such vari abi li ty i n drug acti on may be pharmacoki netic or
pharmacodynami cs.
Mal ignant hyperthermi a (MH) suscepti bil i ty results from a compl ex i nteraction
between multi ple genes and envi ronment.
A genetic basis for increased anesthetic requi rements i s begi nni ng to emerge,
suggested, for instance, by the observati on that desfl urane requi rements are
increased i n subjects wi th red hai r versus dark hai r.
In addi ti on to the geneti c control of peripheral noci cepti ve pathways,
consi derable evidence exists for geneti c vari abi l i ty in the descendi ng central
pai n modul atory pathways, potenti al l y expl aining the i nteri ndividual variabi li ty
in analgesic responsiveness.
The l arge i nteri ndi vi dual vari abil i ty i n the magni tude of response to injury,
incl udi ng activati on of infl ammatory and coagulation cascades, apoptosis, and
fibrosi s, suggests the i nvol vement of genetic regul atory factors.
The standard si ngl e gene paradi gm i s i nsuffi ci ent to adequatel y descri be the
ti ssue response to severe systemi c sti muli . Instead, organ i njury mi ght better
be defi ned by patterns of al tered gene and protei n expressi on.
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for monogeni c di sorders such as hypertrophi c cardi omyopathy, l ong-QT syndrome, si ckle cel l
anemi a, or fami l ial hypercholesterol emi a, which are highly penetrant (carri ers of the mutant gene
wil l l ikely have the disease) and i nheri ted in mendeli an fashi on (hence, termed mendel i an
di seases). However, most of the geneti c di versi ty in the popul ati on i s attri butable to more
widespread DNA sequence vari ati ons (pol ymorphi sms), whi ch can be ei ther nucl eoti de base
substi tuti ons (si ngl e nucl eoti de polymorphi sms, SNPs), short sequence repeats (mi crosatel l ites),
or insertion/deleti on of one or more nucleotides (indel s), and may or may not be associated wi th a
specific phenotype (Fi g. 7-1). To be cl assified as a pol ymorphi sm, the DNA sequence al ternati ves
(i .e., al lel es) must exi st wi th a frequency of at least 1% i n the popul ati on. About 10 mi l li on SNPs
are esti mated to exi st i n the human genome, approxi matel y once every 300 base pai rs, located i n
genes as wel l as in the surrounding regions of the genome. Pol ymorphi sms may directl y alter the
amino acid sequence and therefore potenti al l y alter protei n functi on, or al ter regul atory DNA
sequences that modul ate protei n expressi on. Sets of nearby SNPs on a chromosome are i nheri ted
i n bl ocks, referred to as haplotypes. As i t wil l be shown l ater, hapl otype anal ysis i s a useful way
of appl yi ng genotype i nformati on i n di sease gene di scovery.
Many common di seases li ke atherosclerosi s, coronary artery di sease, hypertensi on, di abetes,
cancer, asthma and our responses to i njury, drugs, and nonpharmacol ogi cal therapi es are
FIGURE 7-1. Categories of genetic pol ymorphi sms. A. Si ngl e nucl eoti de pol ymorphi sms
(SNP) can be silent or have functi onal consequences rangi ng from changes i n amino aci d
sequence or premature termi nation of protei n synthesis (i f they occur in the coding regi ons
of the gene) to al terati ons in the expressi on of the gene, resulti ng i n more or l ess protei n (i f
they occur i n regul atory regi ons of the gene such as the promoter region or the i ntron/exon
boundari es). B. Mi crosatell i te pol ymorphi sm with varying number of di nucl eoti de (CA)
n

repeats. C. Inserti on-del etion pol ymorphi sm. NOTE: locusthe locati on of a gene/geneti c
marker i n the genome; al lel esal ternati ve forms of a gene/geneti c marker; genotypethe
observed al l eles for an i ndi vi dual at a geneti c locus; heterozygoustwo di fferent al l el es are
present at a locus; homozygoustwo i denti cal al l eles are present at a l ocus. An SNP at
positi on 1691 of a gene, with al l el es G and A woul d be wri tten as 1691G>A.
geneti cal l y compl ex, characteristicall y involving an i nterplay of many geneti c vari ati ons i n
mol ecul ar and biochemi cal pathways (i .e., pol ygeni c) and genetic-envi ronmental interacti ons (i .e.,
mul tifactorial ). Therefore, compl ex phenotypes can be viewed as the integrated effect of many
suscepti bi l i ty genes and many envi ronmental exposures (Fi g. 7-2). The proportion of phenotypi c
vari ance that i s the resul t of genetic factors is referred to as heri tabi l ity and can be esti mated by
examini ng the i ncreased simi lari ty of a phenotype in rel ated as compared to unrel ated i ndi vi dual s.
One of the major chal l enges and ongoing research efforts faci ng the postgenomi c peri od i s to
connect the nearly 30,000 protei n-coding genes of mammal i an organi sms to the geneti c basi s of
compl ex pol ygeni c di seases and the i ntegrated functi on of compl ex bi ol ogical systems. According
to the common-vari ants/common-di sease hypothesi s,
3
i t i s the common functi onal
pol ymorphi sms that modulate indi vi dual suscepti bi l i ty to common compl ex di seases and the
mani festati on, severity, and prognosis of the di sease process. In the next secti on, we review the
common strategies used to i ncorporate geneti c anal ysi s into cl inical studi es.
Genet i c Anal ysi s of Compl ex Di sease
Most ongoi ng research on compl ex di sorders focuses on identi fyi ng genetic polymorphisms that
enhance suscepti bil i ty to gi ven conditi ons. Often the desi gn of such studi es i s compli cated by the
presence of multi ple ri sk factors, geneenvi ronment i nteracti ons, and a l ack of even rough
estimates of the number of genes underl yi ng such complex traits. Two broad strategi es are bei ng
employed to i denti fy compl ex trai t l oci . The candi date gene approach i s motivated by what i s

known about the trai t bi ol ogi cal l y and can be characteri zed as a hypothesi s-testi ng approach. The
second strategy i s a genome scan, i n whi ch thousands of markers uni forml y distri buted throughout
the genome are used to l ocate genomic regions that may harbor genes i nfl uenci ng the phenotypi c
vari abi l ity. Thi s is a hypothesis-generati ng approach, al l owi ng the detection of previ ously unknown
trai t l oci.
4
Both the candi date gene and genome scan approaches can be i mplemented usi ng one of
two fundamental methods of identi fying polymorphi sms affecting common di seases: l i nkage
anal ysi s or associ ati on studies i n human popul ati ons.
FIGURE 7-2. Common di seases (e.g., coronary artery di sease, hypertensi on, di abetes,
cancer) and i ndi vi dual responses to vari ous perturbati ons (e.g., drug admi ni strati on,
hemodynamic chal l enge, surgi cal stress, trauma) are compl ex, involving mul ti pl e genegene
interactions (pol ygeni c) and geneenvi ronment i nteracti ons (mul tifactorial ) to produce a final
cl i ni cal outcome, or phenotype. In these i nstances, rather than di rectly causi ng the disease,
geneti c vari abil i ty may contri bute to disease onset and/or progression.
P.135
Linkage Analysis
Linkage anal ysi s is used to i dentify the chromosomal locati on of gene variants rel ated to a given
di sease. This approach has been used successful l y to map hundreds of genes for rare, monogenic
di sorders. However, the nature of complex diseases precl udes the use of extended fami li es
wherein the same disease al lel e acts i n most affected i ndi vi dual s throughout a pedi gree. Rather, i n
compl ex di sease a multi tude of genes wi th rare and/or common al l el es create an apparentl y
chaoti c pattern of heterogenei ty wi thi n and between fami l i es. The overal l effect of thi s
heterogeneity, together with the potenti al l y weak i nfl uence of many l oci , pl aces a heavy burden on
the stati sti cal power needed to detect i ndi vi dual contri buti ng genes, and may be the reason why
very few genome scans so far have yi elded di sease l oci that meet genome-wide si gni fi cance
criteri a.
5
However, a few posi ti ve fi ndi ngs have emerged usi ng thi s approach. Combi ni ng li nkage
anal ysi s with advanced mol ecul ar geneti c techniques, the chromosomal l ocation (5q12) of a gene
infl uenci ng stroke was i dentified,
6
and risk of myocardial i nfarction was mapped to a si ngl e regi on
on chromosome 14.
7
Addi ti onal l y, many determi nants of complex cardiovascul ar and renal function
have been mapped in the rat,
8
provi di ng the fi rst rough approxi mati on of genomi c regi ons l i nked
to homeostati c control of sodiumwater excretion and arteri al pressure. However, withi n these
broad regi ons resi de hundreds of genes that may act alone or in concert to i nfluence homeostasi s.
Narrowi ng the regi ons of geneti c i nterest and i denti fying speci fi c genes that partici pate i n
homeostati c control usi ng techni ques of chromosomal substi tution coupl ed with gene expressi on
anal ysi s and physi ol ogical profi li ng is the object of i ntense research effort.
9

Genetic Association Studies
As menti oned earli er, genetic effects on complex disorders are l ikel y to i nvol ve mul ti pl e
suscepti bi l ity markers of individual l y modest i mportance, thereby l imiti ng the appl i cati on of
li nkage anal ysis. Associ ati on studi es examine the frequency of speci fi c genetic polymorphisms i n a
popul ati on-based sampl e of unrel ated di seased i ndi vi dual s and appropri atel y matched unaffected
control s. The i ncreased stati sti cal power to uncover smal l cl i ni cal effects of multi ple genes
10
and
the fact that they do not requi re fami l y based sampl e coll ecti ons are the mai n advantages of thi s
approach over li nkage anal ysi s. Most si gni fi cant informati on has been gathered so far from
association studi es i n whi ch prior knowl edge of the gene or i ts protei n product exi sted. Thi s
candi date gene approach has been widely used to anal yze possibl e associ ati ons between geneti c
vari ants and disease progressi on or outcome, wi th genes sel ected because of a pri ori hypotheses
about thei r potential eti ological rol e in di sease, based on current understandi ng of the di sease
pathophysi ol ogy.
11
For exampl e, genetic vari ants withi n the reninangiotensi n system,
12
ni tri c
oxi de synthase,
13
and
2
-adrenergi c receptors,
14
known to modul ate vascular tone, were tested
and found to be associ ated wi th hypertension. Simi larl y, the possibl e effects of pol ymorphi sms on
geneti c predi sposi ti on for coronary artery di sease
15, 16, 17
or restenosi s after angi opl asty
18, 19
have
been extensively i nvesti gated, and recentl y, two l arge-scal e associ ati on studi es have i dentified
gene vari ants that might affect suscepti bi li ty to myocardial i nfarcti on.
20, 21
Accumul ati ng evi dence
suggests that speci fi c genotypes are associ ated wi th a vari ety of organ-specific perioperative
adverse outcomes, i ncluding neurocogni tive dysfuncti on,
22, 23
renal compromi se,
24, 25
vein graft
restenosis,
26
postoperati ve thrombosis,
27
vascul ar reacti vi ty,
28
severe sepsi s,
29
transplant
rejecti on,
30
and death (for a revi ew, see Ziegel er et al.
31
).

One of the mai n weaknesses of the associ ati on approach i s that, unless the marker of interest
travels (i.e., is in l i nkage di sequi l i bri um) with a functi onal variant, or the marker al l el e is the
actual functi onal variant, the power to detect and map complex trait l oci wi l l be reduced. Other
known li mitati ons of genetic associ ati on studies i ncl ude potenti al fal se-positi ve fi ndings resul ti ng
from population stratificati on (i .e., admi xture of different ethni c or genetic backgrounds i n the
case and control groups)
32
and mul ti pl e comparison i ssues when large numbers of candi date genes
are bei ng assessed.
33
Repl i cation of fi ndi ngs across di fferent popul ati ons or rel ated phenotypes
remai ns the most rel i abl e method of vali dati ng a true relationshi p between geneti c polymorphisms
and di sease,
11
but poor reproducibi l ity i n subsequent studi es i s one of the mai n cri ti cisms of the
candi date gene associ ati on approach.
34
However, a recent meta-anal ysi s suggested that lack of
stati sti cal power may be the mai n contributor to thi s i nconsi stent

repl icati on and proposed more stri ngent stati sti cal cri teri a to excl ude fal se-positi ve results and
the desi gn of large col laborati ve association studi es.
35
Ongoi ng efforts to devel op hi gh-resol uti on
maps of geneti c vari ati on and haplotypes (the International HapMap Project) shoul d faci l itate the
fi ne l ocal i zati on of causal geneti c vari ants for common di seases and vari abl e drug responses and
increase the power of future associ ati on studi es.
Lar ge- Scal e Gene and P r otei n Expr essi on P r of i l i ng
Genomic approaches are anchored i n the central dogma of molecul ar biol ogy, the concept of
transcripti on of messenger RNA (mRNA) from a DNA template, foll owed by transl ati on of RNA i nto
protei n (Fi g. 7-3). Since transcripti on i s a key regul atory step that may eventual l y si gnal many
other cascades of events, the study of RNA level s i n a cell or organ (i .e., quanti fyi ng gene
expressi on) can i mprove the understandi ng of a wi de vari ety of biol ogical systems. Furthermore,
whi l e the human genome contai ns onl y about 30,000 genes, functional vari abil i ty at the protei n
level i s far more diverse, resulti ng from extensi ve posttranscri pti onal, translational , and
posttransl ati onal modi fi cati ons. It i s beli eved that there are approxi matel y 200,000 di sti nct
protei ns i n humans, which are further modi fi ed posttranslati onall y by phosphorylation,
gl ycosylation, oxidati on, and disulfi de structures.
36
Thus, in additi on to the assessment of geneti c
vari abi l ity at the DNA l evel usi ng vari ous genotypi ng techni ques, analysi s of l arge-scal e variabi li ty
at the RNA and protei n l evel usi ng microarray and proteomi c approaches provi des a better
understandi ng of the overall regul atory networks i nvol ved i n compl ex phenotypes.
Mi croarray technol ogies have revol utioni zed the anal ysi s of gene expressi on changes in bi ol ogi cal
events and i n compl ex di seases, by si mul taneousl y exami ning on a genome-wide scale the
P.136
FIGURE 7-3. Central dogma of mol ecul ar bi ol ogy. Protei n expression i nvol ves two mai n
processes, RNA synthesis (transcripti on) and protei n synthesis (transl ati on), with many
intermedi ate regul atory steps. A si ngl e gene can gi ve ri se to mul ti pl e protei n products
(i soforms) vi a al ternative spl i ci ng and RNA edi ti ng. Thus functi onal variabi li ty at the protein
level , ulti matel y responsi bl e for bi ologi cal effects, i s the cumul ati ve resul t of geneti c
vari abi l ity as wel l as extensi ve posttranscripti onal , transl ati onal, and posttranslational
modificati ons.
expressi on of many thousands of transcri pts i n a si ngl e experiment. Some have even call ed
mi croarray anal ysis the essence of genomi cs.
37
Speci al al gori thms used i n the computational
anal yses of the vast amounts of data thus generated enable the identi fi cati on of gl obal patterns of
gene expressi on and groupi ng genes i nto expressi on cl usters. Investi gati ng the rel ati onshi p
between such cl usters of candi date genes provides greater i nsi ght i nto thei r potenti al bi ol ogi cal
rel evance than simple compari sons of up- and down-regul ated genes. In peri operati ve medi ci ne,
DNA mi croarrays may be appl i ed to eval uate and catal og organ-specific responses to surgi cal
stress and severe systemi c sti muli such as cardi opul monary bypass and endotoxemia, whi ch can
be subsequently used to identi fy and val idate targets for therapeutic i ntervention.
38
Several
studi es have profil ed myocardi al gene expression in the i schemi c heart, demonstrati ng al terati ons
in the expressi on of immedi ate-early genes (c-fos, junB),
39
genes codi ng for cal ci um-handl ing
protei ns (cal sequestri n, phosphol amban), and extracel l ul ar matri x and cytoskeletal protei ns.
40

Upregulation of transcripts mechani sti cal l y i nvol ved i n cytoprotecti on (heat shock protei ns),
resistance to apoptosi s, and cel l growth has been found i n stunned myocardi um.
41
Furthermore,
cardi ac gene expressi on profi li ng after cardi opul monary bypass and cardi opl egi c arrest has
identi fi ed the upregul ati on of i nflammatory and transcri pti on acti vators, apoptotic genes, and
stress genes,
42
whi ch appear to be age-rel ated.
43
Microarray technol ogy has also been uti l i zed i n
the quest for novel cardi oprotecti ve genes, wi th the ulti mate goal of desi gni ng strategi es to
acti vate these genes and prevent myocardial i njury. Precondi ti oni ng i s one of such wel l -studi ed
model s of cardioprotection, whi ch can be induced by various triggers including intermi ttent
ischemi a, osmotic or redox stress, heat shock, toxi ns, and interesti ngl y, inhaled anesthetics. The
main functi onal categories of genes identi fi ed as potenti al ly i nvol ved i n cardi oprotecti ve pathways
incl ude a host of transcri pti on factors, heat shock protei ns, antioxi dant genes (heme-oxygenase,
gl utathi one peroxi dase), and growth factors,
44
but di fferent gene programs appear to be acti vated
in i schemic versus anestheti c precondi ti oni ng, resul ti ng in two distinct cardioprotective
phenotypes.
45

Identi fi cation of genes displ aying signi fi cant changes i n expression (di fferenti al l y expressed) by
mi croarray anal ysis can be used as an unbiased method to sel ect candidate genes for future
association studi es. However, before such use, qual ity assurance protocol s are required to val i date
the mi croarray

resul ts. These i ncl ude experi ment repl i cati on, sel ecti on of cut-off values used to i denti fy
di fferenti al l y expressed genes, and confi rmati on of fi ndi ngs by alternati ve methods (quantitati ve
reverse transcriptase pol ymerase chain reaction, Northern blotti ng, or i n si tu hybri di zati on).
5
It i s
important to reali ze that expressi on studies al one cannot prove functi on. To establi sh a causal
rel ati onship between the change i n gene expression and the disease, every new hypothesi s has to
be further tested through either gain- or loss-of-functi on studies i n biologi cal systems (such as
transgenic overexpressi on, domi nant negative, antisense, or gene targeti ng strategi es).
46
In spite
of their l imi tati ons and onl y when coupl ed wi th ri chly annotated comparati ve databases, DNA
mi croarrays have the potential to become useful tools i n compl ex di sease cl assi fi cation, predi cti on
of response to treatment and prognosi s, and identi fi cati on of novel therapeuti c targets.
The transcriptome (the compl ete col lection of transcribed el ements of the genome) is not ful ly
representati ve of the proteome (the complete complement of protei ns encoded by the genome),
si nce many transcri pts are not targeted for translation, as evi denced recentl y wi th the concept of
gene sil enci ng by RNA interference. Al ternati ve spl ici ng, a wide vari ety of posttranslati onal
modi fi cati ons, and proteinprotei n i nteractions responsi ble for bi ol ogical functi on woul d remain
therefore undetected by gene expressi on profi l ing. This has l ed to the emergence of a new fi el d,
proteomi cs, studyi ng the sequence, modificati on, and functi on of all protei ns i n a bi ological
system at a given ti me. Rather than focusi ng on stati c DNA, proteomi c studies exami ne dynami c
protei n products, with the goal of i dentifyi ng protei ns that undergo changes in abundance,
modi fi cati on, or l ocal izati on i n response to a parti cul ar di sease state, trauma, stress, or
therapeutic i ntervention.
47
Thus, proteomics offers a more global and integrated view of biol ogy,
complementing other functional genomi c approaches. Currentl y avai l abl e methods for proteomi c
anal ysi s i ncl ude protei n extraction, separation by two-di mensional gel electrophoresis or
chromatography, fol l owed by identi fi cati on usi ng mass spectrometry. Al though rapi dl y i mprovi ng,
P.137
these methods are currentl y l i mi ted by sensiti vi ty, speci fi city, and throughput.
36
The devel opment
of protei n arrays has the potenti al to become a versati l e and ri gorous hi gh-throughput method for
proteomi c anal ysi s and i s the object of i ntense i nvestigati on.
Integrated genomi c and proteomic data anal ysi s may be appl i ed i n peri operati ve medi ci ne to
el uci date i ndi vi dual responses to surgical injury and provi de useful prognosti c information.
Recentl y, such a combi ned genomic and proteomi c approach was used to determi ne the outcome i n
patients undergoi ng thoracoabdomi nal aorti c aneurysm repair. Expression patterns of 138 genes
from peri pheral bl ood l eukocytes and the concentrati ons of 7 circul ati ng pl asma protei ns
di scri mi nated between the pati ents who devel oped mul ti pl e organ dysfuncti on syndrome (MODS)
and those who di d not. More i mportantl y, these patterns of genome-wide gene expressi on and
pl asma protei n concentrati on were observed before surgical trauma and vi sceral i schemia-
reperfusion injury, suggesti ng that pati ents who devel oped MODS differed i n either thei r geneti c
predi sposi tion or thei r preexi sti ng i nfl ammatory state.
48

GENOMICS AND PERIOPERATIVE RISK PROFILING
Recogni zi ng the si gni fi cant increase i n surgi cal burden because of accel erated agi ng of the
popul ati on and i ncreased rel i ance on surgery for treatment of disease, the National Heart, Blood
and Lung Insti tute has recentl y convened a Worki ng Group on peri operati ve medi cine. The group
concl uded that peri operati ve compl icati ons are significant, costly, vari ably reported, and often
imprecisel y detected, and i denti fi ed a criti cal need for accurate comprehensi ve perioperative
outcome databases. Furthermore, presurgi cal ri sk profi li ng i s i nconsi stent and deserves further
attenti on, especi all y for noncardi ac, nonvascular surgery and ol der patients.
49

One of the hal lmarks of perioperative medi ci ne is the stri king variabi li ty i n patient responses
to surgical procedures, anestheti c agents, hemodynami c chall enge, and the pharmacopoei a
used in the perioperative peri od. Although many preoperati ve predi ctors have been i denti fi ed and
are constantl y bei ng refi ned, risk strati fi cati on based on cl i ni cal , procedural , and bi ol ogi cal
markers expl ai ns onl y a smal l part of the vari abil i ty i n the incidence of peri operative
compl i cati ons. It is becomi ng i ncreasingl y recogni zed that specifi c genotypes may al so predi ct
adverse peri operati ve outcomes i n otherwi se healthy i ndi vi duals. Such adverse outcomes wil l
develop onl y i n pati ents whose combi ned burden of geneti c and envi ronmental ri sk factors exceeds
a certain threshol d, whi ch may vary wi th age. Identi fi cati on of such geneti c contributi ons not onl y
to di sease causati on and suscepti bi l ity, but al so to infl uenci ng the response to di sease and drug
therapy, and i ncorporati on of geneti c ri sk i nformati on i n cl i ni cal decisi on maki ng may lead to
improved heal th outcomes and reduced costs. For instance, understandi ng the geneenvi ronment
interactions i nvol ved i n atheroscleroti c cardi ovascul ar disease and neurological injury may
faci li tate preoperative pati ent opti mi zation and resource util i zati on. Furthermore, understandi ng
the rol e of genotypic vari ati on i n thrombosi s and i nflammati on, the mai n pathophysi ological
mechani sms responsibl e for peri operati ve compli cati ons, may contri bute to the development of
target-specific therapi es, thereby l imiti ng the inci dence of adverse events in high-ri sk pati ents.
Genet i c Suscept i bi l i t y t o Adver se P er i oper at i ve Car di ovascul ar
Out comes
As part of the preoperati ve evaluation, anesthesi ol ogi sts are involved i n assessi ng the risks of
peri operative compli cati ons. It i s commonl y accepted that pati ents who have underl yi ng
cardi ovascul ar di sease are at ri sk for adverse cardi ac events after surgery, and several
mul tifactorial ri sk indi ces have been devel oped and val i dated for pati ents undergoi ng both
noncardiac surgical procedures (such as the Gol dman
50
or the Lee Cardiac Ri sk Index
51
), as wel l as
cardi ac surgery (such as the Hannan
52
or Sergeant
53
scores). However, identi fyi ng pati ents at the
hi ghest ri sk of peri operati ve i nfarcti on remains diffi cult, and ri sk scores, whi l e potenti al l y val uabl e
for popul ati on studi es, are not an ideal tool for directi ng care i n an i ndi vi dual pati ent.
54
Genomi c
approaches have been used i n the search for a better assessment of the indi vi dual coronary risk
profi le. Numerous reports from animal model s; l i nkage anal ysi s; famil y, twin, and popul ati on
association studi es have defi nitely proven the rol e of genetic i nfluences in the i nci dence and
progressi on of coronary artery di sease (CAD). Recent twi n studi es report a heri tabi l i ty of death
from CAD as hi gh as 0.58. Geneti c factors associ ated wi th CAD mortali ty are i n operation
throughout the entire l ifespan, al though they seem to be particul arl y i mportant i n early phases of
l i fe, as mani fested by a decrease i n heritabil i ty wi th age. Moreover, comprehensi ve l inkage
anal ysi s
7
and associ ati on studi es
20, 21
have reemphasized the rol e of geneti c vari abi l ity i n
myocardial i nfarction. Whi le these studi es do not di rectly address the heritabi l i ty of adverse
peri operative myocardi al events, they do suggest a strong geneti c contri buti on

to the risk of adverse cardiovascular outcomes i n general. Indeed, given si mi l ar known risk
factors, many pati ents sti l l mani fest di fferences i n the i nci dence of both earl y and l ate adverse
myocardial events. Li ke most common di seases, peri operative cardiovascular compl i cations i nvol ve
an i nterpl ay of many genetic vari ations of mol ecul ar and biochemi cal pathways and thei r
interactions with envi ronmental factors (e.g., surgi cal procedural, pharmacol ogical), and can
therefore be cl assi fied as compl ex disease phenotypes. On a geneti c l evel, functi onal al lel i c
vari ati ons li kel y modul ate, each wi th a smal l overal l contri bution and rel ati ve ri sk, indi vi dual
suscepti bi l ity to devel op such adverse myocardi al events, and the mani festation, severi ty, and
prognosi s of the di sease process. Unfortunatel y, al though the effects of geneti c predi sposi ti on for
CAD or restenosi s after angiopl asty have been extensi vely i nvestigated, only a paucity of studi es
exist regardi ng geneti c risk factors directl y associated wi th peri operati ve myocardi al outcomes,
mainly foll owi ng surgi cal revascul ari zati on.
26, 55, 56
However, an i ncreasing body of evi dence has
li nked vari ous genotypes to mechani sti c pathways known to be involved i n tri ggeri ng or
modul ati ng the severi ty of peri operati ve myocardi al injury, incl uding thrombosis, i nfl ammatory
response, or vascular reacti vi ty.
The acute phase response or stress response to surgery i s characteri zed by an i ncrease i n
fibri nogen concentrati on, pl atel et adhesi veness, and pl asmi nogen activator i nhibi tor-1 (PAI-1)
producti on. Duri ng cardiac surgery, al terati ons in the hemostati c system are even more compl ex
and multi factori al , i ncl udi ng the effects of hypothermia, hemodi l uti on, and cardiopul monary
bypass (CPB)-induced activati on of coagul ati on, fi bri nol yti c, and i nfl ammatory pathways.
Peri operative thrombotic outcomes fol l owi ng cardiac surgery (e.g., coronary graft thrombosi s,
myocardial i nfarction, stroke, pul monary embol ism) represent one extreme on a conti nuum of
coagulation dysfuncti on, wi th coagulopathy at the other end of the spectrum. Pathophysi ologi cal ly,
the bal ance between bl eedi ng, normal hemostasi s, and thrombosis i s markedly influenced by the
rate of thrombi n formation and platelet activation. Recent evidence suggests genetic variabi li ty
modul ates the activati on of each of these mechani sti c pathways,
57
suggesti ng si gni fi cant
heri tabi l ity of the prothrombotic state. Several genotypes have been associ ated wi th i ncreased
ri sk of coronary graft thrombosi s and myocardi al injury fol l owing CABG. Plasmi nogen activator
i nhi bi tor-1 gene i s an i mportant negati ve regul ator of fi bri nol yti c activity; a geneti c vari ant in the
promoter of the PAI-1 gene, consisting of an insertion (5G)/del eti on (4G) pol ymorphi sm at
positi on -675, has been consi stentl y associated wi th changes i n the pl asma level s of PAI-1. The 4G
al lel e was associ ated with increased risk of early graft thrombosi s after CABG,
58
and a recent
meta-anal ysi s showed a si gnifi cant effect of PAI-1 genotype on i ncidence of myocardial
infarcti on.
59
Si mi larl y, a pol ymorphi sm i n the platelet glycoprotein IIIa, resul ting i n increased
pl atel et aggregati on (Pl
A2
pol ymorphi sm), was found to be a risk factor for thrombotic coronary
graft occlusi on, myocardial i nfarction, and death foll owi ng CABG.
60
Furthermore, the Pl
A2
al l ele has
been associ ated wi th higher postoperative concentrati ons of troponi n I fol l owing CABG, suggesti ng
that thi s platelet polymorphism contri butes to perioperative myocardi al i njury.
61
One of the most
common inherited prothromboti c ri sk factors i s a poi nt mutati on i n coagulation factor V
(1691G>A) resul ting i n resi stance to activated protein C, and referred to as factor V Leiden (FVL).
FVL has been associ ated with vari ous postoperative thrombotic compli cati ons foll owing noncardi ac
surgery (for a revi ew, see Donahue
27
), but interesti ngl y, al so associated wi th a significant
reduction in postoperati ve bl ood l oss and overal l ri sk of transfusi on i n cardi ac surgery pati ents.
62

Geneti c vari ants modul ati ng the magni tude of postoperati ve infl ammatory response have been
identi fi ed. Polymorphi sms i n the promoter of the interl euki n 6 (IL6) gene (-572G>C and -174G>C)
si gni fi cantl y increase the i nflammatory response after heart surgery wi th cardiopul monary bypass
(CPB)
63
and have been associ ated wi th l ength of hospi tal i zati on after CABG.
64
Furthermore, both
apoli poprotei n E genotype (the 4 al l ele)
65
and several vari ants in the tumor necrosis factor genes
P.138
(TNFA-308G>A, LTA+250G>A) have been associated wi th proi nfl ammatory effects i n pati ents
undergoing CPB.
66
Conversel y, a geneti c vari ant modul ati ng the rel ease of the anti -infl ammatory
cytoki ne i nterl eukin 10 (IL10) i n response to CPB has been reported (IL10-1082G>A), wi th hi gh
level s of IL10 bei ng associ ated wi th postoperati ve cardi ovascul ar dysfunction.
67

Several genes predi cti ve of peri operati ve vascular response have been identi fi ed.
Significantly i ncreased vascul ar responsi veness to al pha-adrenergi c sti mul ation
(phenyl ephrine) was found both i n pati ents carryi ng the endothel ial ni tri c oxide synthase 894G>T
pol ymorphi sm
68
and i n pati ents homozygous for D al l ele of the angiotensin converti ng enzyme
inserti on/deletion (I/D) pol ymorphi sm.
28, 69
Al so, variabi li ty i n the
2
-adrenergi c receptor gene has
been associ ated wi th i ncreased mean arterial bl ood pressure to the stress sti muli of tracheal
intubati on.
70

Genet i c Var i abi l i t y and P er i oper at i ve Event - Fr ee Sur vi val
Several large randomi zed cl ini cal tri al s exami ni ng the benefi ts of CABG surgery and percutaneous
coronary i nterventi ons rel ati ve to medi cal therapy and/or to one another have refi ned our
knowl edge of earl y and l ong-term survi val after CABG. Whi le these studi es have hel ped defi ne the
subgroups of pati ents who benefi t from surgi cal revasculari zation, they also demonstrated a
substantial vari abi l i ty in l ong-term survi val after CABG, al tered by important demographi c and
envi ronmental ri sk factors. Increasing evi dence suggests that the angiotensin converti ng enzyme
(ACE) gene i ndel polymorphism may i nfluence post-CABG compl icati ons. In a recent study,
carri ers of the D al l ele had hi gher mortali ty and restenosi s rates after CABG surgery compared
with the I al l ele.
56
Si mi larl y, a functi onal l y i mportant ami no aci d al terati on i n the
3
-integrin chain
of the glycoprotein IIb/IIIa pl atel et receptor (the Pl
A2
pol ymorphi sm) was associ ated wi th an
increased risk (odds rati o of 4.7) for major adverse cardi ac events (a composite of myocardial
infarcti on, coronary bypass graft occlusi on, or death) fol lowi ng CABG surgery. Mechani sti cal l y, thi s
may be rel ated to a geneti cal l y modul ated prothrombotic tendency, as Pl
A2
resul ts in i ncreased
fibri nogen-bi nding and epi nephri ne-i nduced pl atel et aggregati on,
71
and has been previ ousl y
identi fi ed as a ri sk factor for acute coronary thrombosis.
72
We have found prelimi nary evi dence for
association between two functi onal polymorphisms modul ati ng
2
-adrenergi c receptor acti vi ty
(Arg16Gl y and Gl n27Gl u) and i nci dence of death or major adverse cardi ac events foll owing cardi ac
surgery.
73

Genet i c Suscept i bi l i t y t o Adver se P er i oper at i ve Neur ol ogi c
Out comes
Despi te advances i n surgi cal and anestheti c techni ques, significant neurologi c morbi dity
conti nues to occur foll owi ng cardiac surgery, rangi ng i n severi ty from coma and focal stroke
(i nci dence up to 6%) to more subtl e cogni ti ve defi cits (inci dence up to 69%), wi th a substanti al
impact on the risk of peri operati ve death, qual i ty of li fe, and resource uti li zati on. Variabi li ty i n the
reported i nci dence of both earl y and l ate

neurol ogical defici ts remains poorl y expl ai ned by procedural risk factors, suggesti ng that
environmental (operative) and geneti c factors may i nteract to determi ne disease onset,
progressi on, and recovery.
74
Thus, cardi ac surgery represents a unique cli ni cal paradi gm where, i n
addi ti on to geneti c predi sposi ti ons, certain procedural events (such as aorti c mani pul ati on) may
lead to the embol i zati on of materi al to the brai n. The pathophysi ology of peri operati ve
neurol ogical injury is thought to i nvol ve compl ex i nteracti ons between primary pathways
associated wi th atheroscl erosi s and thrombosi s, and secondary response pathways li ke
infl ammati on, vascul ar reacti vi ty, and direct cel lular i njury. Many functional genetic variants have
been reported i n each of these mechanistic pathways involved i n modulating the magnitude and
the response to neurol ogi cal i njury, whi ch may have impli cati ons in chronic as wel l as acute
peri operative neurocogni tive outcomes. Our group has demonstrated a significant associ ati on
between the apol ipoprotein E (APOE) E4 genotype and adverse cerebral outcomes i n cardi ac
surgery pati ents.
22, 74
Thi s is consistent wi th other studi es, suggesti ng a role for the APOE
genotype i n recovery from acute brai n injury, such as intracrani al hemorrhage,
75
cl osed head
P.139
injury,
76
and stroke,
77
as wel l as experi mental model s of cerebral ischemia-reperfusion injury.
78

Unl i ke adul t cardiac surgery patients, i nfants carryi ng the APOE 2 al l ele have recentl y been found
at i ncreased ri sk for developi ng adverse neurodevelopmental sequelae fol lowi ng cardi ac surgery.
79

Mechani sti cal l y, the role of APOE genotypes i n modul ati ng the infl ammatory response,
65
extent of
aorti c atheroma burden,
80
ri sk for coronary atheroscl erosis,
81
and cerebral bl ood fl ow and
autoregulation may expl ai n the observed associati ons wi th i mpaired neurol ogi cal outcomes.
Recent studi es have suggested a rol e for platel et activati on i n the pathophysi ology of adverse
neurol ogical sequel ae. Genetic variants i n surface platelet membrane gl ycoprotei ns, i mportant
mediators of platelet adhesion and plateletpl atel et interacti ons, have been shown to increase the
suscepti bi l ity to prothromboti c events. Among these, the Pl
A2
pol ymorphi sm i n glycoprotein
IIb/IIIa has been rel ated to vari ous adverse thrombotic outcomes, including acute coronary
thrombosi s
72
and atherothromboti c stroke.
82
We found the Pl
A2
al l el e to be associ ated with more
severe neurocogni tive decl i ne after cardiopul monary bypass,
23
whi ch coul d represent an
exacerbation of platel et-dependent thrombotic processes associ ated wi th pl aque emboli sm.
Identi fyi ng novel predi ctors for ri sk of neurol ogical and neurocogni tive dysfuncti on and the
mol ecul ar mechanisms underlying such ri sk wi ll al low i mproved pati ent i nformed consent,
stratificati on and resource al l ocati on, devel opment of neuroprotecti ve agents, and therapeuti c
modal iti es tai lored to the yet-to-be-di scovered mol ecular abnormal iti es.
Genet i c Suscept i bi l i t y t o Adver se P er i oper at i ve Renal
Out comes
Acute renal dysfuncti on i s a common, seri ous compl i cation of cardiac surgery; about 8 to
15% of pati ents devel op moderate renal i njury (>1.0 mg/dL peak creatini ne rise), and up to
5% of them devel op renal fai l ure requi ri ng di al ysi s.
83, 84
Acute renal fai lure is i ndependentl y
associated wi th i n-hospi tal mortali ty rates,
85
exceedi ng 60% in pati ents requi ri ng di al ysi s.
84

Recent studi es have demonstrated that i nheri tance of geneti c polymorphisms i n the apol ipoprotein
E gene (4 al l ele)
25
in the promoter regi on of the IL6 gene (-174C al l ele
86
and -572C al l ele
143
) and
angiotensi nogen gene (842C al l el e)
143
are associ ated with acute renal i njury fol lowi ng CABG
surgery. Further identi fi cati on of genotypes predi cti ve of adverse peri operative renal outcomes
may facil i tate indi viduall y tai lored therapy, ri sk strati fy the patients for i nterventi onal tri al s
targeti ng the gene product i tsel f, and aid i n medi cal decisi on maki ng (e.g., sel ecti ng medi cal over
surgical management).
Genet i c Var i ant s and Ri sk f or P r ol onged P ost oper at i ve
Mechani cal Vent i l at i on
Prolonged mechani cal venti lation (i nabi li ty to extubate patient by 24 hours postoperati vel y)
is a significant compli cati on foll owing cardi ac surgery, occurri ng in 5.6% and 10.5% of
pati ents undergoi ng fi rst and repeat CABG surgery, respecti vel y.
87
Several pul monary and
nonpul monary causes have been i denti fi ed, and scori ng systems based on preoperati ve and
procedural ri sk factors have been proposed and val i dated. Recentl y, geneti c vari ants i n the renin
angi otensi n pathway and i n proi nfl ammatory cytokine genes have been associ ated with respiratory
compl i cati ons postcardi opul monary bypass. The D allele of a common functional
inserti on/deletion (I/D) pol ymorphi sm i n the ACE gene, accounti ng for 47% of vari ance in
ci rculati ng ACE levels,
88
has been associ ated wi th prol onged mechanical venti lati on fol l owi ng
CABG
89
and wi th suscepti bi li ty to and prognosis of ARDS.
90
Furthermore, a hyposecretor haplotype
in the nei ghboring genes tumor necrosis factor alpha (TNFA) and lymphotoxin alpha (LTA) on
chromosome 6 (TNFA-308G/LTA+250G haplotype)
91
and a functi onal pol ymorphism modulating
postoperative interl euki n 6 level s (IL6-174G>C)
86
have been independentl y associ ated with hi gher
ri sk of prol onged mechani cal ventil ati on post-CABG. The associ ati on was more dramati c i n patients
undergoi ng conventional CABG than i n those undergoing off-pump CABG (OPCAB), suggesti ng that
in hi gh-ri sk pati ents identi fi ed by preoperati ve geneti c screeni ng OPCAB may be the opti mal
surgi cal procedure.
A next crucial step i n understandi ng the complexi ty of adverse peri operati ve outcomes i s to assess
the contributi on of variations i n many genes si mul taneousl y and thei r i nteracti on wi th tradi ti onal
ri sk factors to the longi tudi nal predi cti on of outcomes i n i ndi vi dual patients. The use of such
outcome predi cti ve model s i ncorporati ng geneti c i nformati on may hel p strati fy mortali ty and
morbi dity in surgical patients. It may al so i mprove prognosti cation, direct medi cal deci si on maki ng
both i ntraoperati vel y and duri ng postoperati ve fol l ow-up, and even suggest novel targets for
therapeutic interventi on i n the peri operati ve period.
PHARMACOGENOMICS AND ANESTHESIA
Variabi li ty i n response to drug therapy, both in terms of efficacy and safety, i s a rul e by
whi ch anesthesiologi sts l ive. In fact, much of the art of anesthesi ol ogy i s the astute cl inici an
bei ng prepared to deal wi th outli ers. The term pharmacogenomics is used to describe how
inheri ted vari ati ons i n genes modul ating drug acti ons are related to interi ndi vi dual vari abi l ity in
drug response. Such vari abi l ity in drug acti on may be pharmacoki netic or pharmacodynami c (Fi g.
7-4). Pharmacoki netic variabi li ty refers to vari abi l ity in a drug' s absorption, distri buti on,
metabol i sm, and excreti on that medi ates i ts effi cacy and/or toxi city. The mol ecules i nvol ved i n
these processes i ncl ude drug-metaboli zi ng enzymes (such as members of the cytochrome P450, or
CYP, superfami l y) and drug transport molecul es that mediate drug uptake into, and efflux from,
intracel lular sites. Pharmacodynami c vari abil i ty refers to vari abl e drug effects despi te equi valent
drug deli very to molecul ar si tes of acti on. This may reflect vari abi l i ty in the function of the
mol ecul ar target of the drug, or in the pathophysi ologi cal context i n whi ch the

drug interacts wi th i ts receptor target (e.g., affi ni ty, coupli ng, expression).
92
Thus,
pharmacogenomics i nvestigates compl ex, polygeni cal ly determi ned phenotypes of drug effi cacy or
toxi ci ty, with the goal of i dentifyi ng novel therapeuti c targets and customizing drug therapy.
P seudochol i nest er ase Def i ci ency
P.140
FIGURE 7-4. Pharmacogenomi c determi nants of i ndi vi dual drug response operate by
pharmacokineti c and pharmacodynami c mechani sms. A. Geneti c vari ants in drug transporters
(e.g., ATP-bi ndi ng cassette subfami l y B member 1 or ABCB1 gene) and drug-metaboli zi ng
enzymes (e.g., cytochrome P450 2D6 or CYP2D6 gene, CYP2C9 gene, N-acetyltransferase or
NAT2 gene, plasma chol i nesterase or BCHE gene) are responsi bl e for pharmacoki netic
vari abi l ity i n drug response. B. Pol ymorphi sms i n drug targets (e.g.,
1
and
2
-adrenergi c
receptor ADRB1, ADRB2 genes; angiotensin-I converti ng enzyme ACE gene), postreceptor
si gnali ng molecul es (e.g., guani ne nucl eoti debi ndi ng protei n 3 or GNB3 gene), or
molecul es indi rectl y affecting drug response (e.g., vari ous i on channel genes i nvol ved i n
drug-induced arrhythmias) are sources of pharmacodynami c vari abi l i ty.
Histori call y, characteri zation of the genetic basis for pl asma pseudochol inesterase defi ci ency in
1956 was of fundamental i mportance to anesthesi a and the further devel opment and
understandi ng of geneti cal l y determi ned di fferences in drug response.
93
Indi vi duals wi th an
atypi cal form of pseudochol i nesterase resulti ng i n a markedl y reduced rate of drug metabol i sm are
at risk for excessi ve neuromuscular blockade and prol onged apnea. More than 20 variants have
si nce been identi fi ed in the butyrylchol inesterase gene (BCHE), the most common of whi ch are the
A-vari ant (209A>G) and the K-vari ant (1615G>A), wi th various and somewhat poorl y defi ned
phenotypic consequences on prol onged neuromuscul ar bl ockade. Therefore, pharmacogeneti c
testi ng is currentl y not recommended i n the popul ati on at l arge, but onl y as an expl anati on for an
adverse event.
94

Genet i cs of Mal i gnant Hyper t her mi a
Mal ignant hyperthermi a (MH) i s a rare autosomal dominant genetic di sease of skel etal muscle
calci um metabol ism, tri ggered by admini stration of general anesthesi a wi th vol ati le
anesthetic agents or succi nylchol ine i n suscepti bl e i ndi vi duals. The cli ni cal MH syndrome is
characteri zed by skeletal muscle hypermetaboli sm and mani fested as skeletal muscl e ri gi dity,
tachycardi a, tachypnea, hemodynamic i nstabi l ity, increased oxygen consumpti on and CO
2

producti on, l acti c aci dosis, and fever, progressing to mal i gnant ventri cular arrhythmi as,
di ssemi nated i ntravascul ar coagul ati on, and myoglobinuri c renal fai lure. MH suscepti bi l i ty has
been ini ti all y l i nked to the ryonadine receptor (RYRI) gene locus on chromosome 19q.
95
However,
subsequent studi es have shown that MH may represent a common severe phenotype that
origi nates not onl y from poi nt mutati ons in the RYRI gene (Arg614Cys), but al so withi n i ts
functi onal l y and/or structural l y associ ated proteins regulati ng excitati oncontracti on coupl ing
(such as 1DHPR and FKBP12). It i s becomi ng increasi ngl y apparent that MH susceptibi l ity resul ts
from a compl ex i nteracti on between mul ti pl e genes and environment (such as envi ronmental
toxi ns), suggested by the heterogeneity observed in the cl inical MH syndrome and the vari abl e
penetrance of the MH phenotype.
96
Current di agnosti c methods (the caffeine-halothane
contracture test) are i nvasi ve and potenti al l y nonspecific. Unfortunatel y, because of the polygeni c
determi ni sm and vari abl e penetrance, direct DNA testi ng in the general popul ati on for
suscepti bi l ity to MH i s currentl y not recommended; in contrast, testi ng i n indi vi duals from famil i es
with affected i ndi vi dual s has the potenti al to greatl y reduce mortal i ty and morbidi ty.
94

Furthermore, genomi c approaches may help eluci date the molecul ar mechani sms involved in
al tered RYRI-mediated cal ci um si gnali ng and i dentify novel , more speci fi c therapeutic targets.
Genet i c Var i abi l i t y and Response t o Anest het i c Agent s
Anestheti c potency, defi ned by the minimum alveolar concentrati on (MAC) of an i nhal ed
anesthetic that abol ishes purposeful movement in response to a noxious stimul us, varies
among i ndi vi dual s, wi th a coeffi ci ent of vari ati on (the ratio of standard devi ati on to the mean) of
approxi mately 10%.
97
Thi s observed vari abil i ty may be expl ai ned by i nteri ndi vi dual di fferences i n
mul tipl e genes that underl i e responsiveness to anestheti cs, by environmental or physi ologi cal
factors (brain temperature, age), or by measurement errors. Evidence of a geneti c basi s for
increased anestheti c requirements i s begi nni ng to emerge, suggested, for instance, by the
observation that desfl urane requirements are i ncreased i n subjects wi th red hai r versus

dark hai r.
98
Recent studi es eval uating the geneti c control of anestheti c responses, coupl ed wi th
mol ecul ar model ing, neurophysiology, and pharmacol ogi c approaches, have provided i mportant
devel opments i n our understandi ng of general anestheti c mechani sms. Tri ggered by the semi nal
work of Franks and Lieb,
99, 100
research shi fted from the membrane l i pi d bi l ayer to protei n
receptors (speci fi cal ly li gand- and voltage-gated i on channel s) as potenti al anestheti c targets,
ending a few decades of stagnati on that were pri maril y a resul t of an al most universal acceptance
of the dogma of nonspecifi c anestheti c acti on (the so-call ed li pi d theory). Some of the genes
responsi bl e for phenotypic di fferences i n anestheti c effects have been mapped i n vari ous ani mal
model s, i ncl udi ng the fruit fly Drosophil a mel anogaster,
101
the nematode Caenorhabdi ti s
el egans,
102
and the mouse. Later, we summari ze the three broad categori es of geneti c approaches
that have been used i n mammal i an models to provi de mechani sti c insight into the mol ecul ar basi s
P.141
of anesthetic acti on i n humans, wi th an emphasis on geneti cal l y al tered ani mal model s. Fi rst,
cl assi cal genetics studies identi fy mutations i n si ngl e genes that resul t i n i ndividual s qual itati vel y
di fferent from the nonmutant (i .e., wi l d type) i ndi vi dual s. Numerous i nbred mouse strains and
several spontaneousl y arisi ng mutants have been demonstrated to differ in response to
anesthetics.
103
The second approach, quantitati ve geneti cs, studi es the i nheri tance of continuousl y
varyi ng, quanti tati ve trai ts (such as hei ght, wei ght, IQ, bl ood pressure, response to drugs,
noci cepti ve sensi ti vi ty). These traits are controll ed by mul tipl e genes (cal l ed quantitati ve trai t
loci , QTL), each contri buti ng quanti tati vel y to the net trai t and also affected by the environment
to varyi ng degrees. Specifi c chromosomal regi ons that control sensi ti vi ty to propofol
104
and
al cohol
105
have been identi fi ed usi ng the QTL mapping techni que. Because of the many potenti al
anesthetic targets, quantitati ve geneti cs, wi th i ts abil i ty to examine multi ple genes
si multaneously, hol ds great promi se for i dentifyi ng the geneti c control mechanisms of anesthetic
response. The classi c and quanti tati ve geneti c approaches are exampl es of forward genetics in
whi ch the l ine of i nvestigation progresses from an al tered phenotype to the geneti c basi s for that
observed difference (i .e., from phenotype to genotype). In contrast, reverse geneti cs expl ores the
functi onal consequences of di rectly mutating or altering the expression of a known gene (i.e.,
from genotype to phenotype). Specificall y, genomi c mani pul ati on of pl ausi bl e candi date receptors
i s used to i nvesti gate thei r functi on i n vi tro and, through the use of geneti call y engi neered (e.g.,
transgenic, knockout, and knocki n) ani mal s (Fi g. 7-5), to evaluate i n vi vo their rel ati onshi p to
vari ous anesthetic end points, such as i mmobi l ity (i .e., MAC), hypnosi s, amnesi a, and analgesia
(for revi ews, see Homani cs et al
106
and Sonner et al
107
).

Transgeni c ani mals overexpress or mi sexpress an additi onal gene that has been del i beratel y
inserted i nto thei r genome. The forei gn gene (i .e., transgene) i s constructed usi ng recombinant
DNA methodol ogy and used ei ther to transfect embryoni c stem cel ls growing i n cul ture or
mi croi njected i nto the pronucl eus of a ferti li zed egg. However, the random insertion of the
transgene i n the genome that affects its expression pattern and the need for the transgene to
have a dominant effect over the endogenous gene are major di sadvantages of thi s techni que. The
process of gene targeting has enabl ed sci entists to repl ace vi rtual ly any specific gene wi th an
i nacti ve al l el e (i .e., gene knockouts) and ci rcumvent some of the li mitati ons of transgeni c
technol ogy. Knockout ani mals are created by inserting a vector containing the di srupted gene i nto
mouse embryoni c stem cel l s, wi th the goal of i nacti vating both all eles so that the gene i s
nonfuncti onal in all cel ls for the ani mal' s l i feti me (gl obal knockout). Several thousand different
FIGURE 7-5. Geneti cal l y engineered ani mals used i n functi onal genomic studi es. Transgeni c
animal sgene X i s i ntroduced at random somewhere in the genome; knockout ani malsgene
B i s i nacti vated by a di rect mutation; knocki n ani malsgene B* is i ntroduced at a speci fi c
l ocus to repl ace gene B.
strai ns of knockout mice have been created and are used to i nvesti gate speci fi c functi ons of
parti cul ar genes and mechani sms of drug acti on, i ncl udi ng the sensi tivity to general anestheti c i n
mi ce l acking the
3
subunit
108
or the
6
subunit
109
of the GABA
A
receptor. These studies have
identi fi ed two potential downfal l s of the gl obal knockout approach: the genome has enough
redundancy to compensate for the mi ssi ng pai r of al l el es by al tering the expressi on of other genes
(devel opmental compensati on) and second, because the knockout affects al l neurons, i t is
i mpossi bl e to attri bute a phenotype (such as MAC) to a speci fi c neural regi on or ci rcui t. To
el i mi nate some of these confounding probl ems, condi ti onal knockouts seek to del ete a gene in a
parti cul ar cel l type or ti ssue at speci fi c stages of development.
Knocki n ani mals express a si te-di rected mutation i n the targeted gene that remai ns under the
control of endogenous regulatory el ements, all owi ng the mutated gene to be expressed i n the
same amount, at the same ti me, and i n the same ti ssues as the normal gene. This method has
provi ded remarkable i nsi ght i nto the mechani sms of acti on of benzodi azepi nes
110
and i ntravenous
anesthetics. In a semi nal study by Jurd et al, a poi nt mutati on i n the gene encoding the
3
subunit
of the GABA
A
receptor previ ousl y known to render the receptor i nsensi tive to etomidate and
propofol i n vitro
111
was val i dated i n vi vo by creati ng a knockin mouse strain that proved also
essential ly i nsensiti ve to the i mmobi li zi ng actions of etomi date and propofol .
112
A point mutati on
in the
2
subunit of the GABA
A
receptor resul ts i n a knocki n mouse wi th reduced sensiti vi ty to the
sedati ve
113
and hypothermi c effects
114
of etomi date. Knocki n mice harbori ng poi nt mutations i n
the
2A
-adrenergi c receptor have enabl ed the el uci dati on of the rol e of thi s receptor in anestheti c-
spari ng, anal gesic, and sedati ve responses to dexmedetomidi ne.
115

The situation is far more compl ex for i nhal ed anestheti cs, whi ch appear to medi ate thei r effects by
acti ng on several receptor targets. Based on combi ned pharmacologic and geneti c i n vivo studi es
to date, several receptors are unl ikel y to be di rect medi ators of MAC, i ncludi ng the GABA
A
(despi te
thei r compel l i ng rol e i n intravenous anestheti c-induced i mmobi li ty), 5-HT
3
, AMPA, kai nate,
acetylchol ine and
2
-adrenergi c receptors, and potassi um channel s.
116
Gl yci ne, NMDA receptors,
and sodi um channel s remai n li kel y candi dates.
107
These concl usi ons, however, do not appl y to
other anestheti c end points, such as hypnosi s, amnesia, and analgesi a. Such genomi c approaches
have the potenti al to evolve i nto preoperati ve screeni ng profi les useful i n gui di ng therapeuti c
deci si ons, such as prevention of anestheti c awareness in

pati ents wi th a geneti c predi sposi ti on to increased anesthetic requi rements.
Genet i c Var i abi l i t y and Response t o P ai n
Simil ar to the observed variabi li ty i n anesthetic potency, the response to painful stimul i and
anal gesi c mani pulations varies among indi vi duals. The sources of vari abi l ity in the report and
experi ence of pain and anal gesia are mul tifactorial , i ncludi ng factors extri nsic to the organi sm
(such as cul tural factors, or circadi an rhythms) and intri nsi c factors (such as age, gender,
hormonal status, or geneti c makeup). Increasi ng evidence suggests that pai n behavi or i n response
to noxi ous sti muli and its modul ati on by the central nervous system in response to drug
administrati on or envi ronmental sti mul i may be strongly i nfl uenced by geneti c factors.
117

Resul ts from studi es i n twi ns
118
and i nbred mouse strai ns
119
i ndi cate a moderate heritabil i ty for
chroni c pai n and nociceptive sensi tivity, whi ch appears to be medi ated by mul ti pl e genes.
Furthermore, QTL for hot-pl ate sensi tivity and formal i n test have been mapped to mouse
chromosomes 4 (near the -opi oi d receptor gene), 2, and 10, respectively.
120
Vari ous strai ns of
knockout mi ce lacki ng target genes l ike neurotrophins and their receptors (e.g., nerve growth
factor), peri pheral mediators of noci cepti on and hyperalgesia (e.g., substance P), opi oi d and
nonopioid transmi tters and their receptors, and i ntracell ul ar si gnal ing mol ecules have si gnifi cantl y
contri buted to the understandi ng of pai n-processi ng mechani sms.
121

In addi ti on to the geneti c control of peripheral noci cepti ve pathways, considerabl e evi dence
exists for geneti c vari abi l ity in the descendi ng central pai n modul atory pathways, potential ly
explai ni ng the interi ndi vi dual vari abi l ity in analgesi c responsi veness. One good exampl e rel evant
to analgesi c effi cacy i s cytochrome P450D6 (CYP2D6), a member of the superfami ly of mi crosomal
P.142
enzymes that catal yze phase I drug metabol i sm and i s responsibl e for the metabol i sm of a large
number of therapeutic compounds. The rel ati onshi p between the CYP2D6 genotype and the enzyme
metaboli c rate has been extensivel y characteri zed, with at l east 12 known mutati ons leadi ng to a
tetramodal di stri bution of CYP2D6 activity: ultrarapi d metabol i zers (5 to 7% of the popul ati on),
extensi ve metaboli zers (60%), i ntermedi ate metabol i zers (25%), and poor metabol izers (10%).
Currentl y, pharmacogenomic screeni ng tests predi ct CYP2D6 phenotype wi th >95% rel i abi l ity. The
consequences of i nheri ti ng an al l ele that compromi ses CYP2D6 functi on i nclude the i nabi li ty to
metabol i ze codei ne (a prodrug) to morphi ne by O-demethyl ati on, l eadi ng to l ack of anal gesi a but
increased side effects from the parent drug (e.g., fati gue) i n poor metabol i zers.
94, 117

Ani mal studi es have mapped other pol ymorphi c genes i nvol ved i n vari ous analgesic modal iti es. A
QTL responsi ble for 28% of phenotypi c variance in magnitude of systemi c morphine analgesi a i n
mi ce has been mapped to chromosome 10, i n or near the OPRM (-opi oi d receptor) gene, and
several putati ve QTL medi ati ng nitrous oxi de analgesi as have been identi fi ed. The -opi oi d
receptor i s also subject to pharmacodynamic vari abi l i ty; pol ymorphi sms in the promoter regi on of
the OPRM gene modul ati ng i nterl euki n4-medi ated gene expressi on have been correl ated wi th
morphi ne anti nociception. Furthermore, an OPRM188A>G pol ymorphi sm associ ated with decreased
responses to morphi ne-6-gl ucuroni de was i dentifi ed i n humans, wi th i mpl i cations in reduced ri sks
of toxi ci ty i n renal fai lure patients.
94
A sex-specific l ocus on chromosome 8 has been associ ated
with nonopioi d stress-induced analgesia i n femal es onl y and may be rel ated to -opi oi d anal gesi a,
provi ding a possibl e mechanism for sex-geneti c interacti ons i n regulating analgesi c response.
117

Genet i c Var i abi l i t y i n Response t o Ot her Dr ugs Used
P er i oper at i vel y
A wi de vari ety of drugs used i n the peri operati ve peri od di spl ay si gni fi cant pharmacoki netic or
pharmacodynami c vari abi l i ty that i s geneticall y modul ated, some l isted i n Tabl e 7-1. Al though
such geneti c vari ati on i n drug-metaboli zi ng enzymes or drug targets mainly result i n unusual ly
vari abl e drug response, geneti c markers associ ated wi th rare but li fe-threatening side effects have
al so been descri bed. Of note, the most commonl y ci ted categori es of drugs involved in adverse
drug reacti ons incl ude cardiovascular, anti bi oti c, psychiatri c, and anal gesi c medi cations, and
interesti ngl y, each category has a known genetic basi s for increased ri sk of adverse reacti ons.
122

TABLE 7-1 Examples of Genetic Polymorphisms Involved in Variable Responses to
Drugs Used in the Perioperative Period
DRUG CLASS GENE NAME (GENE
SYMBOL)
EFFECT OF
POLYMORPHISM
PHARMACOKINETIC VARIABILITY
-bl ockers Cytochrome P450 2D6
(CYP2D6)
Enhanced drug effect
Codei ne,
dextromethorphan
CYP2D6 Decreased drug effect
Ca channel blockers Cytochrome P450 3A4
(CYP3A4)
Uncertai n
Alfentanil CYP3A4 Enhanced drug response
There are more than 30 fami l ies of drug-metaboli zi ng enzymes i n humans, most wi th geneti c
pol ymorphi sms shown to i nfl uence enzymati c activity. Of speci al i mportance to the
anesthesiol ogi sts i s the CYP2D6, one of the most i ntensivel y studi ed and best understood
examples of pharmacogeneti c vari ati on, i nvol ved i n the metaboli sm of several drugs i ncl udi ng
anal gesi cs (codei ne, dextromethorphan), -bl ockers (Fi g. 7-6), anti arrhythmics (fl ecai ni de,
propafenone, qui ni di ne), and di l ti azem. Another i mportant pharmacogeneti c vari ati on has been
Angi otensi n-II receptor
type 1 bl ockers
Cytochrome P450 2C9
(CYP2C9)
Enhanced blood pressure
response
Warfari n CYP2C9 Enhanced anti coagul ant
effect, ri sk of bl eedi ng
Phenytoin CYP2C9 Enhanced drug effect
ACE i nhi bi tors Angi otensi n-I converti ng
enzyme (ACE)
Bl ood pressure response
Procai nami de N-acetyltransferase 2
(NAT2)
Succi nylchol i ne Butyryl chol i nesterase
(BCHE)
Di goxi n P-gl ycoprotei n (ABCB1,
MDR1)
Increased bi oavai labi li ty
PHARMACODYNAMIC VARIABILITY
-bl ockers

1
and
2
adrenergic
receptors (ADRB1, ADRB2)
Bl ood pressure and heart
rate response, ai rway
responsi veness to
2
-
agoni sts
QT-prolonging drugs
(anti arrhythmi cs,
ci sapride, erythromyci n,
etc.)
Sodi um and potassi um i on
channel s (SCN5A, KCNH2,
KCNE2, KCNQ1)
Long QT-syndrome, ri sk
of torsade de poi ntes
Aspi ri n, gl ycoprotei n
IIb/IIIa i nhi bitors
Gl ycoprotei n IIIa subuni t of
pl atel et glycoprotein IIb/IIIa
(ITGB3)
Variabi li ty i n anti pl atelet
effects
Phenylephri ne Endothel ial ni tri c oxide
synthase (NOS3)
Bl ood pressure response
descri bed i n cytochrome P450C9 (CYP2C9), i nvol ved in metabol izing anticoagulants (warfari n),
anti convul sants (phenytoi n), anti di abeti c agents (gli pi zi de, tol butami de), and nonsteroi dal anti -
infl ammatory drugs (cel ecoxi b, i buprofen), among others. Three known CYP2C9 vari ant al l eles
result in different enzyme acti vi ties (extensi ve, i ntermedi ate, and sl ow metabol izer phenotypes)
and have cl inical impl icati ons in the i ncreased risk of li fe-threatening bl eedi ng compl i cations i n
sl ow metabol izers duri ng standard warfari n therapy. This i l lustrates the concept of hi gh-ri sk
pharmacokineti cs, whi ch appl ies to drugs with low therapeutic ratios eli mi nated by a si ngl e
pathway (i n this case CYP2C9-mediated oxidation); genetic variation in that pathway may l ead to
large changes i n drug clearance, concentrati ons, and effects.
92
Dose adjustments based on the
pharmacogeneti c phenotype have been proposed for drugs metabol i zed vi a both CYP2D6 and
CYP2C9 pathways.
94

Geneti c vari ati on i n drug targets (receptors) can have a profound effect on drug efficacy, and over
25 examples have al ready been i dentified. Functional pol ymorphi sms i n the
2
-adrenoreceptor
(Arg16Gl y, Gln27Gl u) i nfluenci ng the bronchodil ator and vascular responses to -agoni sts have
been descri bed, as wel l as i n the
1
-adrenoreceptor (Arg389Gl y), modul ati ng the response to -
bl ockers.
Fi nal ly, cli ni cal l y i mportant geneti c pol ymorphi sms wi th i ndi rect effects on drug response have
been descri bed. These i ncl ude vari ants i n candi date genes li ke sodium (SCN5A) and potassium ion
channel s (KCNH2, KCNE2, KCNQ1), whi ch al ter suscepti bil i ty to drug-induced long-QT syndrome
and ventricul ar arrhythmi as (torsade de poi ntes) associ ated wi th the use of drugs l i ke
erythromycin, terfenadine, disopyramide, sotal ol , ci sapri de, or quinidi ne. Carriers of such
suscepti bi l ity al lel es have not mani fest a QT-interval prolongation or fami l y history of sudden
death unti l QT-prolongi ng drug chall enge i s superimposed.
92
Predi sposi ti on to QT-interval
prolongation (consi dered a surrogate for ri sk of li fe-threatening ventricular arrhythmias) has been
responsi bl e for more drug wi thdrawal s from the market than any other category of adverse events
in recent ti mes, so understanding genetic predisposi ng factors consti tutes one of the hi ghest
FIGURE 7-6. Geneti cal l y mediated vari ati on i n pl asma metoprol ol concentrations i n CYP2D6
poor () versus extensive metaboli zers (^), foll owing a single oral dose of metoprol ol
tartrate (200 mg). Beta
1
-bl ocking effects occur at metoprol ol plasma concentrati ons in the 30
to 540 nmol /L range. The concentrati on-effect curve begi ns reachi ng a plateau between 200
and 300 nmol /L, and higher pl asma level s produce l i ttl e addi tional beta
1
-blocking effect and
di minished rel ati ve beta
1
-sel ecti vi ty wi th i ncreased beta
2
-bl ocki ng effects. (Repri nted from
Bukaveckas BL, Val des R, Li nder MW: Pharmacogeneti cs as rel ated to the practi ce of
cardi othoraci c and vascular anesthesi a. J Cardi othorac Vasc Anesth 18:353, 2004, wi th
permi ssi on.)
pri oriti es of current pharmacogenomi c efforts.

Pharmacogenomics i s emergi ng as an addi ti onal modifyi ng component to anesthesi a along wi th
age, gender, comorbi diti es, and medi cati on use. Speci fi c testing and treatment guidel i nes all owing
cl i ni ci ans to appropriatel y modify drug util i zati on (e.g., adjust dose or change drug) al ready exi st
for a few compounds
94
and wi l l li kel y be expanded to al l rel evant therapeuti c compounds, together
with identi fi cati on of novel therapeutic targets.
GENOMICS AND CRITICAL CARE
Genet i c Var i abi l i t y i n Response t o I nj ur y
Systemi c i njury (incl udi ng trauma and surgi cal stress), shock, or infecti on tri gger physi ol ogical
responses of fever, tachycardi a, tachypnea, and leukocytosi s that col lecti vel y define the systemic
infl ammatory response syndrome. Thi s can progress to severe sepsi s, septi c shock, and multi ple
organ dysfuncti on syndrome, the pathophysi ol ogy of whi ch remai ns poorl y understood. With the
genomi c revol uti on, a new paradi gm has emerged i n cri ti cal care medi ci ne: outcomes of criti cal
il l ness are determi ned by the i nterpl ay between the injury and repair processes tri ggered by the
initi al i nsul ts.
123
Negative outcomes are thus the combi ned resul t of di rect ti ssue injury, the side
effects of resulti ng repai r processes, and secondary i njury mechani sms l eadi ng to subopti mal
repai r. Regul ati on of these repai r mechani sms is currentl y being extensivel y investi gated at the
genomic, proteomi c, and pharmacogenomic levels, aiming to model adapti ve and mal adapti ve
responses to injury, ai d i n devel opment of di agnosti c i ndi ces predi ctive of i njury, moni tor progress
of repair, and eventual ly desi gn novel therapeuti c modal i ti es that take i nto account the indi vi dual
geneti c makeup.
The l arge i nteri ndi vi dual vari abil i ty i n the magni tude of response to injury, i ncl udi ng
acti vation of infl ammatory and coagul ati on cascades, apoptosi s,
124
and fi brosi s, suggests the
invol vement of geneti c regul atory factors. Several functi onal geneti c pol ymorphi sms i n mol ecul es
invol ved in vari ous components of the i nfl ammatory response have been associ ated with
di fferences i n susceptibi l ity to and mortal i ty from sepsi s

of different eti ol ogi es, i ncludi ng postoperati ve sepsi s (for review, see Lin et al
125
). These incl ude
pol ymorphi sms in bacteri al recogni ti on mol ecules l i ke l ipopolysaccharide-bi nding protein (LBP),
bacteri ci dal /permeabi li ty i ncreing protein (BPI), CD14, tol l -li ke receptors (TLR4), and pro-
infl ammatory cytoki nes l i ke tumor necrosis alpha (TNFA),
126, 127
lymphotoxin alpha (LTA),
29, 128

interleuki n-1 (IL1) and IL1 receptor antagoni st (IL1RN),
129
and interl euki n-6 (IL6).
130
Si mi l arl y,
functi onal geneti c vari ants i n the PAI-1
131
and ACE
90, 132
genes have been associ ated wi th poor
outcomes in sepsi s, reflecti ng the complex interacti on between i nfl ammati on, coagul ati on,
endothel i al function, and vascul ar tone i n the pathogenesi s of sepsi s-induced organ dysfunction.
Thi s conti nui ng effort to identi fy ini ti al SNP-di sease associ ati ons is fol l owed by a process of
sel ecti ng reli able predi cti ve SNPs by val i dation i n i ndependent popul ati ons and determi ni ng whi ch
and how many markers wi ll maximize the power to predi ct ri sk for sepsi s or mortali ty fol lowi ng
injury.
Funct i onal Genomi cs of I nj ur y
At a cel lular level, injuri ous stimul i tri gger adaptive stress responses determi ned by
quantitati ve and quali tati ve changes i n interdi gitati ng cascades of biol ogi cal pathways
interacting i n compl ex, often redundant ways. As a result, numerous cli ni cal trial s attempti ng to
bl ock single infl ammatory medi ators, such as TNF in sepsi s, have been largel y unsuccessful .
133

Gi ven these compl ex interconnecti ons, the standard si ngl e gene paradi gm is i nsuffi ci ent to
adequately describe the ti ssue response to severe systemi c sti muli . Instead, organ i njury mi ght
better be defi ned by patterns of altered gene and protei n expressi on.
134
DNA mi croarray
technol ogy has become a powerful hi gh-throughput method of analyzi ng changes i nduced by
vari ous injuri es on a genome-wide scale, by quanti fyi ng mRNA abundance and generati ng an
P.143
P.144
expressi on profi l e (the transcriptome) for the cell or ti ssue of i nterest. Several studies have
reported the gene expressi on profil es in both cri ticall y i l l pati ents and i n ani mal model s of
sepsis,
135, 136
acute l ung i njury,
137
and burn i njury.
138
Furthermore, two l arge-scal e nati onal
programs are usi ng gene and protei n expressi on profi l es in circul ati ng l eukocytes to investi gate
the biol ogi cal reasons behi nd the extreme vari abi l ity i n pati ent outcomes after simi lar traumatic
insults (the NIH-funded Trauma Gl ue Grant; http://www.gl uegrant.org) and to el uci date regulatory
mechani sms in response to septic chal lenge in high-ri sk pati ents (the German Nati onal Genome
Research Network).
134

Since only less than hal f of the changes at mRNA level are usuall y translated into changes i n
protei n expressi on, transcripti onal profi l i ng has to be complemented by characterizing the i njury
proteome for a more complete understanding of the host response to i njury. Al though the protei n
arrays are evol vi ng rapi dly, the mai n technol ogy for proteomi c analysi s remai ns two-di mensional
gel el ectrophoresi s foll owed by mass spectrometry. Such integrated anal ysis of neutrophi l s
transcriptome and proteome i n response to li popol ysacchari de stimul ati on has i dentified
upregulation of a vari ety of genes including transcri pti onal regulators (NF-B), cytoki nes (TNF,
IL6, IL1), and chemoki nes (MCP-1, MIP-3) and confi rmed the poor concordance between
transcripti onal and transl ati onal responses.
139

Model ing di sease entiti es l i ke sepsi s and mul ti pl e organ dysfuncti on syndrome, whi ch are compl ex,
nonl inear systems, requires the abi l ity not only to measure many di verse mol ecul ar events
si multaneously, but al so to integrate the data using novel anal ytical tool s based on compl ex
systems theory and nonli near dynami cs.
140
Such anal ysi s mi ght hel p i dentify the key signal i ng
nodes against whi ch therapeuti cs can be directed.
FUTURE DIRECTIONS
I nt egr at i on of Omi c I nf or mat i on: Syst em Bi ol ogy
Appr oaches
The Human Genome Project provi des the sequence of nucl eoti des, local i zati on of genes, and ami no
aci d sequence i n encoded proteins. However, less than 5% of the human genome represents DNA
whose sequence ul ti mately encodes a protein. Al though regul atory sequences and boundari es
between the codi ng (i .e., exons) and noncodi ng (i .e., introns) regi ons of the genes are now bei ng
recogni zed and i nvesti gated, reaching the goal s of functi onal genomi cs woul d requi re detai l ed
knowl edge of regul atory networks of gene expressi on as wel l as devel opmental and metabol ic
pathways. As mentioned earli er, mi croarray studi es have reveal ed that many concurrently
regul ated genes share the same bi ochemical pathway and that cel l ul ar states can be ascri bed to
di sti nct and uni que transcripti onal profil es. These studies have provi ded a framework on whi ch
proteome anal yses are based. Proteomi cs compl ements genome-based approaches by enabli ng the
identi fi cation and characterizati on of di fferenti al protei n expression, turnover and local i zati on,
posttransl ati onal modi fi cati ons (e.g., addi tion of sugar moi eti es or l i pi d attachments to a protei n),
and interacti on wi th other bi ologi cal molecul es, thus provi di ng new i nsights i nto the complex
cel lul ar processes involved i n the response to anesthesi a and surgical i njury. The potenti al for
protei n chips to functi on as versatil e and ri gorous hi gh-throughput methods for proteomi c
anal yses is the object of intense investi gati on. Other more recent functi onal genomic and
proteomi c approaches i nclude proteinprotei n, protei n-DNA, or other componentcomponent
interaction mapping (interactome); systemati c phenotypic anal yses (phenome); and transcri pt or
protei n three-di mensional local i zati on mappi ng (local izome).
141
To overcome the i ntri nsi c
li mi tati ons of al l indi vi dual omic approaches, i ntegrati on of data obtai ned from several di sti nct
approaches usi ng systems biol ogy strategies has been proposed. This may lead to better
functi onal annotati ons for the gene products and functional rel ati onshi ps between them and all ow
the formul ati on of rel evant bi ol ogical hypotheses, whi ch can subsequently be tested usi ng ei ther
synthetic bi ol ogy or mathemati cal modeli ng of compl ex si gnal ing networks.
141
Such i ntegrati ve
approaches to speci fi cal l y study cardi ovascul ar functi on (the Cardi ome Project) have al ready been
outl i ned. Furthermore, the scienti fi c community needs to wrap the profi l ing data withi n the
bi ologi cal phenomenology, the so-call ed phenome in which the model under study is compl etel y
characteri zed i n terms of the changes at the cell ul ar, biochemi cal , organ and system l evel (Fi g. 7-
7).
5

Tar get ed Dr ug Devel opment
Genomi c and proteomi c approaches are rapi dl y becomi ng pl atforms for al l aspects of drug
di scovery and devel opment, from target i denti ficati on and vali dati on to i ndi vi dual i zati on of drug
therapy. As mentioned earl i er, the human genome contai ns about 30,000 genes encodi ng for
approxi mately 200,000 protei ns, whi ch represent potenti al drug targets. However, onl y about 120
drug targets are currentl y bei ng marketed, thus making i dentificati on of novel therapeutic targets
an area of intense research. Foll owing gene identi fi cation, i ts therapeutic potential needs to be
val i dated by defi ni ng the sequence functi on and i ts rol e i n disease and demonstrati ng that the
gene product can be mani pul ated with beneficial effect and no toxic effects. A devel opi ng fi el d,
toxi cogenomi cs, studies the i nfluence of toxic or potenti al l y toxic substances on di fferent model
organisms

by eval uati ng the gene expressi on changes i nduced by novel drugs i n a gi ven ti ssue.
Sponsored by the Nati onal Insti tutes of Heal th, a nationwide col laborati ve effort cal led the
Pharmacogeneti cs Research Network (http://0-
www.ni gms.ni h.gov.i nnopac.up.ac.za:80/pharmacogeneti cs/) is ai mi ng to establi sh a strong
pharmacogenomics knowl edge base (http://www.pharmgkb.org/) as wel l as create a shared
computati onal and experimental i nfrastructure requi red to connect human sequence vari ati on wi th
drug responses and transl ate informati on i nto novel therapeutics.
Et hi cal Consi der at i ons
Although one of the ai ms of the Human Genome Project i s to i mprove therapy through genome-
FIGURE 7-7. Integration of omic information. Cellular function is organi zed as a
mul til ayered set of interdependent processes controll ed at the level of the genome (DNA),
transcriptome (messenger RNA), proteome (the col lecti on of al l protei ns encoded wi thi n the
DNA of a genome), physiome (regul atory networks and si gnal i ng pathways), and phenome
(the quanti tati ve descri pti on of the integrated functions of the li vi ng organi sm and i ts
interactions both wi th the environment and within the phenotype itself). Rel ati ng genome
vari abi l ity to complex trai ts requires integrati ve systems biol ogy approaches that wi ll provide
quantitati ve and mechani sti c descri ptions that uni fy si gnal i ng networks and i dentify cri tical
regul atory nodes for therapeutic mani pul ati on.
P.145
based predi cti on, there i s a ri sk for di scri mi nation agai nst individual s who are geneticall y
predi sposed for a medi cal di sorder. Such discri mi nation may i ncl ude barri ers to obtai ni ng health,
li fe, or long-term care insurance or obtaining empl oyment. Thus, extensi ve efforts are made to
protect pati ents parti cipating i n geneti c research from prejudi ce, di scri minati on, or uses of genetic
information that wi l l adversely affect them. To address the concerns of both bi omedi cal research
and health communiti es, the U.S. Senate approved i n 2003 the Geneti c Information and
Nondi scrimi nati on Act, which provi des the strong safeguards requi red to protect the publ i c
parti cipating i n human genome research.
Another ethi cal concern is the transferabil i ty of geneti c tests across ethni c groups, parti cul arly i n
the predi cti on of adverse drug responses. It i s known that most pol ymorphi sms associated wi th
vari abi l ity i n drug response show significant di fferences i n al l el e frequenci es among popul ati ons
and raci al groups. Furthermore, the patterns of l i nkage di sequi l i bri um are markedl y different
between ethni c groups, whi ch may lead to spuri ous fi ndi ngs when markers, i nstead of causal
vari ants, are used i n di agnosti c tests extrapolated across populations. In expl oring raci al
di spari ti es in heal th and di sease outcomes, consi derabl e debate has focused on whether race and
ethni c identi ty are primari ly social or bi ological constructs and the contri buti on of geneti c
vari abi l ity i n expl ai ni ng observed di fferences i n the rates of di sease between raci al groups. Wi th
the goal of personal i zed medi ci ne bei ng the predi cti on of ri sk and treatment of disease on the
basi s of an i ndi vi dual ' s geneti c profi le, some have argued that bi ologic considerati on of race wi l l
become obsol ete. However, in thi s di scovery phase of the postgenome era, conti nui ng to
incorporate racial i nformati on i n geneti c studies shoul d i mprove our understandi ng of the
architecture of the human genome, and i ts i mpl i cations for novel strategi es ai mi ng at i dentifying
vari ants protecti ng against, or conferring suscepti bil i ty to, common diseases and modul ati ng drug
effects.
142

CONCLUSION
The Human Genome Project has revoluti oni zed al l aspects of medi ci ne, al l owing us to assess the
i mpact of geneti c vari abi li ty on disease taxonomy, characterization, and outcome and i ndi vi dual
responses to vari ous drugs and i njuri es. Mechanisticall y, informati on gl eaned through genomi c
approaches is al ready unravel i ng l ong-standi ng mysteries behi nd general anestheti c acti on and
adverse responses to drugs used peri operati vel y. However, a strong need remains for prospecti ve,
well -powered genetic studi es in hi ghl y phenotyped surgi cal popul ations, whi ch requi re the
development of multi dimensional peri operati ve databases. For the anesthesi ol ogi st, thi s may soon
transl ate i nto prospecti ve risk assessment i ncorporati ng geneti c profi l i ng of markers i mportant i n
thromboti c, i nfl ammatory, vascul ar, and neurologic responses to peri operati ve stress, wi th
impli cati ons rangi ng from indivi dual i zed addi ti onal preoperati ve testi ng and physiologi cal
optimizati on, to choi ce of peri operati ve monitori ng strategi es and cri tical care resource uti li zation.
Furthermore, geneti c profi l ing of drug-metaboli zi ng enzymes, carri er protei ns, and receptors,
using currentl y avai labl e hi gh-throughput mol ecul ar technol ogies, wi ll enabl e personali zed choi ce
of drugs and dosage regi mens tai lored to sui t a pati ent's pharmacogeneti c profi l e. At that poi nt,
peri operative physi cians wil l have far more robust informati on to use in desi gning the most
appropriate and safest anestheti c pl an for a gi ven pati ent.
Future trends and chal lenges i n peri operati ve genomi cs are sti l l being defi ned but mainl y concern
interdiscipl i nary studies designed to combi ne an analyti cal system approach, mathematical
model i ng, and engi neeri ng pri nci pl es wi th the mul ti pl e mol ecular and geneti c factors and sti mul i,
and the macroscale interacti ons that determi ne the pathophysiologi cal response to surgery.
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> Tabl e of Contents > Secti on II - Basi c Pri nci pl es of Anesthesi a Practi ce > Chapter 8 - El ectri cal and Fi re
Saf ety
Chapter 8
Electrical and Fire Safety
Jan Ehrenwerth
Harry A. Seifert
KEY POINTS
A basi c pri nci ple of el ectri ci ty i s known as Ohm' s law.
To have the completed circui t necessary for current fl ow, a cl osed l oop must
exist and a vol tage source must dri ve the current through the impedance.
To recei ve a shock, one must contact the el ectri cal ci rcuit at two poi nts, and
there must be a vol tage source that causes the current to fl ow through an
i ndi vi dual .
In electri cal terminol ogy, groundi ng i s appl i ed to two separate concepts: the
groundi ng of electri cal power and the groundi ng of el ectri cal equipment.
To provide an extra measure of safety from gross electri cal shock (macroshock),
the power suppl i ed to most operati ng rooms is ungrounded.
The l ine i sol ati on moni tor (LIM) i s a device that conti nuousl y moni tors the
integrity of an i sol ated power system.
The ground fault ci rcui t interrupter (GFCI) i s another popul ar devi ce used to
prevent i ndividual s from recei vi ng an electri cal shock i n a grounded power
system.
An el ectricall y suscepti bl e pati ent (i.e., one who has a di rect, external
connecti on to the heart) they may be at risk from very small currents; thi s i s
call ed microshock.
Problems can arise i f the el ectrosurgi cal return pl ate i s i mproperl y appl i ed to
the pati ent or i f the cord connecti ng the return plate to the el ectrosurgi cal unit
(ESU) i s damaged or broken.
The myri ad of electri cal and el ectronic devi ces in the modern operati ng room greatl y i mprove
patient care and safety. However, these devices also subject both the patient and operati ng room
personnel to i ncreased ri sks. To reduce the ri sk of el ectri cal shock, most operati ng rooms have
el ectrical systems that i ncorporate speci al safety features. It is incumbent upon the
anesthesiol ogi st to have a thorough understanding of the basi c pri nci pl es of electri ci ty and an
appreci ati on of the concepts of el ectrical safety appli cabl e to the operating room envi ronment.
PRINCIPLES OF ELECTRICITY
A basi c pri nci ple of el ectri ci ty i s known as Ohm' s law, whi ch i s represented by the equati on:
E = I R
where E is el ectromoti ve force (in volts), I is current (i n amperes), and R is resi stance (i n ohms).
Ohm' s law forms the basis for the physi ol ogic equati on BP = CO SVR; that i s, bl ood

pressure (BP) i s equal to the cardi ac output (CO) times the systemi c vascular resi stance (SVR). In
this case, the blood pressure of the vascular system is anal ogous to vol tage, the cardi ac output to
current, and systemi c vascul ar resi stance to the forces opposing the fl ow of electrons. El ectri cal
power i s measured i n watts. Wattage (W) i s the product of the vol tage (E) and the current (I), as
defi ned by the formula:
W = E I
The amount of el ectrical work done is measured i n watts mul tipl i ed by a uni t of ti me. The watt-
second (a joule, J) i s a common designati on for el ectri cal energy expended in doing work. The
energy produced by a defibril l ator i s measured in watt-seconds (or joul es). The ki lowatt-hour is
used by el ectrical util i ty companies to measure l arger quantiti es of el ectrical energy.
Wattage can be thought of as a measure not only of work done but al so of heat produced in any
el ectrical ci rcuit. Substi tuting Ohm' s l aw i n the formul a
W = E I
W = (I R) I
W = I
2
R

Thus, wattage i s equal to the square of the current I
2
(amperage) ti mes the resi stance R. Using
these formulas, i t i s possi ble to cal cul ate the number of amperes and the resi stance of a gi ven
Fi res i n the operati ng room are just as much a danger today as they were 100
years ago when patients were anestheti zed wi th fl ammabl e anestheti c agents.
The fi re tri ad consists of a heat or igni ti on source, a fuel , and an oxidi zer.
The two major i gni tion sources for OR fi res are the ESU and the l aser.
It i s known that desi ccated carbon dioxi de absorbent can, i n rare circumstances,
react wi th sevofl urane to produce a fi re.
All OR personnel shoul d be famil i ar wi th the locati on and operati on of the fire
exti ngui shers.
P.150
device i f the wattage and the vol tage are known. For exampl e, a 60-watt l ight bul b operati ng on a
household 120-vol t circui t woul d require 0.5 ampere, of current for operati on. Rearrangi ng the
formula so that
I = W/E
we have
I = (60 watts)/(120 vol ts)
I = 0.5 ampere
Usi ng thi s in Ohm' s l aw
R = E/I
the resistance can be cal cul ated to be 240 ohms:
R = (120 volts)/(0.5 ampere)
R = 240 ohms
It i s obvious from the previ ous discussion that 1 vol t of electromoti ve force (EMF) fl owi ng through
a 1-ohm resi stance wi l l generate 1 ampere of current. Si mi l arl y, 1 ampere of current i nduced by 1
vol t of electromoti ve force wil l generate 1 watt of power.
DIRECT AND ALTERNATING CURRENTS
Any substance that permi ts the fl ow of electrons i s cal led a conductor. Current is characteri zed by
el ectrons fl owing through a conductor. If the el ectron fl ow i s al ways i n the same di rection, it i s
referred to as di rect current (DC). However, if the electron flow reverses di recti on at a regular
interval, it i s termed al ternating current (AC). Ei ther of these types of current can be pul sed or
conti nuous i n nature.
1

The previous di scussi on of Ohm's l aw i s accurate when appl i ed to DC ci rcuits. However, when
deal ing wi th AC circui ts, the si tuati on i s more compl ex because the flow of the current i s opposed
by a more compl i cated form of resi stance, known as i mpedance.
IMPEDANCE
Impedance, desi gnated by the l etter Z, i s defi ned as the sum of the forces that oppose el ectron
movement i n an AC ci rcuit. Impedance consi sts of resi stance (ohms) but al so takes capacitance
and inductance i nto account. In actual ity, when referri ng to AC ci rcui ts, Ohm's l aw i s defi ned as
E = I Z
An insulator i s a substance that opposes the fl ow of el ectrons. Therefore, an i nsul ator has a hi gh
impedance to electron fl ow, whereas a conductor has a l ow i mpedance to el ectron fl ow.
In AC ci rcui ts the capaci tance and i nductance can be i mportant factors i n determini ng the total
i mpedance. Both capaci tance and inductance are infl uenced by the frequency (cycl es per second or
hertz, Hz) at whi ch the AC current reverses directi on. The i mpedance i s di rectly proportional to
the frequency (f) ti mes the i nductance (IND):
Z (f IND)
and the i mpedance i s i nversel y proporti onal to the product of the frequency (f) and the
capaci tance (CAP):
Z 1/(f CAP)
As the AC current increases i n frequency, the net effect of both capaci tance and inductance
increases. However, because i mpedance and capaci tance are i nversel y rel ated, total impedance
decreases as the product of the frequency and the capaci tance i ncreases. Thus, as frequency
increases, i mpedance fall s and more current i s al lowed to pass.
2

CAPACITANCE
A capaci tor consi sts of any two paral l el conductors that are separated by an i nsul ator (Fi g. 8-1). A
capaci tor has the abil i ty to store charge. Capaci tance is the measure of that substance' s abi l ity to
store charge. In a DC ci rcui t the capacitor pl ates are charged by a vol tage source (i .e., a battery)
and there i s onl y a momentary current fl ow. The ci rcui t is not compl eted and no further current
can flow unl ess a resistance i s connected between the two pl ates and the capaci tor i s di scharged.
3

In contrast to DC circui ts, a capacitor i n an AC ci rcuit permi ts current fl ow even when the ci rcuit
is not completed by a resi stance. Thi s i s because of the nature of AC circui ts, i n whi ch the current
flow is constantl y being reversed. Because current fl ow resul ts from the movement of el ectrons,
the capaci tor pl ates are alternately chargedfi rst posi ti ve and then negative wi th every reversal
of the AC current directi onresul ti ng in an effecti ve current fl ow as far as the remai nder of the
ci rcuit i s concerned, even though the ci rcuit i s not completed.
4

Because the effect of capaci tance on i mpedance varies di rectly wi th the AC frequency (Hz), the
greater the AC frequency, the lower the i mpedance. Therefore, hi gh-frequency currents (0.5 to 2
mi ll i on Hz), such as those used by electrosurgical uni ts (ESUs), wil l cause a marked decrease in
impedance. For exampl e, a 20-mi ll i onohm i mpedance i n a 60-Hz AC circui t wil l be reduced to just
a few hundred ohms when the frequency is i ncreased to 1 mi ll i on Hz.
5

El ectri cal devi ces use capaci tors for various benefi ci al purposes. There is, however, a phenomenon
known as stray capaci tancecapaci tance that was not desi gned i nto the system but i s incidental
to the constructi on of the equi pment.
6
Al l AC-operated equi pment produces stray capaci tance. An
ordinary power cord, for exampl e, consi sti ng of two i nsulated wi res runni ng next to each other wil l
generate si gni fi cant capaci tance si mpl y by bei ng pl ugged i nto a 120-vol t circui t, even though the
pi ece of equi pment is not turned on. Another exampl e of stray capaci tance i s found i n el ectri c
motors. The ci rcuit wiri ng i n electri c motors generates stray capacitance to the metal housi ng of
the motor.
7
The cl inical importance of capaci tance wi ll be emphasi zed l ater i n the chapter.

INDUCTANCE
Whenever el ectrons fl ow i n a wire, a magneti c fi eld i s i nduced around the wi re. If the wi re is
coil ed repeatedly around an i ron core, as i n a transformer, the magneti c fi el d can be very strong.
Inductance is a property of AC ci rcuits i n whi ch an opposi ng EMF can be el ectromagneti cal ly
generated in the ci rcui t. The net effect of inductance is to increase i mpedance. Because the effect
FIGURE 8-1. A capacitor consists of two paral l el conductors separated by an insul ator. The
capacitor is capable of stori ng charge suppl i ed by a vol tage source.
P.151
of i nductance on i mpedance is al so dependent on AC frequency, i ncreases i n frequency wil l
increase the total impedance. Therefore, the total impedance of a coil wi l l be much greater than
its si mple resi stance.
4

ELECTRICAL SHOCK HAZARDS
Al t er nat i ng and Di r ect Cur r ent s
Whenever an i ndi vi dual contacts an external source of electri city, an el ectri cal shock i s possibl e.
An el ectrical current can sti mulate skeletal muscl e cel l s to contract, and thus can be used
therapeuticall y i n devi ces such as pacemakers or defibri ll ators. However, casual contact wi th an
el ectrical current, whether AC or DC, can l ead to i njury or death. Al though it takes approximatel y
three times as much DC as AC to cause ventri cul ar fi bri l lation,
3
this by no means renders DC
harmless. Devi ces such as an automobi le battery or a DC defi bri l lator can be sources of direct
current shocks.
In the Uni ted States, uti l ity compani es supply el ectri cal energy i n the form of alternati ng currents
of 120 vol ts at a frequency of 60 Hz. The 120 volts of EMF and 1 ampere of current are the
effecti ve vol tage and amperage in an AC ci rcuit. Thi s i s al so referred to as RMS (root-mean-
square). It takes 1.414 amperes of peak amperage i n the si nusoi dal curve to gi ve an effecti ve
amperage of 1 ampere. Simil arl y, it takes 170 vol ts (120 1.414) at the peak of the AC curve to
get an effecti ve vol tage of 120 vol ts. The 60 Hz refers to the number of ti mes i n 1 second that the
current reverses its directi on of fl ow.
8
Both the vol tage and current waveforms form a si nusoi dal
pattern (Fi g. 8-2).
To have the completed circui t necessary for current fl ow, a cl osed l oop must exi st and a
vol tage source must dri ve the current through the i mpedance. If current i s to fl ow i n the
el ectrical ci rcuit, there has to be a vol tage di fferenti al, or a drop i n the dri vi ng pressure across
the i mpedance. Accordi ng to Ohm' s l aw, i f the resistance is held constant, then the greater the
current fl ow, the l arger the vol tage drop must be.
9

The power company attempts to mai ntai n the l ine voltage constant at 120 volts. Therefore, by
Ohm' s law the current fl ow i s i nversel y proportional to the i mpedance. A typi cal power cord
consi sts of two conductors. One, desi gnated as hot carri es the current to the i mpedance; the other
is neutral , and i t returns the current to the source. The potenti al difference between the two is
effecti vel y 120 vol ts (Fi g. 8-3). The amount of current fl owing through a gi ven devi ce is frequentl y
referred to as the load. The l oad of the ci rcuit i s dependent on the i mpedance. A very high
impedance ci rcui t all ows only a smal l current to fl ow and thus has a smal l l oad. A very low
FIGURE 8-2. Si ne wave flow of electrons i n a 60-Hz al ternati ng current.
i mpedance ci rcui t wi l l draw a l arge current and is sai d to be a l arge load. A short ci rcuit occurs
when there i s a zero impedance l oad wi th a very high current flow.
10

Sour ce of Shocks
To practice el ectrical safety i t i s i mportant for the anesthesi ol ogist to understand the basic
pri nci pl es of el ectri city and be aware of how el ectri cal accidents can occur. El ectri cal
acci dents or shocks occur when a person becomes part of or compl etes an el ectri cal ci rcui t. To
recei ve a shock, one must contact the electri cal circui t at two poi nts, and there must be a voltage
source that causes the current to flow through an indi vi dual (Fi g. 8-4).
FIGURE 8-3. A typi cal AC ci rcuit where there is a potenti al difference of 120 vol ts between
the hot and neutral si des of the ci rcuit. The current flows through a resi stance, whi ch in AC
ci rcuits is more accuratel y referred to as i mpedance, and then returns to the electri cal power
company.
FIGURE 8-4. An i ndi vi dual can compl ete an el ectri c circui t and recei ve a shock by comi ng i n
contact wi th the hot side of the ci rcuit (poi nt A). Thi s is because he or she i s standi ng on the
ground (poi nt B) and the contact poi nt A and the ground poi nt B provi de the two contact
poi nts necessary for a completed circui t. The severity of the shock that the i ndi vi dual
recei ves i s dependent on hi s or her ski n resi stance.
When an i ndi vi dual contacts a source of el ectri ci ty, damage occurs in one of two ways. Fi rst, the
el ectrical current can di srupt the normal el ectri cal functi on of cel l s. Dependi ng on i ts magni tude,
the current can contract muscl es, al ter brai n functi on, paral yze respi rati on, or di srupt normal
heart functi on, l eading to ventri cul ar fi bril l ati on. The second mechani sm involves the dissipation of
el ectrical energy throughout the body' s ti ssues. An electri cal current passi ng through any
resistance raises the temperature of that substance. If enough thermal energy i s rel eased, the
temperature wi l l ri se suffi cientl y to produce a burn. Acci dents i nvol vi ng househol d currents usuall y
do not result i n severe burns. However, in acci dents i nvol vi ng very high vol tages (i .e., power
transmi ssi on l ines), severe burns are common.
The severi ty of an el ectri cal shock is determined by the amount of current (number of amperes)
and the durati on of the current fl ow. For the purposes of thi s discussi on, el ectrical

shocks are di vi ded i nto two categori es. Macroshock refers to l arge amounts of current fl owi ng
through a person, whi ch can cause harm or death. Mi croshock refers to very small amounts of
current and appl i es only to the el ectricall y suscepti bl e pati ent. Thi s i s an i ndi vi dual who has an
external condui t that i s in di rect contact wi th the heart. This can be a paci ng wire or a sali ne-fil l ed
catheter such as a central venous or pul monary artery catheter. In the case of the el ectri cal l y
suscepti bl e pati ent, even mi nute amounts of current (mi croshock) may cause ventri cul ar
fibri ll ati on.
Tabl e 8-1 shows the effects typi cal l y produced by vari ous currents foll owing a 1-second contact
with a 60-Hz current. When an i ndi vi dual contacts a 120-vol t househol d current, the severi ty of
the shock wi ll depend on hi s or her ski n resi stance, the durati on of the contact, and the current
densi ty. Skin resi stance can vary from a few thousand to 1 million ohms. If a person with a skin
resistance of 1,000 ohms contacts a 120-vol t circui t, he or she woul d recei ve 120 mi l l iamperes
(mA) of current, which woul d probabl y be lethal . However, i f that same person' s skin resi stance is
100,000 ohms, the current flow would be 1.2 mA, whi ch would barely be percepti bl e.
P.152
TABLE 8-1 Effects of 60-Hz Current on an Average Human for a 1-Second Contact
CURRENT EFFECT
MACROSHOCK
1 mA (0.001 A) Threshol d of percepti on
5 mA (0.005 A) Accepted as maxi mum harmless current i ntensi ty
1020 mA
(0.010.02 A)
Let-go current before sustai ned muscle contraction
50 mA (0.05 A) Pai n, possi bl e fai nting, mechanical i njury; heart and respi ratory
functi ons conti nue
100300 mA
(0.10.3 A)
Ventri cul ar fi bri l lation wi ll start, but respi ratory center remains
intact
I = E/R = (120 volts)/(1,000 ohms) = 120 mA
I = E/R = (120 volts)/(100,000 ohms) = 1.2 mA
The l onger an indi vidual i s i n contact wi th the el ectrical source, the more dire the consequences
because more energy wi l l be rel eased and more ti ssue damaged. Al so, there wi ll be a greater
chance of ventri cul ar fibril l ati on from excitati on of the heart during the vul nerabl e peri od of the
el ectrocardi ogram (ECG) cycl e.
Current densi ty i s a way of expressi ng the amount of current that i s appli ed per uni t area of
ti ssue. The di ffusion of current i n the body tends to be i n al l di recti ons. The greater the current or
the smal l er the area to which i t i s appli ed, the hi gher the current densi ty. In rel ati on to the heart,
a current of 100 mA (100,000 A) i s general l y requi red to produce ventri cul ar fi bri l lation when
appl ied to the surface of the body. However, onl y 100 A (0.1 mA) i s requi red to produce
ventri cul ar fi bril l ati on when that mi nute current i s appl i ed di rectl y to the myocardi um through an
instrument havi ng a very smal l contact area, such as a paci ng wi re el ectrode. In thi s case, the
current densi ty is 1,000-fol d greater when appl i ed di rectl y to the heart; therefore, onl y 1/1,000 of
the energy i s requi red to cause ventricul ar fibri ll ati on. In this case, the electri cal ly suscepti ble
patient can be electrocuted wi th currents wel l below 1 mA, whi ch i s the threshol d of percepti on for
humans. The frequency at whi ch the current reverses is al so an important factor i n determini ng
the amount of current an i ndi vi dual can safel y contact. Uti l ity compani es in the Uni ted States
produce electri ci ty at a frequency of 60 Hz. They use 60 Hz because hi gher frequenci es cause
greater power l oss through transmission li nes and lower frequenci es cause a detectabl e fl icker
from li ght sources.
11
The let-go current i s defined as that current above which sustai ned
muscul ar contracti on occurs and at whi ch an i ndividual woul d be unabl e to l et go of an energi zed
wire. The let-go current for a 60-Hz AC power i s 10 to 20 mA,
10, 12, 13
whereas at a frequency of 1
mi ll i on Hz, up to 3 amperes (3,000 mA) i s general l y consi dered safe.
3
It shoul d be noted that very
hi gh frequency currents do not excite contracti le ti ssue; consequentl y, they do not cause cardi ac
arrhythmi as.
It can be seen that Ohm' s law governs the flow of electri city. For a compl eted ci rcuit to exist,
there must be a cl osed l oop with a dri vi ng pressure to force a current through a resi stance, just
as i n the cardi ovascul ar system there must be a blood pressure to drive the cardiac output
through the peri pheral resi stance. Fi gure 8-5 il l ustrates that a hot wi re carryi ng a 120-vol t
pressure through the resi stance of a 60-watt l i ght bul b produces a current fl ow of 0.5 ampere. The
vol tage i n the neutral wire i s approximatel y 0 vol ts, whi l e the current i n the neutral wire remains
at 0.5 ampere. Thi s correlates with our cardi ovascul ar anal ogy, where a mean blood pressure
decrease of 80 mm Hg between the aorti c root and the right atri um forces a cardi ac output of 6
6,000 mA (6 A) Sustai ned myocardi al contracti on, fol l owed by normal heart rhythm;
temporary respi ratory paral ysi s; burns i f current densi ty i s hi gh
MICROSHOCK
100 A (0.1
mA)
Ventri cul ar fi bri l lation
10 A (0.01
mA)
Recommended maxi mum 60-Hz l eakage current
A, amperes; mA, mi l l i amperes; A, mi croamperes.
L/min
-1
through a systemic vascul ar resi stance of 13.3 resi stance units. However, the fl ow (i n thi s
case, the cardiac output, or i n the case of the el ectri cal model , the current) is sti l l the same
everywhere in the ci rcui t. That i s, the cardiac output on the arterial side is the same as the
cardi ac output on the venous si de.

Gr oundi ng
To ful ly understand electri cal shock hazards and their preventi on, one must have a thorough
knowl edge of the concepts of grounding. These concepts of groundi ng probabl y consti tute the
most confusi ng aspects of el ectrical safety because the same term i s used to descri be several
di fferent pri ncipl es. In el ectrical termi nology, groundi ng i s appl ied to two separate concepts. The
first is the groundi ng of electri cal power, and the second i s the groundi ng of el ectri cal equipment.
Thus, the concepts that (1) power can be grounded or ungrounded and that (2) power can suppl y
el ectrical devi ces that are themselves grounded or ungrounded are not mutuall y excl usi ve. It i s
vital to understand this poi nt as the basi s of electri cal safety (Tabl e 8-2). Whereas el ectri cal
power is grounded i n the home, it i s usual ly ungrounded i n the operating room. In the home,
el ectrical equipment may be grounded or ungrounded, but i t should al ways be grounded i n the
operating room.
FIGURE 8-5. A 60-watt l ight bul b has an i nternal resi stance of 240 ohms and draws 0.5
ampere of current. The vol tage drop in the ci rcui t is from 120 i n the hot wi re to 0 i n the
neutral wi re, but the current is 0.5 ampere i n both the hot and neutral wi res.
P.153
ELECTRICAL POWER: GROUNDED
El ectri cal uti l iti es uni versal ly provi de power that i s grounded (by convention, the earthground
potential i s zero, and al l voltages represent a difference between potenti al s). That i s, one of the
wires suppl yi ng the power to a home i s i ntentional ly connected to the earth. The uti li ty compani es
do thi s as a safety measure to prevent el ectrical charges from bui l di ng up i n thei r wiring during
el ectrical storms. Thi s al so prevents the very hi gh vol tages used i n transmi tti ng power by the
util i ty from enteri ng the home i n the event of an equi pment fai l ure in thei r hi gh-vol tage system.
3

The power enters the typi cal home via two wi res. These two wires are attached to the mai n fuse or
the ci rcuit breaker box at the servi ce entrance. The hot wire suppl i es power to the hot
di stri bution strip. The neutral wire i s connected to the neutral di stributi on stri p and to a servi ce
entrance ground (i .e., a pi pe buri ed i n the earth) (Fi g. 8-6). From the fuse box, three wi res l eave
to suppl y the el ectrical outl ets in the house. In the Uni ted States, the hot wire i s col or-coded
bl ack and carri es a voltage 120 vol ts above ground potential . The second wi re is the neutral wire
col or-coded whi te; the thi rd wi re is the ground wire, which is either col or-coded green or i s
uni nsulated (bare wi re). The ground and the neutral wires are attached at the same point in the
ci rcui t breaker box and then further connected to a cold-water pipe (Fi gs. 8-7 and 8-8). Thus, thi s
grounded power system i s al so referred to as a neutral grounded power system. The black wire i s
not connected to the ground, as this would create a short circui t. The bl ack wi re i s attached to the
hot (i.e., 120 volts above ground) di stri buti on stri p on whi ch the ci rcui t breakers or fuses are
located. From here, numerous branch circui ts suppl y electri cal power to the outlets i n the house.
Each branch ci rcui t i s protected by a ci rcui t breaker or fuse that l i mi ts current to a speci fi c
maxi mum amperage. Most el ectri cal ci rcui ts i n the house are 15- or 20-ampere circui ts. These
typi cal l y suppl y power to the electri cal outlets and l ights i n the house. Several hi gher amperage
ci rcuits are also provi ded for devices such as an electri c stove or an electri c cl othes dryer. These
devices are powered by 240-vol t circui ts, whi ch can draw from 30 to 50 amperes of current. The
ci rcuit breaker or fuse wi ll i nterrupt the flow of current on the hot si de of the l i ne in the event of
a short ci rcuit or i f the demand pl aced on that ci rcui t i s too hi gh. For exampl e, a 15-ampere
branch ci rcui t wi l l be capabl e of supporti ng 1,800 watts of power.
TABLE 8-2 Differences between Power and Equipment Grounding in the Home and the
Operating Room
POWER EQUIPMENT
Home +
Operating room +
+, grounded; , ungrounded; , may or may not be grounded.
FIGURE 8-6. In a neutral grounded power system, the el ectric company suppli es two li nes to
the typical home. The neutral is connected to ground by the power company and agai n
connected to a service entrance ground when i t enters the fuse box. Both the neutral and
ground wi res are connected together in the fuse box at the neutral bus bar, whi ch i s al so
attached to the servi ce entrance ground.
FIGURE 8-7. Inside a fuse box with the circui t breakers removed. The arrowheads indi cate
the hot wi res energizing the stri ps where the ci rcui t breakers are l ocated. The arrows poi nt
to the neutral bus bar where the neutral and ground wi res are connected.
W = E I
W = 120 vol ts 15 amperes
W = 1,800 watts
Therefore, if two 1,500-watt hai r dryers were simul taneousl y pl ugged i nto one outl et, the l oad
woul d be too great for a 15-ampere circui t, and the ci rcui t breaker woul d open (tri p) or the fuse
woul d mel t. Thi s i s done to prevent the suppl y wi res i n the ci rcuit from melti ng and starting a fi re.
The amperage of the ci rcui t breaker on the branch ci rcui t i s determined by the thi ckness of the
wire that it suppl i es. If a 20-ampere breaker i s used wi th wi re rated for onl y 15 amperes, the wi re
coul d mel t and start a fi re before the ci rcuit breaker would trip. It i s i mportant to note that a 15-
ampere ci rcui t breaker does not protect an i ndi vi dual from l ethal shocks. The 15 amperes of
current that would tri p the circui t breaker far exceeds the 100 to 200 mA that wi ll produce
ventri cul ar fi bril l ati on.
The wi res that l eave the ci rcuit breaker suppl y the electri cal outl ets and l i ghti ng for the rest of the
house. In older homes the el ectri cal cabl e consi sts of two wi res, a hot and a neutral , which supply
power to the electri cal outlets (Fi g. 8-9). In newer homes, a thi rd wi re has been added to the
el ectrical cabl e (Fi g. 8-10). Thi s thi rd wire i s ei ther green or uni nsul ated (bare)

and serves as a ground wi re for the power receptacle (Fi g. 8-11). On one end, the ground wi re is
attached to the electri cal outlet (Fi g. 8-12); on the other, i t is connected to the neutral
di stri bution strip i n the circui t breaker box al ong with the neutral (white) wi res (Fi g. 8-13).
FIGURE 8-8. An ol der styl e electri cal outlet consi sti ng of just two wi res (a hot and a
neutral ). There is no ground wi re.
P.154
P.155
FIGURE 8-9. The arrowhead indi cates the ground wi re from the fuse box attached to a col d-
water pipe.
FIGURE 8-10. Modern el ectrical cabl e i n whi ch a thi rd, or ground, wi re has been added.
FIGURE 8-11. Modern el ectrical outl et i n whi ch the ground wire i s present. The arrowhead
poi nts to the part of the receptacle where the ground wi re connects.
FIGURE 8-12. Detai l of modern electri cal power receptacl e. The arrow poi nts to the ground
wire, whi ch i s attached to the groundi ng screw on the power receptacl e.
It shoul d be real i zed that in both the ol d and new si tuati ons, the power i s grounded. That i s, a
120-vol t potenti al exi sts between the hot (bl ack) and the neutral (whi te) wire and between the hot
wire and ground. In thi s case, the ground i s the earth (Fi g. 8-14). In modern home constructi on,
there i s sti ll a 120-vol t potenti al di fference between the hot (bl ack) and the neutral (whi te) wi re
as wel l as a 120-vol t di fference between the equi pment ground wi re (which i s the third wire), and
between the hot wi re and earth (Fi g. 8-15).
FIGURE 8-13. The ground wires from the power outl et are run to the neutral bus bar, where
they are connected wi th the neutral wi res (arrowheads).
FIGURE 8-14. Di agram of a house wi th older style wiri ng that does not contai n a ground
wire. A 120-vol t potenti al di fference exi sts between the hot and the neutral wire, as well as
A 60-watt l i ght bul b can be used as an exampl e to further il l ustrate this point. Normall y, the hot
and neutral wires are connected to the two wires of the l ight bul b socket, and throwi ng the switch
wil l i ll umi nate the bul b (Fi g. 8-16). Simil arl y, if the hot wi re i s connected to one si de of the bulb
socket and the other wire from the l i ght bul b i s connected to the equi pment ground wi re, the bul b
wil l sti l l il l uminate. If there is no equi pment ground wire, the bul b wi ll stil l l ight if the second wi re
is connected to any grounded metal li c object such as a water pi pe or a faucet. Thi s il l ustrates the
fact that the 120-vol t potenti al di fference exi sts not onl y between the hot and the neutral wi res
but al so between the hot wi re and any grounded object. Thus, i n a grounded power system, the
current wi l l flow between the hot wi re and any conductor wi th an earth ground.
between the hot wi re and the earth.
FIGURE 8-15. Di agram of a house wi th modern wi ring i n whi ch the third, or ground, wi re
has been added. The 120-vol t potenti al di fference exi sts between the hot and neutral wires,
the hot and the ground wires, and the hot wi re and the earth.
As previ ously stated, current fl ow requi res a cl osed l oop wi th a source of voltage. For an
individual to receive an el ectri c shock, he or she must contact the l oop at two points. Because we
may be standi ng on ground or be in contact with an object that i s referenced to ground, only one
addi ti onal contact point i s necessary to compl ete the circui t and thus recei ve an electri cal shock.
Thi s is an unfortunate and i nherentl y dangerous consequence of grounded power systems. Modern
wiri ng systems have added the thi rd wi re, the equi pment ground wi re, as a safety measure to
reduce the severity of a potential electri cal shock. Thi s i s accompli shed by provi ding an al ternate,
low-resistance pathway through whi ch the current can fl ow to ground.
Over time the i nsul ati on coveri ng wi res may deteri orate. It i s then possibl e for a bare, hot wi re to
contact the metal case or frame of an electri cal devi ce. The case would then become energized
and constitute a shock hazard to someone comi ng in contact wi th i t. Fi gure 8-17 il l ustrates a
typi cal short ci rcui t, where the individual has come i n contact wi th the hot case of an instrument.
Thi s il l ustrates the type of wiring found i n ol der homes. There i s no ground wi re in the el ectrical
outl et, nor i s the electri cal apparatus equi pped wi th a ground wi re. Here, the individual compl etes
the ci rcuit and receives a severe shock. Fi gure 8-18 il l ustrates a simi lar example, except that now
the

equi pment ground wi re i s part of the electri cal di stri bution system. In this exampl e, the
equi pment ground wi re provi des a pathway of low i mpedance through whi ch the current can
travel ; therefore, most of the current woul d travel through the ground wi re. In thi s case, the
person may get a shock, but i t i s unl i kel y to be fatal .
FIGURE 8-16. A simpl e li ght bulb ci rcuit i n whi ch the hot and neutral wires are connected
with the corresponding wi res from the li ght bulb fi xture.
P.156
P.157
The el ectri cal power suppl ied to homes i s al ways grounded. A 120-vol t potenti al al ways exi sts
between the hot conductor and ground or earth. The thi rd or equipment ground wi re used i n
modern el ectri cal wi ri ng systems does not normal l y have current flowing through it. In the event
of a short ci rcuit, an el ectri cal devi ce wi th a three-prong pl ug (i .e., a ground wire connected to its
case) wil l conduct the majori ty of the short-ci rcuited or faul t current through the ground wire
and away from the i ndi vi dual . Thi s provi des a si gni fi cant safety benefi t to someone accidentall y
contacting the defective devi ce. If a large enough faul t current exi sts, the ground wire also wi l l
FIGURE 8-17. When a faul ty piece of equi pment without an equi pment ground wire i s
pl ugged into an el ectri cal outl et not containi ng a ground wire, the case of the instrument wi ll
become hot. An i ndi vi dual touchi ng the hot case (poi nt A) wil l recei ve a shock because he or
she is standing on the earth (point B) and compl etes the ci rcuit. The current (dashed l i ne)
wil l fl ow from the i nstrument through the individual touchi ng the hot case.
FIGURE 8-18. When a faul ty piece of equi pment contai ni ng an equi pment ground wi re is
properl y connected to an electri cal outlet wi th a groundi ng connecti on, the current (dashed
li ne) wil l preferenti al l y flow down the low-resistance ground wi re. An i ndi vi dual touching the
case (point A) whi le standi ng on the ground (poi nt B) wil l sti l l compl ete the ci rcui t; however,
only a smal l part of the current wi l l go through the i ndi vi dual .
provi de a means to compl ete the short ci rcuit back to the ci rcuit breaker or fuse, and this wil l
ei ther mel t the fuse or tri p the circui t breaker. Thus, in a grounded power system, i t i s possi bl e to
have ei ther grounded or ungrounded equi pment, dependi ng on when the wi ri ng was i nstall ed and
whether the el ectri cal devi ce i s equi pped wi th a three-prong pl ug containing a ground wi re.
Obvi ously, attempts to bypass the safety system of the equipment ground shoul d be avoi ded.
Devices such as a cheater pl ug (Fi g. 8-19) should never be used because they defeat the safety
feature of the equipment ground wi re.
ELECTRICAL POWER: UNGROUNDED
Numerous el ectronic devices, together wi th power cords and puddl es of sal ine sol uti ons on
the fl oor, make the operating room an electri cal ly hazardous envi ronment for both patients
and personnel . Bruner et al
14
found that 40% of el ectrical accidents i n hospi tal s occurred in the
operating room. The complexity of el ectrical equi pment in the modern operating room demands
that electrical safety be a factor of paramount i mportance. To provi de an extra measure of safety
from macroshock, the power suppl i ed to most operati ng rooms i s ungrounded. In this ungrounded
power system, the current i s i sol ated from ground potenti al. The 120-vol t potenti al difference
exists only between the two wi res of the isolated power system, but no circui t exists between the
ground and ei ther of the isolated power li nes.
Suppl yi ng ungrounded power to the operating room requi res the use of an isol ati on transformer
(Fi g. 8-20). Thi s device uses el ectromagneti c inducti on to i nduce a current i n the ungrounded or
secondary windi ng of the transformer from energy suppl i ed to the pri mary winding. There i s no
di rect el ectri cal connection between the power suppl i ed by the uti l ity company on the primary si de
and the power i nduced by the transformer on the ungrounded or secondary side. Thus, the power
suppli ed to the operati ng room is i sol ated from ground (Fi g. 8-21). Because the 120-vol t potenti al
exists only between

the two wires of the i sol ated circui t, nei ther wire i s hot or neutral wi th reference to ground. In
this case, they are simply referred to as li ne 1 and l ine 2 (Fi g. 8-22). Usi ng the exampl e of the
li ght bulb, if one connects the two wi res of the bul b socket to the two wi res of the isolated power
FIGURE 8-19. Ri ght . A cheater pl ug that converts a three-prong power cord to a two-
prong cord. Lef t . The wire attached to the cheater pl ug i s rarel y connected to the screw i n
the mi ddle of the outl et. Thi s total l y defeats the purpose of the equipment ground wi re.
P.158
system, the li ght wil l i ll umi nate. However, if one connects one of the wi res to one si de of the
isol ated power and the other wire to ground, the l ight wi ll not i ll umi nate. If the wi res of the
isol ated power system are connected, the short circui t wi ll tri p the ci rcui t breaker. In compari ng
the two systems, the standard grounded power has a di rect connecti on to ground, whereas the
isol ated system i mposes a very hi gh i mpedance to any current fl ow to ground. The added safety of
this system can be seen i n Fi gure 8-23. In thi s case, a person has come i n contact wi th one si de
of the isolated power system (poi nt A). Because standi ng on ground (poi nt B) does not constitute
a part of the isolated ci rcuit, the i ndi vi dual does not compl ete the loop and wi l l not receive a
shock. Thi s is because the ground i s part of the pri mary ci rcui t (soli d l i nes), and the person i s
contacting onl y one si de of the i sol ated secondary ci rcui t (cross-hatched l i nes). The person does
not compl ete ei ther ci rcuit (i .e., have two contact poi nts); therefore, thi s situation does not pose
an electri c shock hazard. Of course, if the person contacts both li nes of the isolated power system
(an unl i kel y event), he or she would receive a shock.
FIGURE 8-20. A. Isol ated power panel showi ng ci rcui t breakers, LIM, and isol ati on
transformer (arrow). B. Detai l of an isolation transformer wi th the attached warni ng l i ghts.
The arrow poi nts to ground wire connecti on on the pri mary si de of the transformer. Note that
no si mil ar connection exists on the secondary side of the transformer.
FIGURE 8-21. In the operating room, the i sol ati on transformer converts the grounded power
on the primary si de to an ungrounded power system on the secondary si de of the
transformer. A 120-vol t potenti al di fference exi sts between l i ne 1 and li ne 2. There i s no
di rect connecti on from the power on the secondary si de to ground. The equi pment ground
wire, however, i s sti l l present.
FIGURE 8-22. Detai l of the i nside of a ci rcuit breaker box i n an i sol ated power system. The
bottom arrow poi nts to ground wi res meeti ng at the common ground terminal. Arrows 1 and 2
indicate li nes 1 and 2 from the i sol ated power ci rcuit breaker. Nei ther l i ne 1 nor li ne 2 i s
connected to the same termi nals as the ground wires. Thi s is i n marked contrast to Fi gure 8-
13, where the neutral and ground wires are attached at the same poi nt.
If a faul ty electri cal appli ance wi th an i ntact equipment ground wi re i s pl ugged i nto a standard
household outl et, and the home wi ri ng has a properl y connected ground wi re, then the amount of
el ectrical current that wi ll fl ow through the i ndi vi dual i s consi derably l ess than what wi ll flow
through the low-resistance ground wi re. Here, an i ndi vi dual woul d be fai rl y wel l protected from a
serious shock. However, i f that ground wire were broken, the i ndi vi dual mi ght recei ve a l ethal
shock. No shock woul d occur i f the same faul ty piece of equi pment were pl ugged i nto the i sol ated
power system, even if the equi pment ground wire were broken. Thus, the isolated power system
provi des a si gni fi cant amount of protecti on from macroshock. Another feature of the isol ated
power system is that the faul ty pi ece of equipment, even though i t may be parti al l y short-
ci rcuited, wi l l not usuall y tri p the circui t breaker. Thi s is an important feature because the faul ty
pi ece of equi pment may be part of a l i fe-support system for a pati ent. It i s i mportant to note that
even though the power is isolated from ground, the case or frame of all el ectri cal equipment i s
stil l connected to an equi pment ground. The third wi re (equi pment ground wi re) i s necessary for a
total electri cal safety program.
Fi gure 8-24 il l ustrates a scenari o i nvol vi ng a faul ty piece of equipment connected to the i sol ated
power system. Thi s does not represent a hazard; it merel y converts the i sol ated power back to a
grounded power system as exists outsi de the

operati ng room. In fact, a second fault is necessary to create a hazard.
The previous di scussi on assumes that the isol ated power system i s perfectly i sol ated from ground.
FIGURE 8-23. A safety feature of the i sol ated power system i s i ll ustrated. An i ndividual
contacting one si de of the isol ated power system (poi nt A) and standi ng on the ground (poi nt
B) wil l not receive a shock. In thi s instance, the i ndivi dual i s not contacti ng the ci rcuit at two
poi nts and thus i s not completi ng the ci rcui t. Point A (cross-hatched l i nes) is part of the
i sol ated power system, and poi nt B is part of the primary or grounded si de of the ci rcui t
(soli d l i nes).
P.159
FIGURE 8-24. A faul ty pi ece of equi pment pl ugged i nto the i sol ated power system does not
present a shock hazard. It merel y converts the i sol ated power system into a grounded power
system. The fi gure i nsert i l lustrates that the i sol ated power system is now i denti cal to the
grounded power system. The dashed li ne indi cates current fl ow in the ground wi re.
Actual ly, perfect i sol ati on i s i mpossi bl e to achi eve. All AC-operated power systems and el ectri cal
devices mani fest some degree of capacitance. As previousl y di scussed, el ectrical power cords,
wires, and el ectri cal motors exhibi t capaci tive coupl i ng to the ground wi re and metal condui ts and
leak smal l amounts of current to ground (Fi g. 8-25). Thi s so-call ed leakage current parti al l y
ungrounds the i sol ated power system. Thi s does not usual l y amount to more than a few
mi ll i amperes i n an operati ng room. So an i ndi vi dual comi ng in contact with one side of the isolated
power system woul d recei ve onl y a very smal l shock (1 to 2 mA). Although this amount of current
woul d be percepti bl e, i t woul d not be dangerous.
THE LINE ISOLATION MONITOR
The li ne i sol ati on moni tor (LIM) i s a device that conti nuousl y moni tors the i ntegrity of an
isol ated power system. If a faul ty pi ece of equi pment i s connected to the isolated power
system, this wi l l, in effect, change the system back to a conventional grounded system. Al so, the
faul ty piece of equi pment wi ll continue to function normal l y. Therefore, it i s essenti al that a
warni ng system be in place to al ert the personnel that the power is no longer ungrounded. The
LIM conti nuousl y moni tors the isolated power to ensure that i t is i ndeed isol ated from ground, and
the devi ce has a meter that di splays a conti nuous i ndi cation of the i ntegri ty of the system (Fi g. 8-
26). The LIM i s actuall y measuri ng the i mpedance to ground of each si de of the i sol ated power
system. As previ ousl y discussed, wi th perfect i solati on, i mpedance woul d be infi ni tel y hi gh and
there woul d be no current fl ow i n the event of a fi rst fault si tuati on (Z = E / I; i f I = 0, then Z =
). Because al l AC wi ri ng and al l AC-operated electri cal devi ces have some capaci tance, smal l
leakage currents are present that parti al l y degrade the i sol ati on of the system. The meter of the
LIM wil l i ndi cate (i n mi l li amperes) the total amount of leakage i n the system resul ti ng from
capaci tance, el ectrical wi ri ng, and any devi ces pl ugged i nto the i sol ated power system.
FIGURE 8-25. The capaci tance that exi sts i n AC power l i nes and AC-operated equi pment
resul ts i n smal l leakage currents that parti al l y degrade the i sol ated power system.
The readi ng on the LIM meter does not mean that current i s actual ly fl owing; rather, it i ndi cates
how much current would flow in the event of a first faul t. The LIM i s set to al arm at 2 or 5 mA,
dependi ng on the age and brand of the system. Once this preset l i mi t is exceeded, vi sual and
audi bl e al arms are tri ggered to i ndicate that the i sol ati on from ground has been degraded beyond
a predetermi ned l i mi t (Fi g. 8-27). Thi s does not necessari l y mean that there i s a hazardous
si tuati on, but rather that the system is no longer total l y i sol ated from ground. It would requi re a
second faul t to create a dangerous situation.
FIGURE 8-26. The meter of the l i ne isolation moni tor is cali brated i n mil l iamperes. If the
isol ati on of the power system i s degraded such that >2 mA (5 mA in newer systems) of
current could flow, the hazard li ght wil l i ll umi nate and a warni ng buzzer wi l l sound. Note the
button for testi ng the hazard warni ng system. A. Ol der LIM that wi l l tri gger an al arm at 2
mA. B. Newer l i ne i sol ati on monitor that wi ll trigger an al arm at 5 mA.
FIGURE 8-27. When a faul ty piece of equi pment i s pl ugged i nto the i sol ated power system,
it wi l l markedl y decrease the i mpedance from l i ne 1 or l i ne 2 to ground. Thi s wi l l be detected
by the LIM, whi ch wi l l sound an al arm.
For example, if the LIM were set to al arm at 2 mA, usi ng Ohm' s l aw, the i mpedance for ei ther si de
of the isolated power system woul d be 60,000 ohms:
Z = E/I
Z = (120 volts)/(0.002 ampers)
Z = 60,000 ohms
Therefore, if ei ther si de of the i sol ated power system had less than 60,000 ohms i mpedance to
ground, the LIM woul d tri gger an alarm. This might occur i n two situations. In the fi rst, a faul ty
pi ece of equi pment is pl ugged into the isol ated power system. In thi s case, a true faul t to ground
exists from one l ine to ground. Now the system would be converted to the equi valent of a
grounded power system. Thi s faul ty pi ece of equi pment

shoul d be removed and servi ced as soon as possibl e. However, thi s pi ece of equipment could sti ll
be used safel y i f i t were essenti al for the care of the patient. It shoul d be remembered, however,
that conti nuing to use thi s faulty piece of equi pment woul d create the potential for a serious
el ectrical shock. Thi s woul d occur i f a second faul ty pi ece of equi pment were si mul taneousl y
connected to the isolated power system.
The second si tuati on i nvol ves connecti ng many perfectly normal pieces of equi pment to the
isol ated power system. Al though each pi ece of equi pment has onl y a smal l amount of l eakage
current, i f the total leakage exceeds 2 mA, the LIM wil l tri gger an al arm. Assume that i n the same
operating room there are 30 el ectri cal devi ces, each havi ng 100 A of l eakage current. The total
leakage current (30 100 A) woul d be 3 mA. The i mpedance to ground woul d sti l l be 40,000
ohms (120/0.003). The LIM al arm woul d sound because the 2-mA set poi nt was vi ol ated. However,
the system is sti l l safe and represents a state si gnifi cantly different from that i n the fi rst
si tuati on. For thi s reason, the newer LIMs are set to al arm at 5 mA i nstead of 2 mA.
The newest LIMs are referred to as third-generati on moni tors. The fi rst-generati on moni tor, or
stati c LIM, was unabl e to detect balanced faults (i .e., a si tuati on i n whi ch there are equal faul ts to
ground from both li ne 1 and l ine 2). The second-generati on, or dynamic, LIM di d not have thi s
probl em but coul d i nterfere wi th physi ol ogi c moni tori ng. Both of these moni tors woul d tri gger an
al arm at 2 mA, whi ch l ed to annoying fal se al arms. The thi rd-generati on LIM corrects the
problems of its predecessors and has the al arm threshol d set at 5 mA.
15
Proper functi oni ng of the
LIM i s dependent on havi ng both i ntact equi pment ground wi res as wel l as i ts own connection to
ground. First- and second-generati on LIMs could not detect the loss of the LIM ground connecti on.
The thi rd-generati on LIM can detect thi s l oss of ground to the moni tor. In thi s case the LIM alarm
would sound and the red hazard li ght would i l l umi nate, but the LIM meter woul d read zero. This
condi ti on wi ll al ert the staff that the LIM needs to be repai red. However, the LIM sti ll cannot
detect broken equipment ground wires. An example of the third-generati on LIM is the Iso-Gard
made by the Square D Company (Monroe, NC).

The equi pment ground wi re is agai n an i mportant part of the safety system. If thi s wi re i s broken,
a faulty piece of equi pment that i s pl ugged i nto an outl et woul d operate normal l y, but the LIM
would not al arm. A second faul t coul d therefore cause a shock, wi thout any al arm from the LIM.
Also, i n the event of a second faul t, the equi pment ground wi re provides a l ow-resistance path to
ground for most of the fault current (see Fi g. 8-24). The LIM wi l l only be abl e to regi ster l eakage
currents from pieces of equi pment that are connected to the i sol ated power system and have
intact ground wi res.
If the l ine i solation moni tor al arm i s triggered, the fi rst thi ng to do i s to check the gauge to
determi ne i f i t i s a true faul t. The other possibi l ity is that too many pieces of electri cal equi pment
have been pl ugged i n and the 2-mA l i mi t has been exceeded. If the gauge i s between 2 and 5 mA,
it i s probabl e that too much el ectri cal equipment has been pl ugged i n. If the gauge reads >5 mA,
most l ikely there i s a faul ty pi ece of equi pment present i n the operati ng room. The next step i s to
P.160
P.161
P.162
identi fy the faul ty equi pment, whi ch is done by unpl uggi ng each pi ece of equi pment unti l the
al arm ceases. If the faul ty piece of equipment i s not of a l i fe-support nature, i t shoul d be removed
from the operati ng room. If i t is a vital pi ece of l i fe-support equi pment, i t can be safel y used.
However, it must be remembered that the protecti on of the i sol ated power system and the li ne
isol ati on monitor i s no l onger operati ve. Therefore, if possi ble, no other el ectri cal equipment
shoul d be connected during the remai nder of the case, or unti l the faulty pi ece of equi pment can
be safel y removed.
GROUND FAULT CIRCUIT INTERRUPTER
The ground fault ci rcui t interrupter (GFCI, or occasi onal l y abbrevi ated to GFI) i s another
popul ar devi ce used to prevent indi vi duals from recei vi ng an electri cal shock i n a grounded
power system. El ectrical codes for most new construction require that a GFCI ci rcui t be present i n
potential ly hazardous (e.g., wet) areas such as bathrooms, kitchens, or outdoor electri cal outlets.
The GFCI may be i nstal l ed as an i ndi vi dual power outl et (Fi g. 8-28) or may be a special ci rcuit
breaker to whi ch al l the i ndi vi dual protected outl ets are connected at a si ngl e poi nt. The speci al
GFCI ci rcui t breaker i s l ocated i n the mai n fuse/ci rcui t breaker box and can be di sti ngui shed by i ts
red test button (Fi g. 8-29). As Fi gure 8-5 demonstrates, the current fl owi ng i n both the hot and
neutral wi res i s usual ly equal . The GFCI monitors both sides of the ci rcuit for the equal ity of
current fl ow; if a difference i s detected, the power is i mmediately i nterrupted. If an i ndi vi dual
should contact a faul ty pi ece of equi pment such that current fl owed through the i ndi vi dual , an
i mbal ance between the two si des of the ci rcui t woul d be created, whi ch would be detected by the
GFCI. Because the GFCI can detect very smal l current di fferences (i n the range of 5 mA), the GFCI
wil l open the ci rcui t i n a few mi l li seconds, thereby interrupting the current flow before a
si gni fi cant shock occurs. Thus, the GFCI provi des a hi gh l evel of protecti on at a very modest cost.
FIGURE 8-28. A GFCI electri cal outl et wi th i ntegrated test and reset buttons.
The di sadvantage of usi ng a GFCI i n the operating room i s that it interrupts the power wi thout
warni ng. A defecti ve piece of equi pment coul d no longer be used, whi ch might be a probl em i f i t
were of a l i fe-support nature, whereas i f the same faul ty piece of equipment were plugged i nto an
isol ated power system, the LIM would al arm, but the equipment coul d sti l l be used.
MICROSHOCK
As previ ously discussed, macroshock involves rel ati vel y l arge amounts of current appl i ed to
the surface of the body. The current i s conducted through al l the tissues i n proporti on to
thei r conducti vi ty and area i n a pl ane perpendi cul ar to the current. Consequentl y, the densi ty of
the current (amperes per meter squared) that reaches the heart i s consi derabl y less than what is
appl i ed to the body surface. However, an el ectri cal l y susceptibl e pati ent (i .e., one who has a
di rect, external connection to the heart, such as through a CVP catheter or transvenous cardi ac
paci ng wi res) may be at ri sk from very smal l currents; thi s i s call ed mi croshock.
16
The catheter
orifice or el ectrical wi re with a very smal l surface area i n contact wi th the heart produces a
rel ati vely l arge current densi ty at the heart.
17
Stated another way, even very smal l amounts of
current appl i ed di rectl y to the myocardi um wi l l cause ventri cul ar fi bri l l ation. Microshock i s a
parti cul arl y di ffi cul t problem because of the insidi ous nature of the hazard.
In the el ectri cal l y suscepti bl e pati ent, ventricular fi bri ll ati on can be produced by a current that is
bel ow the threshold of human perception. The exact amount of current necessary to cause
ventri cul ar fi bril l ati on i n thi s type of pati ent i s unknown. Whalen et al
18
were abl e to produce
fibri ll ati on with 20 A of current appl i ed directl y to the myocardi um of dogs. Raftery

et al
19
produced fi bri l l ati on wi th 80 A of current i n some pati ents. Hul l
20
used data obtai ned by
Watson et al
21
to show that 50% of pati ents woul d fi bri l late at currents of 200 A. Because 1,000
A (1 mA) i s general ly regarded as the threshol d of human percepti on with 60-Hz AC, the
el ectricall y susceptibl e pati ent can be electrocuted with one-tenth the normall y percepti ble
currents. Thi s is not onl y of academi c interest but al so of practi cal concern because many cases of
ventri cul ar fi bri l l ati on from mi croshock have been reported.
22, 23, 24, 25, 26, 27

The stray capacitance that i s part of any AC-powered electri cal instrument may resul t in
si gni fi cant amounts of charge bui l dup on the case of the i nstrument. If an individual
si multaneously touches the case of an instrument where thi s has occurred and the electri cal ly
suscepti bl e pati ent, he or she may unknowi ngly cause a di scharge to the pati ent that resul ts i n
ventri cul ar fi bril l ati on. Once agai n, the equi pment ground wi re consti tutes the major source of
FIGURE 8-29. Speci al GFCI ci rcui t breaker. The arrowhead poi nts to the di sti ngui shi ng red
test button.
P.163
protecti on against microshock for the electri cal l y suscepti ble pati ent. In thi s case, the equipment
ground wi re provides a l ow-resistance path by whi ch most of the l eakage current is di ssi pated
instead of stored as a charge.
Fi gure 8-30 il l ustrates a situation involving a pati ent wi th a sal i ne-fil l ed catheter i n the heart with
a resi stance of ~500 ohms. The ground wi re wi th a resi stance of 1 ohm is connected to the
instrument case. A l eakage current of 100 A wi ll di vi de according to the rel ati ve resi stances of
the two paths. In this case, 99.8 A wi ll flow through the equi pment ground wi re, and onl y 0.2 A
wil l fl ow through the fl ui d-fil l ed catheter. Thi s extremel y smal l current does not endanger the
patient. If, however, the equi pment ground wi re were broken, the el ectricall y suscepti bl e pati ent
would be at great risk because all 100 A of l eakage current coul d flow through the catheter and
cause ventri cular fi bri l lation (Fi g. 8-31).
FIGURE 8-30. The el ectricall y susceptibl e pati ent i s protected from microshock by the
presence of an intact equi pment ground wire. The equi pment ground wi re provides a low-
i mpedance path i n whi ch the majori ty of the l eakage current (dashed l i nes) can fl ow.
FIGURE 8-31. A broken equi pment ground wi re resul ts i n a si gni fi cant hazard to the
el ectricall y susceptibl e pati ent. In thi s case, the enti re l eakage current can be conducted to
the heart and may result i n ventri cul ar fi bri l lation.
Modern pati ent monitors i ncorporate another mechani sm to reduce the ri sk of microshock for
el ectricall y susceptibl e pati ents. Thi s mechanism involves el ectri call y isolating all di rect pati ent
connecti ons from the power suppl y of the monitor by pl aci ng a very hi gh i mpedance between the
patient and any device. This l i mi ts the amount of i nternal l eakage through the pati ent connecti on
to a very small val ue. Currentl y the standard is <10 A. For instance, the output of an ECG
moni tor' s power supply i s el ectri call y isolated from the pati ent by pl aci ng a very hi gh i mpedance
between the moni tor and the pati ent's ECG l eads.
6, 28
Isolation techniques are desi gned to i nhi bi t
hazardous el ectri cal pathways between the patient and the moni tor whi le allowi ng the passage of
the physi ol ogi c si gnal .
An i ntact equipment ground wi re i s probabl y the most i mportant factor i n preventi ng mi croshock.
There are, however, other thi ngs that the anesthesi ol ogi st can do to reduce the i ncidence of
mi croshock. One should never si mul taneousl y touch an el ectrical devi ce and a sal ine-fil l ed central
catheter or external pacing wi res. Whenever one i s handl ing a central catheter or paci ng wi res, i t
is best to i nsul ate oneself by weari ng rubber gl oves. Al so, one shoul d never l et any external
current source, such as a nerve stimul ator, come i nto contact with the catheter or wi res. Fi nall y,
one should be al ert to potenti al sources of energy that can be transmi tted to the patient. Even
stray

radiofrequency current from the electrosurgi cal uni t (cautery) can, with the ri ght condi ti ons, be a
source of mi croshock.
29

It must be remembered that the LIM i s not designed to provi de protection from mi croshock. The
mi croampere currents i nvol ved i n mi croshock are far bel ow the LIM threshol d of protecti on. In
addi ti on, the LIM does not regi ster the l eakage of i ndi vi dual monitors, but rather i ndi cates the
status of the total system. The LIM reading i ndi cates the total amount of leakage current resul ting
from the entire capacitance of the system. Thi s i s the amount of current that woul d fl ow to ground
in the event of a first-faul t si tuati on.
The essence of el ectrical safety i s a thorough understandi ng of al l the pri nci pl es of groundi ng.
Accordi ng to Bruner, Groundi ng is neither safe nor unsafe. Its si gni fi cance is dependent on what
i s grounded and i n what context.
9
The objecti ve of el ectrical safety i s to make i t di ffi cul t for
el ectrical current to pass through peopl e. For this reason, both the pati ent and the
anesthesiol ogi st should be isolated from ground as much as possi ble. That i s, thei r resistance to
current flow should be as high as i s technologicall y feasi ble. In the i nherentl y unsafe el ectri cal
envi ronment of an operati ng room, several measures can be taken to hel p protect against
contacting hazardous current fl ows. First, the grounded power provided by the uti li ty company can
be converted to ungrounded power by means of an i sol ation transformer. The LIM wi ll continuously
moni tor the status of thi s isol ati on from ground and warn that the i sol ati on of the power (from
ground) has been lost in the event that a defecti ve pi ece of equi pment i s pl ugged i nto one of the
isol ated ci rcui t outlets. In addi ti on, the shock that an i ndi vi dual coul d receive from a faulty piece
of equi pment i s determi ned by the capacitance of the system and i s li mi ted to a few mi l li amperes.
Second, al l equi pment pl ugged i nto the i sol ated power system has an equi pment ground wire that
is attached to the case of the i nstrument. This equipment ground wi re provi des an alternati ve low-
resi stance pathway enabl i ng potential ly dangerous currents to fl ow to ground. Thus, the pati ent
and the anesthesi ologist shoul d be as insul ated from ground as possi bl e and al l el ectrical
equi pment shoul d be grounded.
The equi pment ground wi re serves three functions. Fi rst, i t provi des a l ow-resistance path for faul t
currents to reduce the ri sk of macroshock. Second, it di ssi pates l eakage currents that are
potential ly harmful to the el ectricall y susceptibl e pati ent. Third, i t provi des informati on to the LIM
on the status of the ungrounded power system. If the equi pment ground wi re i s broken, a
si gni fi cant factor i n the preventi on of el ectrical shock i s l ost. Additi onal l y, the isolated power
system wil l appear safer than i t actual ly i s, because the LIM i s unabl e to detect broken equi pment
ground wi res.
Because power cord plugs and receptacl es are subjected to greater abuse in the hospi tal than i n
the home, the Underwriters Laboratori es (Mel vi l le, NY) has i ssued a strict speci fi cation for speci al
P.164
hospi tal -grade pl ugs and receptacl es (Fi g. 8-32). The pl ugs and receptacl es that conform to thi s
specificati on are marked by a green dot.
30
The hospi tal -grade plug i s one that can be vi sual l y
inspected or easi ly di sassembled to ensure the i ntegri ty of the ground wi re connection. Mol ded
opaque pl ugs are not acceptabl e. Edwards reported that of 3,000 nonhospi tal -grade receptacles
install ed i n a new hospi tal bui l di ng, 1,800 (60%) were defecti ve after 3 years.
31
When 2,000 of
the nonhospi tal -grade receptacles were repl aced with ones of hospi tal grade, no fai l ures had
occurred after 18 months of use.
ELECTROSURGERY
On that fateful October day in 1926 when Dr. Harvey W. Cushi ng fi rst used an el ectrosurgi cal
machine i nvented by Professor Wil l iam T. Bovi e to resect a brai n tumor, the course of modern
surgery and anesthesia was forever al tered.
32
The ubiqui tous use of el ectrosurgery attests to the
success of Professor Bovie' s i nventi on. However, this technology was not adopted without a cost.
The wi despread use of el ectrocautery has, at the very l east, hastened the eli minati on of expl osi ve
anesthetic agents from the operati ng room. In additi on, as every anesthesi ol ogi st is aware, few
things in the operati ng room are i mmune to i nterference from the Bovie. The hi gh-frequency
el ectri cal energy generated by the electrosurgery uni t (ESU) interferes with everything from the
ECG si gnal to cardi ac output computers, pul se oximeters, and even implanted cardi ac
pacemakers.
33

The ESU operates by generating veryhi gh-frequency currents (radiofrequency range) of anywhere
from 500,000 to 1 mi l li on Hz. Heat is generated whenever a current passes through a resi stance.
The amount of heat (H) produced is proporti onal to the square of the current and i nversel y
proporti onal to the area through whi ch the current passes (H = I
2
/A).
34
By concentrating the
energy at the ti p of the Bovie pencil , the surgeon can produce either a cut or a coagul ati on at
any given spot. This very high frequency current behaves differentl y from the standard 60-Hz AC
current and can pass di rectl y across the precordi um wi thout causi ng ventri cul ar fi bril l ati on.
34
Thi s
i s because hi gh-frequency currents have a low ti ssue penetration and do not exci te contracti l e
cel ls.
The l arge amount of energy generated by the ESU can pose other probl ems to the operator and
FIGURE 8-32. A. A hospi tal -grade pl ug that can be vi suall y i nspected. The arrow poi nts to
the equi pment ground wi re whose i ntegri ty can be readi l y veri fi ed. B. A hospi tal -grade pl ug
that can be easi ly di sassembl ed for i nspecti on. Note that the prong for the ground wi re
(arrow) i s l onger than the hot or neutral prong, so that it i s the fi rst to enter the receptacl e.
C. The arrow poi nts to the green dot denoting a hospital -grade power outl et.
P.165
the pati ent. Dr. Cushi ng became aware of one such probl em. He wrote, Once the operator
recei ved a shock whi ch passed through a metal retractor to hi s arm and out by a wi re from hi s
headl i ght, whi ch was unpleasant to say the l east.
35
The ESU cannot be safel y operated unless the
energy is properl y routed from the ESU through the pati ent and back to the unit. Ideal l y, the
current generated by the active electrode is concentrated at the ESU ti p consti tuti ng a very smal l
surface area. Thi s energy has a hi gh current densi ty and i s abl e to generate enough heat to
produce a therapeutic cut or coagul ati on. The energy then passes through the pati ent to a
di spersi ve el ectrode of l arge surface area that returns the energy safel y to the ESU (Fi g. 8-33).
One unfortunate qui rk i n termi nology concerns the return (di spersi ve) plate of the ESU. Thi s pl ate,
often incorrectl y referred to as a ground pl ate, i s actual l y a di spersive electrode of large surface
area that safel y returns the generated energy to the ESU via a l ow current densi ty pathway. When
i nqui ri ng whether the di spersive electrode has been attached to the pati ent, operati ng room
personnel frequentl y ask, Is the pati ent grounded? Because the ai m of el ectri cal safety i s to
isol ate the pati ent from ground, thi s expressi on is worse than erroneous; i t can l ead to confusi on.
Because the area of the return plate i s l arge, the current density is low; therefore, no harmful
heat i s generated and no ti ssue destructi on occurs. In a properl y functi oni ng system, the onl y
tissue effect is at the site of the active electrode that i s hel d by the surgeon.
Problems can arise i f the el ectrosurgi cal return plate i s i mproperl y appl i ed to the pati ent or i f
the cord connecti ng the return plate to the ESU i s damaged or broken. In these i nstances,
the hi gh-frequency current generated by the ESU wi l l seek an alternate return pathway. Anythi ng
attached to the pati ent, such as ECG l eads or a temperature probe, can provide thi s al ternate
return pathway. The current densi ty at the ECG pad wi l l be consi derabl y hi gher than normal
because i ts surface area i s much l ess than that of the ESU return plate. Thi s may resul t in a
serious burn at thi s alternate return si te. Simi larl y, a burn may occur at the si te of the ESU return
pl ate if it i s not properl y appl i ed to the pati ent or i f i t becomes parti al l y di sl odged duri ng the
operation (Fi g. 8-34). Thi s is not merely a theoreti cal possi bil i ty but i s evi denced by the numerous
case reports involving pati ents who have received ESU burns.
36, 37, 38, 39, 40, 41

FIGURE 8-33. A properl y appl i ed ESU return pl ate. The current density at the return pl ate i s
low, resul ti ng in no danger to the patient.
The original ESUs were manufactured with the power suppl y connected di rectl y to ground by the
equi pment ground wi re. These devi ces made i t extremely easy for ESU current to return by
al ternate pathways. The ESU woul d continue to operate normall y even without the return pl ate
connected to the pati ent. In most modern ESUs, the power suppl y i s i sol ated from

ground to protect the patient from burns. It was hoped that by i solating the return pathway from
ground, the onl y route for current fl ow would be vi a the return el ectrode. Theoreti cal l y, thi s woul d
el i mi nate al ternate return pathways and greatl y reduce the i nci dence of burns.
5
However, Mitchell
found two si tuati ons in whi ch the current coul d return vi a al ternate pathways, even wi th the
isol ated ESU ci rcuit.
42
If the return pl ate were left either on top of an uni nsul ated ESU cabi net or
in contact with the bottom of the operati ng room tabl e, then the ESU coul d operate fairly normall y
and the current woul d return vi a al ternate pathways. It wi l l be recall ed that the i mpedance is
inversel y proporti onal to the capaci tance ti mes the current frequency. The ESU operates at
500,000 to >1,000,000 Hz, whi ch greatl y enhances the effect of capaci tive coupl i ng and causes a
marked reduction in i mpedance. Therefore, even wi th i sol ated ESUs, the decrease i n impedance
al lows the current to return to the ESU by al ternate pathways. In additi on, the i sol ated ESU does
not protect the pati ent from burns i f the return electrode does not make proper contact wi th the
patient. Although the i sol ated ESU does provi de addi ti onal pati ent safety, i t i s by no means
fool proof protection against the pati ent receiving a burn.
Preventi ng patient burns from the ESU i s the responsi bil i ty of al l professi onal staff i n the
operating room. Not only the ci rcul ati ng nurse, but al so the surgeon and the anesthesi ologist must
be aware of proper techniques and be vi gi l ant to potenti al probl ems. The most important factor is
the proper appl i cati on of the return plate. It i s essenti al that the return pl ate have the appropri ate
amount of el ectrol yte gel and an i ntact return wi re. Reusabl e return plates must be properl y
cl eaned after each use, and disposabl e pl ates must be checked to ensure that the el ectrol yte has
not dri ed out duri ng storage. In addi tion, it i s prudent to pl ace the return plate as cl ose as
possi bl e to the si te of the operati on. ECG pads should be placed as far from the site of the
operation as i s feasi bl e. Operati ng room personnel must be al ert to the possibi l ity that pool s of
flammabl e prep solutions such as ether and acetone can igni te when the ESU i s used. If the ESU
must be used on a pati ent wi th a demand pacemaker, the return el ectrode shoul d be l ocated bel ow
the thorax, and preparations for treati ng potential dysrhythmias shoul d be avai l abl e, i ncl udi ng a
magnet to convert the pacemaker to a fi xed rate, a defi bri l l ator, and an external pacemaker. The
ESU has al so caused other probl ems i n patients with pacemakers, incl udi ng reprogrammi ng and
microshock.
43, 44
If the surgeon requests hi gher than normal power setti ngs on the ESU, thi s
FIGURE 8-34. An improperl y appl ied ESU return pl ate. Poor contact wi th the return pl ate
resul ts i n a hi gh current densi ty and a possi bl e burn to the pati ent.
P.166
should al ert both the ci rcul ati ng nurse and the anesthesiol ogi st to a potenti al probl em. The return
pl ate and cabl e must be i mmedi ately i nspected to ensure that i t i s functi oni ng and properl y
positi oned. If thi s does not correct the probl em, the return plate shoul d be repl aced. If the
problem remai ns, the entire ESU shoul d be taken out of servi ce. Final l y, an ESU that i s dropped or
damaged must be removed i mmedi atel y from the operating room and thoroughl y tested by a
quali fi ed bi omedi cal engineer. Foll owi ng these si mpl e safety steps wil l prevent most patient burns
from the ESU.
The previ ous di scussi on concerned onl y uni polar ESUs. There i s a second type of ESU, in which the
current passes only between the two bl ades of a pair of forceps. Thi s type of devi ce i s referred to
as a bi polar ESU. Because the active and return electrodes are the two blades of the forceps, i t is
not necessary to attach another di spersive electrode to the patient, unless a unipol ar ESU i s al so
bei ng used. The bipol ar ESU generates consi derably l ess power than the unipol ar and i s mai nl y
used for ophthal mi c and neurol ogi c surgery.
2

In 1980 Mirowski et al
45
reported the fi rst human implantati on of a devi ce to treat i ntractable
ventri cul ar tachyarrhythmi as. Thi s devi ce, known as the automati c impl antabl e cardioverter-
defibri ll ator (AICD), i s capabl e of sensing ventricul ar tachycardi a (VT) and ventri cul ar fi bri l l ation
(VF) and then automaticall y defibri ll ati ng the pati ent. Si nce 1980 thousands of pati ents have
recei ved AICD i mpl ants.
46, 47
Because some of these pati ents may now present for noncardi ac
surgery, i t is i mportant that the anesthesi ol ogist be aware of potenti al probl ems.
48
The use of a
uni polar ESU may cause electri cal i nterference that coul d be i nterpreted by the AICD as a
ventri cul ar tachyarrhythmia. Thi s would tri gger a defi bri l l ati on pul se to be del i vered to the pati ent
and woul d l i kel y cause an actual epi sode of VT or VF. The patient with an AICD is al so at ri sk for
VF during electroconvul sive therapy.
48
In both cases, the AICD shoul d be di sabl ed by pl aci ng a
magnet over the device. Al though most AICDs can be di sabled with a magnet, some require a
special devi ce or speci fi c magnet to shut them off. Therefore, i t is best to consul t wi th someone
experi enced wi th the devi ce before starti ng surgery. The device can be reactivated by reversi ng
the process. Al so, an external defi bri l lator and a noninvasi ve pacemaker should be in the
operating room whenever a pati ent with an AICD i s anestheti zed.
El ectri cal safety i n the operati ng room i s a matter of combining common sense wi th some basi c
pri nci pl es of el ectri city. Once operati ng room personnel understand the i mportance of safe
el ectrical practi ce, they are abl e to devel op a hei ghtened awareness to potenti al probl ems. Al l
el ectrical equi pment must undergo routi ne mai ntenance, servi ce, and inspection to ensure that i t
conforms to desi gnated el ectrical safety standards. Records of these test resul ts must be kept for
future i nspecti on because human error can easi l y compound el ectri cal hazards. Starmer et al
49

ci ted one case concerni ng a newl y constructed laboratory where the ground wi re was not attached
to a receptacle. In another study Albi sser et al
50
found a 14% (198/1,424) i nci dence of improperl y
or incorrectl y wi red outl ets. Furthermore, potenti all y hazardous situations shoul d be recogni zed
and corrected before they become a probl em. For i nstance, electri cal power cords are frequently
pl aced on the fl oor where they can be crushed by various carts or the anesthesi a machi ne. These
cords coul d be l ocated overhead or placed in an area of l ow traffi c fl ow. Multi ple-pl ug extension
boxes shoul d not be l eft on the fl oor where they can come i n contact with electrolyte sol utions.
These coul d easi l y be mounted on a cart or the anesthesia machi ne. Pieces of equi pment that have
been damaged or have obvi ous defects i n the power cord must not be used unti l they have been
properl y repai red. If everyone i s aware of what consti tutes a potenti al hazard, dangerous
si tuati ons can be prevented with minimal effort.
Sparks generated by the ESU may provide the igni ti on source for a fi re with resul ting burns to the
patient and operati ng room personnel . This i s a particul ar ri sk when the ESU i s used i n an oxygen-
enri ched envi ronment as may be present i n the pati ent's ai rway or i n cl ose proxi mity to the
patient' s face. Most plasti cs such as tracheal tubes and components of the anestheti c breathi ng
system that woul d not burn in room ai r wi ll i gni te in the presence of oxygen and/or ni trous oxi de.
Tenti ng of the drapes to al low dispersi on of any accumul ated oxygen and/or i ts di lution by room
ai r or use of a ci rcle anesthesia breathi ng system wi th mi ni mal to no l eak of gases around the
anesthesia mask wi ll decrease the ri sk of i gniti on from a spark generated by a nearby ESU.
CONDUCTIVE FLOORING
Conducti ve fl oori ng was mandated for operati ng rooms where fl ammable anesthetic agents were
bei ng admini stered. The conducti ve fl oor was speci fi ed to have a resistance of between 25,000
and 1 mi l li on ohms. Thi s woul d mi ni mi ze the bui l dup of stati c charges that coul d cause a
flammabl e anesthetic agent to i gni te. The standards have been changed to el i mi nate the necessi ty
for conducti ve floori ng i n anestheti zi ng areas where fl ammabl e agents are no l onger used.

ENVIRONMENTAL HAZARDS
There are a number of potential el ectri cal l y related hazards i n the operati ng room that are of
concern to the anesthesi ol ogi st. There is the potenti al for electri cal shock not only to the pati ent
but al so to operati ng room personnel. In addi tion, cabl es and power cords to el ectri cal equi pment
and moni toring devi ces can become hazardous. Fi nal ly, all operati ng room personnel shoul d have a
pl an of what to do i n the event of a power fai l ure.
In today' s operati ng room, there are li terall y dozens of pieces of electri cal equi pment. It i s not
uncommon to have numerous power cords lying on the fl oor, where they are vulnerabl e to
damage. If the insul ati on on the power cabl e becomes damaged, i t i s fai rl y easy for the hot wi re
to come in contact wi th a pi ece of metal equi pment. If the operati ng room di d not have i sol ated
power, that pi ece of equi pment woul d become energi zed and a potenti al el ectri cal shock hazard.
51

Having i sol ated power mi ni mi zes the risk to the pati ent and operati ng room personnel . Cl earl y,
getting electri cal power cords off the floor is desirable. This can be accompli shed by havi ng
el ectrical outl ets i n the ceil i ng or by having ceil i ng-mounted articul ated arms that contai n
el ectrical outl ets. Also, the use of mul tioutl et extension boxes that si t on the floor can be
hazardous. These can be contami nated with fluids, which coul d easil y trip the ci rcuit breaker. In
one case, i t apparentl y tri pped the mai n ci rcui t breaker for the enti re operati ng room, resulti ng i n
a l oss of al l el ectri cal power except for the overhead li ghts.
52

Modern moni tori ng devi ces have many safety features i ncorporated into them. Vi rtual ly all of them
have i sol ated the pati ent i nput from the power suppl y of the devi ce. This was an i mportant feature
that was l acki ng from the ori ginal ECG moni tors. In the earl y days, patients coul d actual ly become
part of the el ectri cal circui t of the monitor. There have been relativel y few probl ems wi th pati ents
and moni toring devi ces si nce the advent of i sol ated i nputs. However, between 1985 and 1994, the
Food and Drug Admini stration (FDA) recei ved approximatel y 24 reports where infants and chi ldren
had received an el ectri cal shock incl uding fi ve chi l dren who di ed by el ectrocuti on.
53, 54
These
el ectrical accidents occurred because the el ectrode l ead wi res from ei ther an ECG moni tor or an
apnea moni tor were pl ugged di rectl y i nto a 120-vol t electri cal outlet i nstead of the appropriate
patient cabl e. In 1997, the FDA issued a new performance standard for el ectrode l ead wi res and
patient cabl es that requi res that the exposed mal e connector pi ns from the el ectrode l ead wi res
must be el iminated. Therefore, the l ead wires must have female connections and the connector
pi ns must be housed i n a protected pati ent cabl e (Fi g. 8-35). Thi s effecti vel y el imi nates the
possi bi li ty of the pati ent being connected directl y to an alternati ng current source si nce there are
no exposed connector pi ns on the l ead wi res.
P.167
All heal th care facil i ti es are requi red to have a source of emergency power. Thi s general ly consi sts
of one or more electri cal generators. These generators are confi gured to start up automati cal l y
and provi de power to the faci l i ty wi thin a few seconds after detecti ng the l oss of power from the
util i ty company. The faci l ity i s requi red to test these generators on a regular basi s. However, not
al l health care faci l iti es test them under actual load. There are numerous anecdotal reports of
generators not functi oning properl y duri ng an actual power fai l ure. If the generators are not
tested under actual load, i t is possi ble that many years wi l l pass before a real power outage puts a
severe demand on the generator. If the faci l i ty has several generators and one of them fai l s, the
i ncreased demand on the others may be enough to cause them to fail i n rapid successi on.
Other situations may al so cause unexpected power outages. In our faci l ity, a construction crew
was remodeli ng an exi sti ng operating room. They accidental ly caused a short ci rcui t i n the power
supply when they were working on an el ectrical panel . Thi s caused the GFI in the basement to
trip, thus shutting off power to a whol e secti on of the operating room. Consequently, several
operati ng rooms were suddenl y wi thout power at cruci al junctures i n surgery. The operati ng room
personnel were waiti ng for the emergency generators to come on. Obvi ously, thi s was not goi ng to
happen because there was no i nterruption of power from the electrical util i ty. It took
approxi mately 20 to 30 mi nutes until the source of the probl em coul d be i dentified and corrected.
It i s vi tal ly i mportant that each operati ng room have a contingency plan for a power fail ure. In
most cases, the emergency generator wi ll take over, but that is not always goi ng to happen. There
shoul d be a suppl y of battery-operated l i ght sources avai l able in each operati ng room. A
laryngoscope can serve as a readil y avai l abl e source of l ight that al lows one to fi nd fl ashl i ghts and
other pieces of equi pment. The operati ng room' s overhead l ights shoul d al so be connected to some
sort of battery-operated l ighti ng system. A suppl y of battery-operated moni toring devi ces and
pneumati cal ly powered venti lators and anesthesi a machi nes woul d enabl e l ife-support functi ons to
conti nue. The cost of these conti ngenci es is relatively small but the benefi ts can be i ncomparabl y
great i n an emergency.
ELECTROMAGNETIC INTERFERENCE (EMI)
Rapi d advances i n technol ogy have led to an expl osi on i n the number of wi rel ess communi cati on
devices i n the marketplace. These devi ces i ncl ude cel l ul ar telephones, cordl ess tel ephones, wal ki e-
talkies, and even wireless Internet access devices. Al l of these devices have somethi ng i n
common: they emi t EMI. Thi s most commonly mani fests i tsel f when traveli ng on airpl anes. Most
ai rl i nes requi re that these devices be turned off when the pl ane i s taki ng off or l andi ng or, in
FIGURE 8-35. The current standard for patient lead wi res (left) requi res a femal e connector.
The pati ent cabl e (ri ght) has shi el ded connector pi ns that the lead wi res pl ug into.
some cases, duri ng the entire fl i ght. There i s concern that the EMI emitted by these devi ces may
interfere with the pl ane's navigation and communicati on equipment.
In recent years, the number of peopl e who own these devi ces has increased exponentiall y. Indeed,
in some hospi tal s, they form a vital li nk i n the regul ar or emergency communicati on system. It is
not uncommon for physi cians, nurses, paramedi cs, and other personnel to have their own cel l ul ar
tel ephones. In addi ti on, pati ents and visi tors may also have cell ular tel ephones and other types of
communi cati on devi ces. Hospi tal mai ntenance and securi ty personnel frequentl y have walkie-
talkietype radios and some hospitals have even insti tuted an i n-house cel l ul ar telephone network
that augments or repl aces the pagi ng system. There has been concern that the

EMI emi tted by these devices may i nterfere wi th i mpl anted pacemakers or vari ous types of
moni tori ng devi ces i n criti cal care areas.
Several studi es have been done to find out i f cell ular tel ephones cause probl ems with cardi ac
pacemakers. One study by Hayes et al looked at 980 patients with five di fferent types of cel l ul ar
tel ephones.
55
They conducted more than 5,000 tests and found that i n more than 20% of the
cases they coul d detect some i nterference from the cel l ul ar telephone. Pati ents were symptomati c
in 7.2% of the cases, and cl i ni cal l y si gni fi cant i nterference occurred in 6.6% of the cases. When
the tel ephone was held i n the normal posi ti on over the ear, cl inicall y si gni fi cant interference was
not detected. In fact, the i nterference that caused cl i ni cal symptoms occurred onl y i f the
tel ephone was di rectl y over the pacemaker. Other studi es have demonstrated changes such as
erroneous sensi ng and pacer i nhi bi ti on.
56, 57
Agai n, these occurred onl y when the telephone was
cl ose to the pacemaker. The changes were temporary, and the pacemaker reverted to normal
when the cell ul ar tel ephone was moved to a safe di stance. Currentl y, the FDA guidel ines are that
the cel l ul ar telephones be kept at l east 6 i nches from the pacemaker. Therefore, the cel l ul ar
tel ephone shoul d not be carried i n the shi rt pocket, whi ch i s adjacent to the pacemaker.
Automati c i mplantable cardi overter-defibri ll ators compri se another group of devices of concern to
bi omedi cal engi neers. Fetter et al conducted a study of 41 pati ents who had AICDs.
58
They had a
0% i nci dence of oversensi ng and concl uded that the cel lular tel ephones di d not interfere wi th the
AICDs that they tested. They di d, however, recommend keeping the cell ul ar tel ephone at least 6
inches from the devi ce.
El ectromagneti c i nterference extends well beyond that of cel lular tel ephones. Walkie-talkies,
whi ch are frequently used by hospi tal mai ntenance and securi ty personnel; paging systems; poli ce
radios; and even tel evi si ons al l emi t EMI, which coul d potenti all y interfere wi th medi cal devi ces of
any nature. Al though there are many anecdotal reports, the amount of avai labl e sci entific
information on thi s problem i s scanty. Reports of interference incl ude venti lator and i nfusion
pumps that have been shut down or reprogrammed, interference wi th ECG moni tors, and even an
el ectronic wheel chai r that was accidental ly started because of EMI. It i s a di ffi cul t problem to
study because there are many different types of devi ces that emit EMI and a vast array of medi cal
equipment that has the potenti al to interact wi th these devi ces. Even though a devi ce may seem
safe in the medi cal envi ronment, i f two or three cel l ul ar telephones or walkie-talkies are brought
together i n the same area at the same ti me, there may be unanticipated probl ems or i nterference.
Any ti me a cel lular tel ephone i s turned on, it i s actuall y communicati ng wi th the cell ular network,
even though a cal l i s not i n progress. Therefore, the potenti al to i nterfere wi th devices exi sts. The
Emergency Care Research Insti tute (ECRI) reported i n October 1999 that wal ki e-talkies were far
more l i kely to cause probl ems wi th medical devices than cell ular tel ephones.
59
Thi s i s because
they operate on a lower frequency than cell ul ar tel ephones and have a higher power output. The
ECRI recommends that cell ular tel ephones be mai ntained at a di stance of 1 meter from medi cal
devices, whil e wal ki e-talkies be kept at a distance of 6 to 8 meters.
Some hospi tal s have made restrictive pol i cies on the use of cel l ul ar telephones, parti cul arl y i n
criti cal care areas.
60
These pol i ci es are supported by li ttl e scienti fi c documentati on and are nearl y
impossibl e to enforce. The ubi qui tous presence of cel l ul ar telephones carri ed by hospi tal personnel
and vi si tors makes enforci ng a ban vi rtual l y i mpossi bl e. Even when people try to compl y wi th the
ban, fail ure is nearl y i nevi tabl e because the general publ i c is usuall y unaware that a cel l ul ar
P.168
tel ephone i n the standby mode is stil l communi cating wi th the tower and generating EMI.
The real sol uti on i s to harden devices agai nst electromagnetic interference. Thi s i s di fficul t to do
because of the many di fferent frequenci es on which these devices operate. Educati on of medi cal
personnel i s essential . When worki ng in an operating room or cri ti cal care area, all personnel must
be al ert to the fact that el ectroni c devi ces and pacemakers can be interfered with by EMI. Creating
a restrictive pol i cy woul d certai nly irritate personnel and vi si tors, and, i n some cases, may
actual l y compromise emergency communicati ons.
61

CONSTRUCTION OF NEW OPERATING ROOMS
Frequentl y, an anesthesi ol ogi st is asked to consul t wi th hospital admini strators and archi tects in
desi gni ng new, or remodel i ng ol der, operati ng rooms. In the past a stri ct el ectri cal code was
enforced because of the use of fl ammable anesthetic agents. Thi s code i ncl uded a requi rement for
isol ated power systems and LIMs. The National Fire Protecti on Association (NFPA) revi sed its
standard for health care faci l iti es in 1984 (NFPA 99-1984). These standards do not require
isol ated power systems or LIMs i n areas desi gnated for use of nonfl ammabl e anestheti c agents
only.
62, 63
Al though not mandatory, NFPA standards are usual l y adopted by local authori ties when
revi sing thei r el ectrical codes.
Thi s change i n the standard creates a di l emma. The NFPA 99Standard for Heal th Care Facil i ti es,
1990 Editi on, mandates that wet location pati ent care areas be provided wi th speci al protecti on
against el ectrical shock. Section 3-4.1.2.6 further states that this speci al protection shal l be
provi ded by a power di stri buti on system that i nherentl y l i mi ts the possibl e ground fault current
due to a first fault to a low val ue, wi thout interrupti ng the power suppl y; or by a power
di stri bution system in which the power suppl y i s i nterrupted i f the ground fault current does, i n
fact, exceed a value of 6 mi l li amperes.
The decisi on of whether to instal l i sol ated power hi nges on two factors. The fi rst is whether or not
the operati ng room is considered a wet locati on, and, i f so, whether an i nterrupti bl e power suppl y
is tol erabl e. Where power i nterrupti on i s tolerable, a GFCI i s permi tted as the protecti ve means.
However, the standard al so states that the use of an i sol ated power system (IPS) shall be
permi tted as a protective means capabl e of l imiti ng ground faul t current wi thout power
interrupti on.
Most people who have worked in an operating room would attest to its bei ng a wet l ocati on. The
presence of bl ood, body fl ui ds, and sali ne sol utions spi ll ed on the fl oor al l contribute to maki ng
this a wet environment. The cystoscopy suite serves as a good exampl e.
Once the premi se that the operati ng room is a wet l ocati on i s accepted, i t must be determi ned
whether a GFCI can provi de the means of protection. The argument against usi ng GFCIs i n the
operating room i s il l ustrated by the fol lowi ng exampl e. Assume that duri ng an open heart
procedure the cardiopul monary bypass pump and the patient moni tors are plugged i nto outl ets on
the same branch ci rcuit. Al so assume that during bypass, the ci rcul ati ng nurse now pl ugs i n a
faul ty headli ght. If there i s a GFCI protecti ng the circui t, the faul t wi ll be detected and the GFCI
wil l i nterrupt all power to the pump and the moni tors. Thi s undoubtedl y woul d cause a great deal
of confusi on and consternati on among the operati ng room personnel and may place the pati ent at
ri sk for injury. The pump would have to be manual l y operated whi le the probl em was bei ng
resolved. In addition, the GFCI coul d not be reset (and power restored) unti l the headl i ght was
identi fi ed as the cause of the faul t and unpl ugged from the outlet. However, i f the operati ng room
were protected wi th an i sol ated power system and LIM, the same scenari o woul d cause the LIM to
al arm, but the pump and

patient moni tors would conti nue to operate normal l y. There would be no i nterruption of power,
and the probl em coul d be resol ved without ri sk to the patient.
It shoul d be real i zed that a GFCI i s an acti ve system. That i s, a potenti al l y hazardous current i s
al ready fl owi ng and must be acti vel y interrupted, whereas the isol ated power system (with LIM) i s
designed to be safe during a first-faul t situati on. Thus, i t is a passi ve system because no
P.169
mechani cal acti on is requi red to acti vate the protecti on.
64

It i s li kel y that hospital administrators may want to eli mi nate isolated power systems in new
operating room construction as a cost-savi ng measure. Others,
64, 65, 66
however, have advocated
the retention of isolated power systems. Not to do thi s woul d be a short-si ghted, foolhardy
measure. This i s especi al l y true because the cost of addi ng i sol ated power i s esti mated to be 1%
of the cost of constructi ng an operati ng room.
64
Al though not perfect,
67
the i sol ated power system
and LIM do provi de both the pati ent and operating room personnel wi th a significant amount of
protecti on in an el ectricall y hazardous environment. The val ue of the isolated power system is
il l ustrated i n a report by Day in 1994.
68
He reported four i nstances of el ectri cal shock to operati ng
room personnel i n a 1-year peri od. The operating sui te had been renovated and the i sol ated power
system removed, and it was not unti l the operati ng room personnel recei ved a shock that a
probl em was di scovered.
Anesthesi ol ogists need to be aware of thi s cost-savi ng atti tude and strongly encourage that new
operating rooms be constructed wi th i sol ated power systems. The rel ati vel y smal l cost savi ngs
that the al ternati ve would represent do not justi fy the el iminati on of such a useful safety system,
and the use of GFCIs i s not practi cal i n the operati ng room envi ronment.
El ectri cal safety shoul d be the concern of everyone in the operati ng room. Acci dents can be
prevented onl y if proper i nstall ati on and maintenance of the appropri ate safety equi pment in the
operating room have occurred and the operati ng room personnel understand the concepts of
el ectri cal safety and are vi gi lant i n their efforts to detect new hazards.
69

FIRE SAFETY
Fi res i n the operati ng room are just as much a danger today as they were 100 years ago
when pati ents were anesthetized wi th fl ammable anesthetic agents.
70, 71
For more than 100
years, the practi ce of anesthesi a throughout the worl d i nvol ved the use of fl ammable and
explosive inhal ati onal anestheti cs such as ether and cycl opropane. It i s onl y i n the l ast 30 to 40
years that these agents have been phased out of use in the devel oped countri es. Of the earl y
inhalational anestheti cs, onl y ni trous oxide was nonfl ammabl e, yet i t is si mi l ar to oxygen i n that i t
can readil y support combusti on. Si nce the potential consequences of a fi re or expl osi on with ether
or cycl opropane coul d be so devastating, everyone who worked i n the operati ng room acti vel y
observed fire safety practi ces on a dai ly basi s.
72, 73

Today, the ri sk of an operati ng room fire i s probabl y as great or greater than the days when ether
and cycl opropane were used. This i s because of the routi ne use of potenti al sources of i gni ti on
(such as el ectrosurgical cauteries and fiberopti c l i ght sources) in an envi ronment ri ch i n
fl ammabl e materi al s (i .e., fuel s). The probl em i s compounded by a markedl y decreased awareness
of the potenti al for an operati ng room fi re. With the possibl e excepti on of l aser surgery i n or
around the ai rway, there is rarely any speci al attention pai d to fire safety. However, ESUs, and
not l asers, are probably responsibl e for starting the majority of operating room fires. In fact, ESUs
were i mpl i cated i n the vast majori ty of the 146 devi ce-associated surgi cal fires reported to the
FDA between January 1995 and June 1998.
74

For a fire to start, three el ements are necessary. Thi s is call ed the Fi re Tri ad. The first part
of the tri ad i s a heat or i gni tion source, the second part i s fuel, and the thi rd part is an
oxi di zer.
75
A fi re occurs when there i s a chemi cal reacti on of a fuel rapi dly combining wi th an
oxi di zer to release energy in the form of heat and l i ght. In the operati ng room there are many
heat or igni ti on sources and these i nclude the ESU, l asers, electri cal tools such as dri l ls, and the
ends of fi beropti c l ight cords. The mai n oxi di zers i n the operati ng room are air, oxygen, and
ni trous oxide. Oxygen and ni trous oxide functi on equal ly wel l as oxi di zers, so a combi nation of
50% oxygen and 50% ni trous oxi de woul d support combusti on as wel l as 100% oxygen. Fuel for a
fi re can be found everywhere i n the operati ng room. Paper drapes have l argel y repl aced cl oth
drapes and these are much easi er to i gni te and they can burn wi th greater i ntensi ty.
76, 77
Other
sources of fuel i nclude gauze dressi ngs, endotracheal (ET) tubes, gel mattress pads, and even
faci al or body hai r
78
(Tabl e 8-3).

TABLE 8-3 Fuel Sources Commonly Found in the Operating Room
Prep Agents
Al cohol
Degreasers (acetone, ether)
Adhesi ves (ti ncture of benzoi n, Aeropl ast)
Chl orhexi di ne digl uconate (Hibi tane)
Iodophor (Dura-Prep)
Drapes and Covers
Pati ent drapes (paper, pl asti c, cl oth)
Equi pment drapes (paper, pl asti c, cl oth)
Blankets and sheets
Pi l l ows, mattresses, and paddi ng
Gowns
Masks
Shoe covers
Gl oves (l atex, nonl atex)
Clothi ng
Compressi on (anti -embol i sm) stockings
Patient
Hai r
Al i mentary tract gases (methane, hydrogen)
Desi ccated ti ssue
Dressings
Gauze and sponges
Petrol atum-i mpregnated dressi ngs
Xeroform
Adhesi ve tape (cl oth, pl asti c, paper)
Elasti c bandages
Stockinettes
Sutures
Steri -Strips
Col lodi on
Oi ntments
Petrol atum
Anti bi oti cs (bacitracin, neomycin, polymyxin B)
Ni tropaste (Ni tro-Bi d)
EMLA
Lip balms
Anesthesi a Equipment
Breathing circui t hoses
Masks
Endotracheal tubes
Oral and nasal ai rways
Laryngeal mask airways
Nasogastri c tubes
Sucti on catheters and tubi ng
Scavenger hoses
Vol ati l e anestheti cs
CO
2
absorbers
Intravenous tubing
Pressure monitor tubi ng and pl asti c transducers
Fi re preventi on i s accompli shed by not al l owing all three of the elements to come together at the
same ti me.
79
The probl em in the operati ng room i s that frequentl y each of the l imbs of the fi re
triad i s control l ed by a di fferent i ndi vi dual. For i nstance, the surgeon i s frequentl y i n charge of the
igniti on source, the anesthesi ologi st i s usual ly admini steri ng the oxidi zer, and the OR nurse
frequently controls the fuel sources. It i s not al ways evi dent to any one i ndi vi dual that al l of these
el ements may be coming together at the same ti me. This i s especi al l y true i n any case where
there i s the possi bil i ty of oxygen or an oxygenni trous oxide mixture bei ng del i vered around the
surgi cal site. In these ci rcumstances, the risk of an OR fire i s markedl y increased and the need for
communi cati on among the surgeon, the anesthesi ol ogist, and the OR nurses i s especi al l y
important.
There are several dangers that may result from an operati ng room fi re. The most obvi ous i s that
the pati ent and operati ng room personnel can suffer severe burns. However, a less obvi ous but
potenti al l y more deadl y ri sk can be posed by the products of combusti on (cal led toxi cants).
When materi als, especi al l y pl astics, are burned, a vari ety of i njuri ous compounds can be
produced. These i nclude carbon monoxi de, ammonia, hydrogen chl oride, and even cyanide.
Toxi cants can produce injury by damaging airways and l ung tissue, and can cause asphyxia.
Operating room fires can often produce signi fi cant amounts of smoke and toxicants, but may not
cause enough heat to acti vate overhead spri nkl er systems. If enough smoke is produced, the
operating room personnel may have to evacuate the operati ng room. Thus, i t is essenti al to have
a prearranged evacuati on pl an for both the OR personnel and the pati ent.
Operati ng room fi res can be di vi ded i nto two di fferent types. The more common type of fi re occurs
in or on the pati ent. These would incl ude endotracheal tube fi res, fi res duri ng l aparoscopy or
bronchoscopy, or a fire i n the oropharynx, whi ch may occur duri ng a tonsi l lectomy Fi res occurri ng
on the pati ent mai nl y involve head and neck surgery done under regi onal anesthesia or moni tored
anesthesia care when the patient i s recei vi ng high fl ows of suppl emental oxygen via a face mask
or nasal prongs. Since these fires occur i n an oxygen-enri ched envi ronment, items such as
surgi cal towel s, drapes, or even the body hair can be readi l y i gni ted and produce a severe burn
(Fi g. 8-36). The other type of operati ng room fi re i s one that i s remote from the pati ent. Thi s
would include an el ectri cal fire i n a pi ece of equi pment or a CO
2
absorber fi re.
Other Equipment
Charts and records
Cardboard, wooden, and parti cl eboard boxes and cabi nets
Packi ng materi al s [cardboard, expanded pol ystyrene (Styrofoam)]
Fi beropti c cabl e covers
Wire covers and insulation
Fi beropti c endoscope coveri ngs
Sphymomanometer cuffs and tubing
Pneumatic tourni quet cuffs and tubing
Stethoscope tubing
Vascular shunts (Gore-tex, Dacron)
Dial ysis and extracorporeal ci rculation ci rcuits
Wound drai ns and col lection systems
Mops and brooms
Textbooks and instructi on manual s
Although major igniti on sources for OR fi res are the ESU and the l aser, the ends of some
fiberopti c li ght cords can also become hot enough to start a fire i f they are pl aced on paper
drapes. And al though the ESU is responsi bl e for i gni ting the majority of the fi res,
74
it i s the l aser
that has generated the most attention and research. Laser i s the acronym that stands for l ight
amplification by sti mulated emission of radi ati on. A l aser consi sts of an energy source and
material that the energy

exci tes to emi t li ght.
80, 81, 82
The materi al that the energy exci tes i s cal led the lasi ng medi um and
provi des the name of the parti cul ar type of l aser. The important property of l aser l ight is that i t i s
coherent, meani ng that i s monochromatic (or even of a singl e wavel ength). Thi s coherent l i ght can
be focused i nto very smal l spots that have very high power densi ty.
There are many different types of medical lasers, and each has a speci fi c appl icati on. The argon
laser is used in eye and dermatologi c procedures, as i t i s absorbed by hemogl obi n and has a
modest ti ssue penetration of between 0.05 and 2.0 mm. The potassi um-ti tanyl -phosphate (KTP) or
frequency-doubl ed yttri um al uminum garnet (YAG) l asers are al so absorbed by hemoglobi n and
have tissue penetrati ons si mil ar to that of the argon l aser. The Dilaser has a wavel ength that is
easi l y changed and can be used i n di fferent appl i cati ons, parti cul arl y i n dermatol ogic procedures.
The neodymi um-doped yttrium al umi num garnet (Nd-YAG) laser is the most powerful of the
medical lasers. Si nce the ti ssue penetrati on i s between 2 and 6 mm, i t can be used for tumor
debul ki ng, parti cul arly i n the trachea and mai n-stem bronchi , or in the upper ai rway. The energy
can be transmi tted through a fi beropti c cabl e that i s pl aced down the sucti on port of a fi beropti c
bronchoscope. The l aser can then be used in a contact mode to treat a tumor mass. The carbon
di oxi de (CO
2
) l aser has very l i ttl e ti ssue penetrati on and can be used where great preci sion is
needed. It i s also absorbed by water, so that mi ni mal heat is di spersed to surroundi ng ti ssues.
The CO
2
laser is used primarily for procedures i n the oropharynx and i n and around the vocal
FIGURE 8-36. Si mul ati on of fire caused by electrode during surgery. A. Mannequin prepared
and draped for surgery. Electrosurgi cal uni t monopol ar penci l electrode appl i ed to operati ve
si te at start of surgery. B. Si x seconds after el ectrosurgi cal uni t appl i cati on. Smoke appears
from under the drapes. C. Fourteen seconds after el ectrosurgical uni t appli cati on. Flames
burst through the drapes. D. Twenty-four seconds after electrosurgi cal uni t appl i cation.
Enti re pati ent head and drapes i n fl ames. (From Barker SJ, Pol son JS. Fi re in the operating
room: A case report and l aboratory study. Anesth Analg 93:960965, 2001, with permission.)
P.170
cords. The hel ium-neon laser (He-Ne) produces an i ntense red l i ght and thus can be used for
ai mi ng the CO
2
and the Nd-YAG l asers. It has very l ow power and thus wi l l present no si gni fi cant
danger to OR personnel.
One of the most devastati ng types of OR fi res occurs when an endotracheal tube i s igni ted in the
patient.
83, 84, 85, 86, 87, 88
If the pati ent i s bei ng venti l ated with oxygen and/or ni trous oxi de, the
endotracheal tube wi l l essential ly emi t a blowtorch type of flame that can resul t i n severe injury
to the trachea, l ungs, and surroundi ng ti ssues. In 1987 Wol f and Simpson showed that red rubber,
pol yvi nyl chloride, and si l i cone endotracheal tubes al l have oxygen flammabi l ity indices (defined
as the minimum O
2
fracti on i n N
2
that will just support a candle-l i ke fl ame for a gi ven fuel source
using a standard igniti on source) of less than 26%.
89
Because these tubes wi l l combust at such
low concentrati ons of oxygen, they are not the best choi ce when usi ng l asers or electrocautery i n
or around the airway.
To prevent airway fires and thei r potential ly devastati ng consequences, laser-resistant
endotracheal tubes have been devel oped.
90, 91, 92
Before the advent of these tubes,
anesthesi ol ogi sts often wrapped red rubber or pol yvinyl chl ori de tubes wi th some sort of refl ecti ve
tape. Today, thi s practice i s di scouraged because taped-wrapped tubes can be easi l y ki nked, gaps
in the tape can expose areas of the tube to the l aser, and nonl aser-resi stant tape mi ght be
uni ntenti onal l y used. Instead, anesthesi ol ogists are encouraged to use an endotracheal tube that
is designed to be resistant to the speci fi c l aser that wi ll be used during surgery. For i nstance,
when usi ng the carbon dioxi de l aser, the LaserFl ex
TM
(Mal li nckrodt, Pl easanton, CA) is an excel l ent
choi ce. Thi s is a flexi bl e metal tube that has two cuffs that can be i nflated wi th sal i ne colored with
methyl ene bl ue. The methyl ene bl ue enabl es the surgeon to easi l y recogni ze if he or she has
acci dentall y penetrated one of the cuffs. The LaserFlex
TM
tube i s hi ghl y resi stant to being struck
by the laser. If the Nd-YAG l aser i s being used, then the Lasertubus
TM
(Rsch Inc., Dul uth, GA)
can be used. The Lasertubus
TM
has a soft rubber shaft that is covered by a corrugated si l ver foi l ,
whi ch i s, i n turn, covered i n a Merocel
TM
sponge jacket. To provi de maxi mum protection, the
Merocel
TM
must be kept moist with saline. If everythi ng is done properl y, the tube wi l l resist
igniti on even wi th several strikes from the laser.

As previously stated the ESU is a frequent igniti on source for an OR fire.
93, 94
A typi cal exampl e of
how an ESU coul d cause igni ti on woul d be duri ng a tonsi ll ectomy in a chi l d where the
anesthesiol ogi st was using an uncuffed, fl ammabl e endotracheal tube. In thi s case, the oxygen or
oxygenni trous oxide mi xture coul d l eak around the endotracheal tube and pool at the operati ve
si te, provi di ng an oxygen-enri ched envi ronment. When the surgeon uses the ESU (or l aser) to
cauteri ze the tonsi l bed, the combinati on of high concentrati on of oxidi zer (oxygen or oxygen
ni trous oxide mi xture), fuel (endotracheal tube), and i gni ti on source (the ESU) coul d easil y start a
fi re.
95, 96

The best way to prevent thi s type of fi re is to take steps to prevent the three legs of the fire tri ad
from comi ng together. For example, mi xi ng the oxygen with ai r to keep the i nspired oxygen
concentration as l ow as possibl e, thus reduci ng the avai l abl e oxi dizer. Another possi bil i ty woul d be
to pl ace wet pl edgets around the endotracheal tube, whi ch woul d prevent the escape of oxygen or
oxygenni trous oxide mi xture from the trachea i nto the operati ve fi eld. Thi s reduces the avail able
oxi di zer and woul d keep the endotracheal tube and tissues from becoming desi ccated, thus
reduci ng thei r sui tabi li ty as fuel sources. However, the pl edgets must be kept moi st, or they wi l l
dry out and become an addi ti onal source of fuel for a fi re.
A rel ated si tuati on that requi res a di fferent sol uti on can ari se when a cri ti cal l y i l l pati ent requires
a tracheostomy.
97, 98
These pati ents may requi re very hi gh concentrations of i nspi red oxygen to
maintai n ti ssue oxygenati on, so that any decrease i n F
i
O
2
or i nterrupti on of venti l ation woul d not
be tol erated. In thi s ci rcumstance, the best opti on for preventi ng a fi re woul d be to avoi d the use
of el ectrocautery (i gniti on source) when opening the trachea.
The Nd-YAG l aser can be used to treat tumors of the l ower trachea and mai n-stem bronchi . Most
commonly, the surgeon wi l l use a fi beropti c bronchoscope (FOB) and pass the l aser fi ber through
the sucti on port of the bronchoscope. The FOB can be used i n conjuncti on with a ri gid metal
P.171
bronchoscope or passed through an 8.5 or 9.0 mm polyvinyl chloride (PVC) endotracheal tube. A
special l aser resistant tube woul d not be used i n this ci rcumstance, because the FOB and l aser
fi ber pass through the endotracheal tube and focus on ti ssue distal to the tube. Fi re safety
precauti ons avai l abl e i n this setti ng i ncl ude ti trati ng the concentrati on of i nspi red oxygen to as
low as the pati ent can tol erate whi l e maintai ni ng a saturation of between 90 and 95% (i deal ly
keeping the i nspired oxygen below 30%), keepi ng the ti p of the endotracheal tube and FOB away
from the si te of surgery and out of the li ne of fire of the laser, and removi ng charred and
desi ccated ti ssue from the surgical fiel d. The use of a ri gi d metal bronchoscope instead of an
endotracheal tube wi l l el i mi nate the possibi l ity of setti ng the tube on fire but does not eli mi nate
the possibi l ity of setting the fiberoptic bronchoscope on fi re. Thi s woul d al so necessi tate the use
of a jet venturi system to venti late the pati ent, whi ch woul d, i n turn, del i ver oxygen at a
concentration between 40 and 60%.

There are a number of basi c safety precauti ons that shoul d be taken whenever a laser i s used i n
surgery. Si nce l aser l ight can be refl ected off any metal surface, it i s i mportant that al l OR
personnel wear protecti ve goggl es that are speci fic to the type of l aser being used. The
anesthesiol ogi st needs to be aware that the l aser goggl es may make i t di ffi cul t to read certai n
moni tor displays. In additi on, i t is i mportant that the pati ent's eyes be covered wi th wet gauze or
eye packs. Operati ng room personnel shoul d al so wear hi gh-fil tration masks si nce the l aser
pl ume may contai n vapori zed vi rus particl es or chemi cal toxins. Fi nal l y, al l doors to the OR
should have warni ng si gns that a l aser is i n use, and al l windows should be covered wi th bl ack
window shades.
Laparoscopic surgery i n the abdomen is another potenti al risk for a fi re i n the pati ent. In 1993,
Newman et al showed that nitrous oxi de admini stered to the pati ent as part of thei r anesthetic
can, over 30 minutes, diffuse i nto the abdominal cavi ty and attai n a level that coul d support
combusti on.
99
In fact, when sampling the abdominal gas contents after 30 mi nutes, the mean
ni trous oxide concentration was 36%; however, i n certai n patients i t reached a concentrati on of
47%. Both methane and hydrogen are flammabl e gases that are frequentl y present in bowel gas i n
si gni fi cant concentrations. Methane concentration i n bowel gas can be up to 56% and hydrogen
has been reported as hi gh as 69%. Wi th the maximum abdomi nal concentrati on of 47% ni trous
oxi de mixed wi th carbon di oxide, i t woul d requi re the maxi mum of 56% of methane to be
flammabl e. Therefore, this represents a rel ati vel y smal l hazard. In contrast, a concentrati on of
69% hydrogen is flammable if the ni trous oxi de concentrati on i s greater than 29%. Therefore, a
fire i s possibl e i f the surgeon, whi l e using the ESU, enters the bowel wi th a hi gh concentration of
hydrogen, and the i ntra-abdomi nal ni trous oxi de content i s greater than 29%.
Today, i t i s routine to use carbon dioxi de to i nfl ate the abdomen during l aparoscopi c surgery.
Carbon dioxide is an excellent choice as it does not support combusti on. However, a seri ous fi re
ri sk could occur if a mi xture of carbon di oxi de and oxygen was acci dental l y substituted for the
carbon dioxi de cyli nder. Greil i ch reported such a case in 1995 i n whi ch the abdomen was infl ated
using a tank contai ni ng 14% carbon dioxi de and 86% oxygen.
100
A flash fire occurred when the
surgeon used the ESU. Thi s was possibl e because al l tanks wi th a CO
2
concentrati on greater than
7% have the same pi n index as a tank wi th 100% CO
2.

In recent years, fires on the pati ent seem to have become the most frequent type of OR fire.
These cases occur most often during surgery in and around the head and neck where the pati ent i s
recei vi ng moni tored anesthesi a care (MAC) and supplemental oxygen i s bei ng admini stered by
ei ther a face mask or nasal cannul a.
101, 102, 103, 104, 105
In these cases, the oxygen can col lect under
the drapes if not properl y vented, and when the surgeon uses the ESU or the l aser, a fi re can
easil y start. There are many thi ngs that can act as fuel such as the surgi cal towel s, paper drapes,
di si nfecti ng prep solutions, sponges, plasti c tubi ng from the oxygen face mask, and even the
body hair. These fires start very quickl y and i n onl y a few seconds can turn i nto an i ntense bl aze.
Even if the fi re is qui ckl y extingui shed, the patient wil l usual l y sustai n a si gni fi cant burn.
The most i mportant pri ncipl e that the anesthesi ol ogist has to keep in mind i s to titrate the
inspi red oxygen concentrati on to a level that i s low, yet safe for the patient
.
Oxygen should be
P.172
treated just as any other drug and shoul d be admi ni stered to provi de opti mum benefi ts and
mi ni mal si de effects. If the anesthesi a machine has the abil i ty to del i ver ai r, then the nasal
cannul a or face mask can be attached to the anesthesia ci rcui t by using a smal l #3 or #4 15-mm
ET tube adapter. Thi s i s attached to the ri ght angl e el bow of the circui t. If the anesthesi a machi ne
is equipped with an auxiliary oxygen flowmeter that has a removabl e ni pple adaptor, then a
humi di fi er can be install ed i n place of the nippl e adaptor. The humi difier has a Venturi mechani sm
through which room air i s entrained and thus the oxygen concentration that i s del i vered to the
face mask can be vari ed from 28 to 100%. Fi nall y, if thi s machi ne has a common gas outlet that is
easil y accessibl e, then a nasal cannula or face mask can be attached at thi s point using the same
smal l 3- or 4-mm endotracheal tube adaptor. If it i s not possibl e to dil ute the oxygen wi th ai r,
then i t is i mportant that the drapes be arranged i n such a manner that there i s no oxygen bui l dup
beneath them. Tenti ng the drapes and havi ng the surgeon use an adhesi ve sticky drape that seal s
the operative site from the oxygen flow are steps that wil l hel p reduce the risk of a fi re.
It i s potential ly possi ble to di scontinue the use of oxygen before the surgeon plans to use the ESU
or l aser. Thi s woul d have to be done several mi nutes beforehand to allow any oxygen that has
bui lt up to di ssi pate. If the surgeon is pl anni ng to use the ESU or l aser during the enti re case,
then thi s may not be practical.
In recent years, newer surgi cal prep sol uti ons have been introduced into the OR. These typi cal l y
come prepackaged i n a pai nt sti ck appl i cator wi th a sponge on the end. DuraPrep
TM
is one of
these prep sol uti ons. It consi sts of Iodophor
TM
mi xed with isopropyl al cohol . The concentrati on of
al cohol i n thi s sol uti on i s 74%, whi ch is highly fl ammabl e and can easily be the fuel for an OR fire.
In 2001, Barker and Pol son reported just such a case.
101
In a l aboratory re-creati on of the case,
he found that if the DuraPrep
TM
had been al lowed to dry compl etel y (4 to 5 minutes), then the fi re
di d not occur. The other probl em wi th these types of prep sol uti ons is that small pool s of the
solution can accumulate if the person doi ng the prep i s not careful . The al cohol i n these smal l
puddl es wi ll continue to evaporate for a period of time and the alcohol vapors are al so extremel y
flammable.
It i s important to bear i n mi nd that hal ogenation of hydrocarbon anestheti cs confers rel ati ve, but
not absol ute, resi stance to combusti on. Even the newer, nonfl ammabl e vol ati l e anestheti cs can,
under certai n ci rcumstances, present fi re hazards. For exampl e, sevofl urane i s nonfl ammabl e i n
ai r, but can serve as a fuel at concentrati ons as l ow as 11% i n oxygen and 10% in nitrous
oxi de.
106
In addi ti on, sevofl urane and desi ccated CO
2
absorbent (ei ther soda l i me or Baralyme)
can undergo exothermi c chemi cal reactions that have been i mpl icated i n several fi res that involved
the anesthesi a breathing circui t.
107, 108, 109, 110
At l east some of these fi res have i njured pati ents. To
prevent future fires, the manufacturer of sevofl urane has recommended that anesthesi ol ogi sts
employ several measures, i ncl udi ng avoi di ng the use of desi ccated CO
2
absorbent and moni tori ng
the temperature of the absorber and the i nspi red concentrati on of sevoflurane. If an el evated
temperature or an i nspired sevofl urane concentrati on that di ffered unexpectedly from the
vapori zer setti ng is detected, i t i s recommended that the pati ent be di sconnected from the
anesthesia ci rcui t and monitored for si gns of thermal or chemical injury and that the CO
2

absorbent be removed from the ci rcui t and/or repl aced.
Another way to prevent thi s type of fi re i s to use a CO
2
absorbent that does not contai n a strong
al kal i , as do soda l ime and Baral yme
R
. Amsorb
R
is a CO
2
absorbent that contains cal ci um
hydroxide and cal ci um chl ori de, but no strong al kal i .
111
In experimental studi es, Amsorb
R
is
unreactive wi th currentl y used volatil e anestheti cs and does not produce carbon monoxi de or
Compound A wi th desiccated absorbent. Therefore, i t would not interact wi th sevofl urane and
undergo an exothermic chemical reacti on.
It i s known that desi ccated carbon dioxi de absorbent can i n rare ci rcumstances react with
sevofl urane to produce a fi re. Thi s seems to be a uni que property of sevoflurane and woul d
be hi ghl y unl i kel y wi th i sofl urane or desfl urane. Laster et al publ i shed an experi mental report that
compared the thermal effects of the three agents i n desi ccated Baral yme
R
.
112
They found that with
both i sofl urane and desflurane the temperature
P.173
transi entl y i ncreased to about 100C, then spontaneously decreased. However, with sevofl urane
the temperature continued to increase to more than 200C (and i n one case to over 300C). Two
of the fi ve sevofl urane experi ments resul ted i n fi res, il l ustrati ng the importance of the
sevofl uranedesi ccated Baralyme
R
combi nation as a potenti al source of fi re i n the operati ng room.

If a fire does occur, it is important to exti nguish it as soon as possibl e. The fi rst step i s to
interrupt the fi re triad by removi ng one component. Thi s is best accompli shed by removing the
oxidizer from the fire. Therefore, i f an endotracheal tube i s on fire, disconnecti ng the anestheti c
ci rcuit from the tube, or di sconnecting the i nspi ratory l i mb of the ci rcuit, wi ll usuall y resul t in the
fi re i mmedi atel y goi ng out. It i s not recommended to remove a burni ng endotracheal tube because
this may cause even greater harm to the pati ent. Once the fire i s exti ngui shed, the endotracheal
tube can be safel y removed, the ai rway i nspected via bronchoscopy, and the patient' s trachea
rei ntubated.
If the fi re is on the pati ent, extingui shi ng i t wi th a basi n of sal ine may be the most rapi d and
effecti ve method to put i t out. Use of a sheet or towel may also extingui sh the fire. If the drapes
are burni ng, parti cularl y i f they are paper drapes, they must be removed and pl aced on the fl oor.
Paper drapes are i mpervious to water, thus throwi ng water or sal i ne on them wi l l do li ttl e to
exti ngui sh the fi re. Once the burni ng drapes are removed from the pati ent, the fi re can then be
exti ngui shed wi th a fi re exti ngui sher. In most operati ng room fi res, the spri nkl er system i s not
acti vated. Thi s i s because spri nkl ers are usual ly not l ocated di rectl y over the OR tabl e and OR
fires sel dom get hot enough to acti vate the spri nkl ers.
All operati ng room personnel should be fami li ar wi th the l ocati on and operati on of fi re
exti ngui shers i n the area. These extingui shers are divided i nto three cl asses, termed A, B,
and C. Class A extingui shers are used on paper, cloth, and pl astic materi als. Class B extingui shers
are used for fi res when l i qui ds or grease are i nvol ved, and Cl ass C exti nguishers are used for
energi zed el ectrical equi pment. A si ngl e fi re extingui sher may be useful for any one, two, or al l
three types of fi res. Probabl y the best fire extingui sher for the operating room is the carbon
di oxi de extingui sher. Thi s can be used on Class B and Class C fi res and some Class A fi res. Other
exti ngui shers are water mi st, or new envi ronmental l y fri endl y fl uorocarbon extingui shers that
repl aced the Hal on fi re exti ngui sher. Fi nal ly, many operati ng rooms are equi pped wi th a fi re hose,
whi ch i s pressurized water that i s del ivered at a rate of 50 gal lons/mi nute. Such equipment i s best
l eft to the fi re department to use, unless there i s a need to rescue someone from a fi re. To
effecti vel y use a fire exti ngui sher, the acronym PASS can be used. Thi s stands for Pul l the pin to
acti vate the fi re extingui sher, Ai m at the base of the fire, Squeeze the trigger, and Sweep the
exti ngui sher back and forth across the base of the fi re. When responding to a fi re the acronym
RACE is useful. This stands for Rescue, Alarm, Confine, Exti ngui sh. Cl earl y, havi ng a pl an that
everyone is fami l i ar wi th wi l l greatl y faci l itate extingui shi ng the fire and mi ni mi ze the harm to the
patient and equi pment. Fi re dri l ls are an i mportant part of the pl an and can hel p personnel
become fami l i ar wi th the exi ts, evacuati on routes, and l ocati on of fire exti ngui shers and how to
shut off gas and el ectri cal suppl i es. If al l of the OR personnel communi cate wi th each other, the
ri sk of a fi re wi l l be greatl y reduced. It i s i mportant to never assume that others know what you
are doi ng. Verbal ly confirm that the heat source has been pl aced i n standby and not on the
drapes. Lasers and ESUs shoul d have thei r own hol ders and the surgeon needs to be sure which
control activates the l aser and which control acti vates the ESU. It i s important that al l prep
solutions wi th al cohol be dry before surgery begi ns. Duri ng head and neck surgery, the
anesthesiol ogi st should inform the surgeon that there i s an open source of oxygen bei ng
administered to the pati ent. Onl y through hei ghtened awareness, conti nuing educati on, and
communi cati on can the l egs of the fi re tri ad be kept apart and the ri sk of an OR fire mi ni mized.
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392 (ASTM STP 1040). Phil adel phia, Ameri can Soci ety for Testing and Materi al s, 1989
103. de Ri chemond AL, Bruley ME: Head and neck surgi cal fires. In Ei sele DW (ed):
Complications in Head and Neck Surgery. St. Loui s, Mosby, 1993
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(hazard). Heal th Devices 9:50, 1979
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duri ng operati ons on eyes of consci ous patients. Anesthesi ol ogy 48:286, 1978
106. Wal li n RF, Regan BM, Napol i MD, Stern IJ: Sevofl urane: A new i nhal ati onal anesthetic
agent. Anesth Anal g 54:758, 1975
107. Fatheree RS, Lei ghton BL: Acute respiratory syndrome after an exothermi c baral ymeR-
sevofl urane reacti on. Anesthesi ol ogy 101:531, 2004
108. Castro BA, Freedman LA, Crai g WL, Lynch C: Expl osi on wi thin an anesthesia machi ne:
BaralymeR, high fresh gas flows and sevofl urane concentrati on. Anesthesiol ogy 101:537, 2004
109. Wu J, Previte JP, Adl er E et al : Spontaneous i gni ti on, explosion and fi re with sevofl urane
and bari um hydroxi de li me. Anesthesi ology 101:534, 2004
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111. Murray JM, Renfrew CW, Bedi A, et al : Amsorb: A new carbon dioxi de absorbent for use
in anestheti c breathi ng systems. Anesthesiology 91:1342, 1999
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desiccated absorbent. Anesth Analg 99:769, 2004
> Tabl e of Contents > Secti on II - Basi c Pri nci pl es of Anesthesi a Practi ce > Chapter 9 - Aci d-Base, Fl ui ds,
and El ectrol ytes
Chapter 9
Acid-Base, Fluids, and Electrolytes
Donald S. Prough
Scott W. Wolf
J. Sean Funston
Christer H. Svensn
KEY POINTS
The HendersonHasselbal ch equati on descri bes the rel ati onshi p between pH,
PaCO
2
, and serum bi carbonate. The Henderson equation defi nes the previous
rel ati onship but substi tutes hydrogen concentrati on for pH.
The pathophysiol ogy of metabol ic alkal osi s i s di vi ded i nto generati ng and
maintenance factors. A parti cularly important maintenance factor i s renal
hypoperfusion, often a resul t of hypovol emi a.
Metabol ic acidosis occurs as a consequence of the use of bi carbonate to
buffer endogenous organi c aci ds or as a consequence of external bi carbonate
loss. The former causes an increase i n the ani on gap (Na
+
- [Cl
-
+ [HCO
3
-
]]).
When substituti ng mechani cal venti l ation for spontaneous venti l ation in a
patient wi th severe metabol i c aci dosi s, it i s i mportant to mai ntain an
appropriate level of ventil atory compensati on, pendi ng effecti ve treatment of
the pri mary cause for the metabol ic acidosis.
Sodi um bi carbonate, never proved to alter outcome i n pati ents wi th l acti c
acidosis, should be reserved for those patients wi th severe acidemia.
The additi on of i atrogeni c respi ratory alkal osi s to metabol ic alkal osi s can
produce severe al kal emi a.
Ti ght control of bl ood gl ucose i n criti cal ly i ll pati ents has been associ ated
with substanti al i mprovements i n mortali ty.
In pati ents undergoi ng moderate surgi cal procedures, generous
administrati on of flui ds i s associ ated with fewer mi nor compl i cations, such as
nausea, vomiti ng, and drowsi ness.
As a consequence of underlying di seases and of therapeutic mani pul ati ons, surgical patients
may devel op potenti al l y harmful disorders of aci d-base equi l ibrium, intravascul ar and
extravascul ar vol ume, and serum electrolytes. Preci se peri operati ve management of aci d-base
status, flui ds, and electrolytes may li mi t peri operati ve morbi dity and mortali ty.
ACID-BASE INTERPRETATION AND TREATMENT
To faci li tate management of peri operati ve aci d-base di sturbances, thi s chapter revi ews the
pathogenesis, major compli cations, physi ol ogi c compensatory mechanisms, and treatment

of the four simple acid-base di sorders: metabol ic alkal osi s, metabol ic acidosis, respi ratory
al kalosis, and respiratory aci dosi s.
Over vi ew of Aci d- Base Equi l i br i um
The conventi onal approach to descri bing aci d-base equi li brium i s the Henderson
Hasselbal ch equati on:

where 6.1 = the pK
a
of carbonic acid and 0.03 is the sol ubi li ty coeffi ci ent i n bl ood of carbon
di oxi de (CO
2
). Conventi onal acid-base termi nol ogy defi nes aci d-base di sturbances as metabol ic
(i .e., those in whi ch the bi carbonate concentrati on [HCO
-
3
] i s pri mari l y i ncreased or decreased)
and respi ratory (i.e., those i n whi ch PaCO
2
is pri mari l y i ncreased or decreased). pH, the term
used to defi ne the acidi ty or al kali nity of solutions or blood, is the negati ve logari thm of the
hydrogen i on concentrati on ([H
+
]). The si mpl er Henderson equati on (the ori gins of which
precede the HendersonHasselbal ch equati on)
1
cl earl y expresses the relationship between the
three major vari abl es measured or cal cul ated i n blood gas sampl es:
In pati ents undergoing col on surgery, careful peri operati ve fl uid restriction
has been associ ated wi th l ower mortal i ty and better wound heal i ng.
Homeostatic mechani sms are usual ly adequate for the maintenance of
el ectrol yte balance. However, criti cal i ll nesses and their treatment strategi es
can cause signi ficant perturbati ons i n electrolyte status, possi bl y l eadi ng to
worsened pati ent outcome.
Cal ci um, phosphorus, and magnesium are al l essenti al for mai ntenance and
functi on of the cardi ovascul ar system. In addi tion, they al so provi de the
mi li eu that ensures neuromuscul ar transmi ssi on. Di sorders affecti ng any one
of these el ectrol ytes may lead to si gni fi cant dysfuncti on and possi bl y result
in cardiopul monary arrest.
Disorders of the concentration of sodi um, the pri nci pal extracel lular cation,
are dependent on the total body water concentrati on and can l ead to
neurol ogic dysfunction. Di sorders of potassi um, the princi pal intracel lul ar
cati on, are infl uenced pri mari l y by insul ts that resul t i n i ncreased total body
losses of potassi um or changes i n distri buti on.
P.176

To convert pH to [H
+
], assume that [H
+
] is 40 mmol/L at a pH of 7.4; that an increase in pH of
0.10 pH uni ts reduces [H
+
] to 0.8 the starting [H
+
] concentrati on; that a decrease i n pH of
0.10 pH uni ts i ncreases the [H
+
] by a factor of 1.25; and that small changes (i.e., <0.05 pH
uni ts) produce approximately a 1.0 mmol /L i ncrease in [H
+
] for each 0.01 decrease i n pH or a
decrease i n [H
+
] of one mmol /L per 0.01 i ncrease i n pH. These rules-of-thumb only
approxi mate the l ogarithmic relationship between pH and [H
+
]. The more the pH deviates from
7.4, the l ess accurate the rules become.
The alternati ve Stewart approach to aci d-base i nterpretati on di sti ngui shes between the
i ndependent vari abl es and dependent vari abl es that defi ne pH.
1, 2
The i ndependent vari abl es are
PaCO
2
, the strong (i .e., hi ghl y di ssoci ated) i on di fference (SID), and the concentrati on of
protei ns, whi ch usual l y are not strong i ons. The strong ions i ncl ude sodium (Na
+
), potassium
(K
+
), chlori de (Cl
-
), and lactate. The SID, cal culated as (Na
+
+ K
+
- Cl
-
), under normal
ci rcumstances is approxi mately 42 mEq/L. In general , the Stewart approach provi des more
insi ght i nto the mechanisms underl yi ng acid-base di sturbances, i n contrast to the Henderson
Hasselbal ch approach, whi ch i s more descri ptive. However, the cli nical interpretati on or
treatment of common aci d-base disturbances i s rarely handi capped by the simpl er constructs of
the conventional HendersonHasselbal ch or Henderson equati ons.
Met abol i c Al kal osi s
Metabol ic al kalosis, usual l y characteri zed by an al kal emi c pH (>7.45) and
hyperbicarbonatemia (>27.0 mEq/L), is the commonest acid-base abnormal ity in cri ticall y
il l pati ents and i s associated wi th i ncreased cost, morbi dity, and mortali ty.
3
Factors that
generate metaboli c alkal osi s include nasogastric suction and diureti c administrati on (Tabl e 9-
1).
4
Mai ntenance of metabol i c al kal osi s is dependent on a conti nued sti mulus, such as renal
hypoperfusi on, hypokal emi a, hypochl oremi a, or hypovol emi a, for distal tubular reabsorpti on of
[HCO
-
3
].
TABLE 9-1 Generation and Maintenance of Metabolic Alkalosis
GENERATION EXAMPLE MAINTENANCE
I. Loss of aci d from extracell ul ar space
A. Loss of gastric fluid Vomi ti ng;
nasogastri c drai nage
effecti ve arteri al
vol ume (EAV)
B. Loss of aci d i nto uri ne; conti nued
Na
+
del i very to the di stal tubul e i n
presence of hyperaldosteronism
1. Pri mary
al dosteroni sm
2. Di ureti c
administrati on
1. K
+
depletion +
al dosterone excess
2. EAV + K
+

depl etion
II. Excessive HCO
3
-
loads
A. Absol ute
NaHCO
3

administrati on
EAV
Metabol ic al kalosis exerts mul tipl e physi ologi c effects. Metaboli c al kal osi s is associ ated with
hypokal emi a, i oni zed hypocal cemi a, secondary ventricul ar arrhythmi as, increased di goxi n
toxi ci ty, and compensatory hypoventi l ati on (hypercarbi a), al though PaCO
2
rarel y exceeds 55
mmHg (Table 9-2).
4
Al kal emi a al so increases bronchial tone and, through a combinati on of
i ncreased bronchi al tone and decreased venti l atory effort, may promote atelectasi s. Alkal emi a
may reduce ti ssue oxygen avai labi l i ty by shi fti ng the oxyhemogl obin di ssoci ati on curve to the
left and by decreasi ng cardi ac output. Duri ng anestheti c management, i nadvertent addi tion of
iatrogeni c respiratory al kal osis to preexi sti ng metaboli c alkal osi s may produce cardiovascular
depressi on, dysrhythmi as, and the other compl i cations of severe al kal emi a (Tabl e 9-3).
1. HCO
3
-
Lactate, acetate,
ci trate admi nistrati on
EAV
2. Metabol i c conversion of sal ts of
organic acid ani ons to HCO
3
-
Alkal i admini stration
to pati ents wi th renal
fai l ure
Renal fai lure
B. Rel ati ve
1. Alkal i ne l oads i n renal fail ure
III. Posthypercapnic state Abrupt correcti on of
chroni c hypercapnia
EAV
TABLE 9-2 Rules of Thumb for Respiratory Compensation in Response to Metabolic
Alkalosis and Metabolic Acidosis
Metabol ic al kalosis
1. PaCO
2
increases approxi matel y 0.5 to 0.6 mmHg for each 1.0 mEq/L i ncrease i n
[HCO
-
3
]
2. The l ast two di gi ts of the pH shoul d equal the [HCO
-
3
] + 15
Metabol ic acidosis
1. PaCO
2
= [HCO
-
3
] 1.5 + 8

2. PaCO
2
decreases 1.2 mmHg for every 1.0 mEq/L i n [HCO
-
3
] to a minimum of 10
to 15 mmHg
3. The l ast two di gi ts of the pH equal [HCO
-
3
] + 15
TABLE 9-3 Metabolic Alkalosis Plus Hyperventilation
In pati ents in whom arteri al bl ood gases have not yet been obtained, serum el ectrol ytes and a
hi story of major risk factors, such as vomi ti ng, nasogastric suction, or chronic di ureti c use, can
suggest metabol ic al kal osi s. Total CO
2
(usual l y abbrevi ated on el ectrol yte reports as CO
2
)
shoul d be about 1.0 mEq/L greater than [HCO
3
-
] calculated on simul taneousl y obtai ned arterial
blood gases. If either calculated [HCO
3
-
] on the arteri al bl ood gases or CO
2
on the serum
el ectrol ytes exceeds normal (24 and 25 mEq/L, respecti vely) by

>4.0 mEq/L, either the pati ent has a pri mary metabol i c al kalosis or has conserved bicarbonate
in response to chroni c hypercarbia. Recogniti on of hyperbi carbonatemia on the preoperati ve
serum electrolytes justi fi es arterial bl ood gas anal ysis and should al ert the anesthesi ol ogi st to
the li kel i hood of factors that generate or mai ntai n metabol ic alkal osi s.
Treatment of metabol ic al kal osi s consi sts of eti ol ogi c and nonetiol ogi c therapy. Etiol ogi c
therapy consists of measures such as expansi on of i ntravascul ar vol ume or the admini stration
of potassium. To restore intravascul ar vol ume, admi ni strati on of 0.9% sal i ne tends to increase
serum [Cl
-
] and decrease serum [HCO
3
-
].
5
Al though hypoprotei nemia can cause a mi ld
metaboli c al kal osi s,
6
such changes usual l y requi re no speci fi c treatment. Nonetiol ogi c therapy
incl udes admi ni strati on of acetazol amide (a carboni c anhydrase i nhi bitor that causes renal
bi carbonate wasti ng) or [H
+
] as ammoni um chl ori de, argi ni ne hydrochlori de, or 0.1 N
hydrochl ori c aci d (100 mmol /L), or aci d di al ysi s. Of the precedi ng, 0.1 N hydrochlori c aci d most
rapidl y corrects l ife-threatening metabol ic al kalosi s but must be i nfused i nto a central vei n;
peri pheral i nfusion wil l cause severe ti ssue damage.
Met abol i c Aci dosi s
Metabol ic acidosis, usual l y characteri zed by an aci demi c pH (<7.35) and
hypobi carbonatemi a (<21 mEq/L), can be i nnocuous or reflect a li fe-threatening
emergency.
7
Metabol i c aci dosi s occurs as a consequence of bufferi ng by bi carbonate of
endogenous or exogenous aci d l oads or as a consequence of abnormal external l oss of
NORMAL CHRONIC DIURETIC
ADMINISTRATION
INTRAOPERATIVE
HYPERVENTILATION
BLOOD GASES
pH 7.40 7.47 7.62
PaCO
2
(mmHg)
40 45 30
[HCO
3
-
]
(mEq/L)
24 32 29
ELECTROLYTES
CO
2
(mEq/L)
25 33 30
Note: Respi ratory al kal osi s, produced by an i nappropri atel y high minute venti l ation,
has been added to the previ ousl y compensated metaboli c al kal osi s induced by chroni c
di uretic admi ni strati on. CO
2
, Total CO
2
.
P.177
bi carbonate. Approxi matel y 70 mmol of aci d metabol ites are produced, buffered, and excreted
dai ly; these i ncl ude about 25 mmol of sulfuric aci d from amino aci d metabol ism, 40 mmol of
organi c aci ds, and phosphori c and other aci ds.
8
Extracell ular volume (ECV) i n a 70-kg adult
contai ns 336 mmol of bi carbonate buffer (24 mEq/L 14 l of ECV). Glomerul ar fi l trati on of
pl asma volume necessitates reabsorpti on of 4,500 mmol of bi carbonate dai l y, of whi ch 85% i s
reabsorbed i n the proxi mal tubule and 10% in the thi ck ascending l imb, and the remai nder i s
ti trated by proton secreti on in the coll ecti ng duct.
8

Cal cul ati on of the ani on gap (Na
+
- [Cl
-
] + [HCO
3
-
]) di sti ngui shed between two types of
metaboli c aci dosi s (Tabl e 9-4).
9
The ani on gap i s normal (<13 mEq/L) in situations, such as
di arrhea, bi l i ary drai nage, and renal tubul ar aci dosi s, i n whi ch bi carbonate i s lost external ly.
The ani on gap also is normal or reduced i n hyperchl oremic aci dosi s associ ated wi th
peri operative i nfusi on of substantial quanti ti es of 0.9% sal i ne.
5, 10, 11
Metabol i c aci dosi s
associated wi th a hi gh anion gap (>13 mEq/L) occurs because of producti on of excess l acti c
acid or ketoacids, i ncreased retenti on of waste products (such as sulfate and phosphate) that
are inadequatel y excreted i n uremi c states, and i ngestion of toxi c quanti ti es of substances such
as aspi rin, ethyl ene gl ycol , and methanol. In those ci rcumstances, bi carbonate ions are
consumed i n buffering hydrogen i ons, whil e the associated ani on repl aces bicarbonate in
serum. Because three-quarters of the normal ani on gap consi sts of al bumi n, the cal culated
ani on gap shoul d be corrected for hypoal bumi nemi a by addi ng to the calcul ated anion gap the
di fference between measured serum al bumin and a normal al bumin concentrati on of 4.0 g/dL
mul tipl i ed by 2.0 to 2.5.
12, 13

Suffici ent reducti ons in pH may reduce myocardial contractil i ty, i ncrease pul monary
vascul ar resi stance, decrease systemi c vascul ar resistance, and i mpair the response of the
cardi ovascul ar system to endogenous or exogenous catecholami nes. It i s parti cul arl y i mportant
to note that fai l ure of a pati ent to appropri atel y hyperventi late in response to metabol ic
acidosis i s physi ologicall y equi valent to respi ratory aci dosi s and suggests i mpendi ng
deteri orati on. If a patient wi th metabol ic acidosis requi res mechani cal venti l ati on, every
attempt should be made to mai ntain an appropriate level of ventil atory compensati on unti l the
pri mary process can be corrected (see Tabl e 9-2). Tabl e 9-5 il l ustrates fai lure to mai ntai n
TABLE 9-4 Differential Diagnosis of Metabolic Acidosis
ELEVATED ANION GAP NORMAL ANION GAP
Three di seases
1. Uremia
2. Ketoaci dosi s
3. Lacti c aci dosi s
Toxi ns
1. Methanol
2. Ethyl ene gl ycol
3. Sal i cylates
4. Paral dehyde
1. Renal tubular aci dosi s
2. Diarrhea
3. Carboni c anhydrase i nhi biti on
4. Ureteral di versi ons
5. Earl y renal fail ure
6. Hydronephrosis
7. HCl admi ni strati on
8. Sal i ne admi ni strati on
Correction of the ani on gap for hypoal bumi nemi a i s essenti al for effecti ve
peri operative use.
compensatory hyperventi l ati on.
The anestheti c i mpl icati ons of metabol ic acidosis are proporti onal to the severity of the
underlying process. Although a pati ent wi th hyperchl oremi c metabol ic aci dosi s may be
rel ati vely heal thy, those wi th l actic aci dosi s, ketoaci dosi s, uremi a, or toxic i ngestions wil l be
chroni cal l y or acutel y i l l.

Preoperati ve assessment shoul d emphasi ze volume status and renal functi on. If shock is the
eti ol ogy, di rect arteri al pressure moni tori ng and prel oad may requi re assessment via
echocardi ography or pul monary arteri al catheterizati on. Intraoperati vel y, one should be
concerned about the possi bi li ty of exaggerated hypotensi ve responses to drugs and posi ti ve
pressure ventil ati on. Preoperati ve compensatory hyperventi lation should be maintai ned duri ng
anesthesi a and moni tored usi ng capnography and arteri al bl ood gases. In pl anni ng i ntravenous
flui d therapy, consi der that bal anced sal t sol utions tend to i ncrease [HCO
3
-
] and pH and 0.9%
sali ne tends to decrease [HCO
3
-
] and pH.
5, 10

The treatment of metabol i c acidosis consists of the treatment of the pri mary pathophysi ol ogi c
process (i .e., hypoperfusi on, hypoxia, and if pH is severely decreased, administration of
NaHCO
3
-
). Hyperventil ati on, though an i mportant compensatory response to metabol i c aci dosi s,
is not defi ni tive therapy for metabol ic acidosis. The ini ti al dose of NaHCO
3
can be cal cul ated as:

where 0.3 = the assumed distri buti on space for bi carbonate and 24 mEq/L i s the normal value
for [HCO
3
-
] on arteri al bl ood gas determinati on. The cal culation markedl y underesti mates
dosage i n severe metabol ic aci dosi s. In i nfants and chi ldren, an appropri ate i ni ti al dose i s 1.0
to 2.0 mEq/kg of body wei ght.
One conti nuing controversy i s the use of NaHCO
3
to treat aci demi a induced by l acti c
acidosis. In cri ti cal l y il l pati ents wi th l actic acidosis, there were no i mportant differences
between the physi ologi c effects (other than changes i n pH) of 0.9 M NaHCO
3
and 0.9 M sodium
chlori de.
14
Importantl y, NaHCO
3
did not improve the cardi ovascul ar response to catechol ami nes
and actual l y reduced plasma ioni zed calci um.
14
Al though many cl inici ans conti nue to admi ni ster
TABLE 9-5 Failure to Maintain Appropriate Ventilatory Compensation for Metabolic
Acidosis
SPONTANEOUS
VENTILATION
MECHANICAL
VENTILATION
Arteria
1
pH 7.29 7.13
bl ood
gases
PaCO
2

(mmHg)
29 49
[HCO
3
-
]
(mEq/L)
14 16
In the presence of metabol i c aci dosi s, an otherwi se innocuous increase i n PaCO
2
may
create a li fe-threatening decrease i n pH.
P.178
NaHCO
3
to pati ents wi th persi stent l acti c aci dosi s and ongoi ng deteri oration, nei ther NaHCO
3

nor di chl oroacetate
15
has improved outcome. The buffer THAM (tri s-hydroxymethyl
aminomethane) i s effective at reducing [H
+
] and does not generate CO
2
as a byproduct of
buffering
16
; however, there i s no general l y accepted i ndi cati on for THAM.

Respi r at or y Al kal osi s
Respi ratory alkal osi s, usual ly characterized by an al kal emi c pH (>7.45) and always
characteri zed by hypocarbi a (PaCO
2

35 mmHg), descri bes an i ncrease in minute

ventil ati on that i s greater than that required to excrete metaboli c CO
2
production. Because
respiratory al kal osi s may be a sign of pain, anxiety, hypoxemi a, central nervous system (CNS)
di sease, or systemi c sepsi s, the devel opment of spontaneous respi ratory al kal osi s in a
previ ousl y normocarbi c pati ent requi res prompt eval uati on. The hyperventi l ation syndrome, a
di agnosi s of excl usion, i s most often encountered in the emergency department.
17

Respi ratory alkal osi s, l ike metaboli c alkal osi s, may produce hypokal emi a, hypocal cemi a, cardi ac
dysrhythmi as, bronchoconstri cti on, and hypotension, and may potentiate the toxici ty of
di goxi n. In addi ti on, both brai n pH and cerebral bl ood fl ow are ti ghtly regul ated and respond
rapidl y to changes in systemic pH.
18
Doubl ing mi nute venti lation reduces PaCO
2
to 20 mmHg
and hal ves cerebral bl ood fl ow; conversel y, hal ving minute venti l ation doubles PaCO
2
and
doubl es cerebral bl ood fl ow. Acute hyperventi l ati on may be useful i n neurosurgi cal procedures
to reduce brai n bulk and to control i ntracrani al pressure (ICP) duri ng emergent surgery for
noncrani al i njuries associ ated with acute cl osed head trauma. In those si tuati ons,
intraoperative moni toring of arteri al bl ood gases, correl ated wi th capnography, wi l l document
adequate reducti on of PaCO
2
. Acute profound hypocapni a (<20 mmHg) may produce EEG
evidence of cerebral ischemi a. If PaCO
2
is mai ntained at abnormall y hi gh or l ow level s for 8 to
24 hours, cerebral bl ood fl ow wi l l return toward previous l evel s, associ ated wi th a return of
cerebrospi nal fl ui d [HCO
3
-
] toward normal .
19

Treatment of respi ratory alkal osi s per se i s often not required. In most patients, the most
important steps are recogniti on and treatment of the underl yi ng eti ol ogy.
17
For i nstance,
correcti on of hypoxemia or hypoperfusion-induced l acti c aci dosi s shoul d resul t i n resol uti on of
the associ ated i ncreases i n respiratory dri ve. Preoperati ve recogni ti on of chroni c
hyperventi lation necessitates i ntraoperati ve mai ntenance of a si mi l ar PaCO
2
.

Respi r at or y Aci dosi s
Respi ratory aci dosi s, usual ly characterized by a l ow pH (<7.35) and always characteri zed by
hypercarbi a (PaCO
2

45 mmHg), occurs because of a decrease i n mi nute al veolar venti lation (

A
), an increase i n production of carbon dioxi de (

CO2
), or both, from the equation:

where K = constant (rebreathi ng of exhaled, carbon dioxi de-contai ning gas may also i ncrease
PaCO
2
). Respi ratory aci dosi s may be ei ther acute, without compensati on by renal [HCO
3
-
]
retention, or chronic, with [HCO
3
-
] retention offsetti ng the decrease i n pH (Tabl e 9-6). A
reduction in

A
may be because of an overal l decrease i n mi nute ventil ati on (

E
) or to an increase i n the amount of wasted venti lation (

D
), according to the equati on:

P.179
Decreases in

E
may occur because of central venti latory depressi on by drugs or central nervous system
injury, because of i ncreased work of breathi ng, or because of ai rway obstruction or
neuromuscul ar dysfunction. Increases i n

D
occur wi th chroni c obstructive pul monary disease, pul monary emboli sm, and most acute
forms of respi ratory fai l ure.

CO2
may be i ncreased by sepsi s, hi gh-gl ucose parenteral feedi ng, or fever.
Patients with chroni c hypercarbi a because of i ntri nsi c pul monary disease requi re careful
preoperati ve eval uati on. The venti l atory restricti on i mposed by upper abdomi nal or thoraci c
surgery may compound ventilatory insufficiency. Admini stration of opi oi ds and sedati ves, even
in small doses, may cause hazardous venti latory depressi on. Preoperative eval uati on shoul d
consi der direct arterial pressure moni toring and frequent intraoperati ve bl ood gas
determi nati ons, as well as postoperati ve pain management. Intraoperatively, a pati ent wi th
chroni c hypercapnia shoul d be ventil ated to mai ntai n a normal pH. An abrupt i ncrease in
mi nute ventil ati on may resul t in profound al kal emi a (anal ogous to the addi tion of
hyperventi lation to metabol ic al kalosi s described in Tabl e 9-3). Postoperativel y, prophylacti c
venti l atory support may be requi red for sel ected pati ents wi th severe l ung di sease and chroni c
hypercarbi a. Epi dural opi oi d admi nistrati on represents one potenti al al ternative that may
provi de adequate postoperati ve anal gesi a wi thout undue depressi on of ventil atory dri ve.
The treatment of respi ratory acidosi s depends on whether the process i s acute or chroni c.
Acute respiratory aci dosi s may requi re mechanical venti lation unl ess a si mpl e etiol ogi c factor
(i .e., narcotic overdosage or resi dual muscul ar bl ockade) can be treated qui ckl y. Bi carbonate
administrati on rarel y is i ndi cated unl ess severe metaboli c aci dosi s is al so present or unless
mechani cal venti l ation is i neffecti ve i n reduci ng acute hypercarbi a. In contrast, chronic
respiratory aci dosi s is rarely managed wi th ventil ati on. Rather, efforts are made to i mprove
pul monary functi on to permi t more effecti ve eli mi nation of carbon di oxi de. In pati ents requi ring
TABLE 9-6 Rules of Thumb for [HCO
3
-
] and pH Changes in Response to Acute and
Chronic Changes in PaCO
2

Decreased PaCO
2
1. pH i ncreases 0.10 for every 10 mmHg decrease i n PaCO
2
.

2. [HCO
3
-
] decreases 2 mEq/L for every 10 mmHg decrease i n PaCO
2
.
3. pH wi l l nearl y normal ize if hypocarbi a is sustai ned.
4. [HCO
3
-
] wil l decrease 5 to 6 mEq/L for each chroni c 10 mmHg in PaCO
2
.
a

Increased PaCO
2
1. pH wi l l decrease 0.05 for every acute PaCO
2
increase of 10 mmHg.

2. [HCO
3
-
] wil l i ncrease 1.0 mEq/L for every PaCO
2
increase of 10 mmHg.
3. pH wi l l return toward normal if hypercarbi a i s sustai ned.
4. [HCO
3
-
] wil l i ncrease 4 to 5 mEq/L for each chroni c 10 mmHg i ncrease i n PaCO
2
.
a
Hospi tal ized pati ents rarel y devel op chronic compensati on for hypocarbia because of
stimul i that enhance distal tubular reabsorpti on of sodi um.
mechani cal venti l ation for acute respi ratory fai l ure, venti l ation wi th a l ung-protecti ve strategy
may resul t i n hypercapni a, whi ch in turn has been managed wi th al kal inizati on.
PRACTICAL APPROACH TO ACID-BASE INTERPRETATION
Rapi d i nterpretati on of a pati ent' s aci d-base status i nvol ves the integrati on of three sets of
data: arteri al blood gases, electrolytes, and hi story. A systemati c, sequential approach
faci li tates interpretati on (Tabl e 9-7). Aci d-base assessment usual ly can be completed before
initi ati ng therapy; however, the fi rst step i n i nterpretati on may di scl ose disturbances (e.g.,
respiratory aci dosi s or metabol ic acidosi s wi th pH <7.1) that requi re immedi ate attenti on.
The next step i s to determi ne whether a pati ent i s aci demi c (pH <7.35) or alkal emi c (pH
>7.45). The pH status wil l usual l y i ndi cate the predomi nant primary process, that i s, aci dosi s
produces acidemia; alkal osi s produces al kal emia. (Note that the suffix -osis indicates a
pri mary process that, i f unopposed, wil l produce the correspondi ng pH change. The suffi x -
emia refers to the pH. A compensatory process i s not considered an -osis.) Of course, a
patient may have mixed -oses, that is, more than one primary process.
The next step i s to determi ne whether the enti re arteri al bl ood gas pi cture i s consi stent wi th a
si mpl e acute respiratory al kal osi s or aci dosi s (see Tabl e 9-6). For example, a patient wi th acute
hypocapni a (PaCO
2
30 mmHg) woul d have a pH i ncrease of 0.10 uni ts to a pH of 7.50 and a
calculated [HCO
3
-
] of 22.
If changes in PaCO
2
, pH, and [HCO
3
-
] are not consi stent with a si mpl e acute respiratory
di sturbance, chroni c respiratory aci dosi s (24 hours) or metaboli c aci dosi s or al kal osi s should
be consi dered. In chroni c respi ratory aci dosi s, pH

becomes nearl y normal as bicarbonate i s retai ned by the kidneys (see Tabl e 9-6), usuall y at a
rati o of 4 to 5 mEq/L per 10 mmHg chroni c increase i n PaCO
2
.
20
For exampl e, chronic
hypoventi lation at a PaCO
2
of 60 mmHg woul d be associ ated with an increase in [HCO
3
-
] of 8 to
10 mEq/L ([HCO
3
-
] of 32 to 34 mEq/L) and a pH of 7.35 to 7.38. If nei ther an acute nor chroni c
respiratory change could have resulted i n the arteri al bl ood gas measurements, then a
metabol i c di sturbance must al so be present.
Respi ratory compensati on for metaboli c di sturbances occurs more rapi dl y than renal
compensati on for respi ratory di sturbances (see Tabl e 9-2). Several general rul es descri be
compensati on. Fi rst, overcompensati on i s rare. Second, i nadequate or excessi ve compensati on
suggests an addi ti onal primary disturbance. Thi rd, hypobi carbonatemi a associ ated with an
i ncreased ani on gap i s never compensatory.
TABLE 9-7 Sequential Approach to Acid-Base Interpretation
1. Is the pH life threatening, requi ri ng immedi ate i nterventi on?
2. Is the pH aci demi c or alkal emi c?
3. Could the enti re arteri al bl ood gas pi cture represent onl y an acute i ncrease or
decrease i n PaCO
2
?
4. If the answer to question #3 i s No, is there evi dence of a chroni c respi ratory
di sturbance or of an acute metabol i c di sturbance?
5. Are appropri ate compensatory changes present?
6. Is an ani on gap present?
7. Do the cl i ni cal data fi t the aci d-base picture?
P.180
The next questi on, whether an ani on gap i s present, shoul d be assessed even i f the arteri al
bl ood gases appear strai ghtforward. The si mul taneous occurrence of metabol ic al kal osi s and
metaboli c aci dosi s (as a consequence of pathophysi ology produci ng a hi gh ani on gap) may
result in an unremarkable pH and [HCO
3
-
]; the combi ned abnormali ty may onl y be appreci ated
by exami ni ng the ani on gap.
21
As noted previ ously, correct assessment of the ani on gap
requi res correcti on for hypoal bumi nemi a.
12, 13
Metabol i c aci doses associ ated wi th i ncreased
anion gaps requi re speci fi c treatments, thus necessi tating a correct diagnosis. This i s
parti cul arl y important in managi ng hyperchloremic metabol i c aci dosi s after admini stration of
large vol umes of 0.9% sal ine peri operati vel y or even in cri tical l y i l l hospi tal i zed pati ents.
22
In
these ci rcumstances, no ani on gap woul d be expected and no speci fic treatment of metabol ic
aci dosi s woul d be requi red.
5, 23

The fi nal question is whether the cl i ni cal data are consi stent wi th the arteri al bl ood gas data.
Fai lure to consi der cl i ni cal status al so may l ead to seri ous errors i n gas aci d-base
interpretati on.
Exampl es
The foregoi ng has summari zed an approach that si mpl i fi es interpretati on. The foll owi ng two
hypotheti cal cases wi l l be approached usi ng the al gori thm and rul es discussed earli er.
Example #1
A 65-year-ol d femal e has undergone 12 hours of an expected 16-hour radi cal neck di ssection
and fl ap constructi on. Estimated bl ood l oss i s 1,000 mL. She has recei ved three uni ts of packed
red bl ood cel l s and ni ne l i ters of 0.9% sal i ne. Her bl ood pressure and heart rate have remai ned
stabl e whi le anestheti zed wi th 0.5% to 1.0% i sofl urane i n 70:30 ni trous oxi de and oxygen.
Uri nary output i s adequate. Arterial bl ood gas level s are shown i n Tabl e 9-8.
The step-by-step i nterpretati on i s as fol l ows:
TABLE 9-8 Hypobicarbonatemia and Hyperchloremic Acidosis during Prolonged
Surgery
Arteri al bl ood gases pH 7.38
PaCO
2
32 mmHg
[HCO
-
3
]
17 mEq/L
Electrol ytes Na
+
140 mEq/L
Cl
-
116 mEq/L
CO
2
18 mEq/L
Ani on Gap 6 mEq/L
Serum al bumi n 2.0 g/dL
1. The pH is not l ife threateni ng.
2. The pH is <7.40 but is not frankl y aci demi c.
3. The arteri al bl ood gases cannot be adequatel y expl ai ned by acute hypocarbi a. The
predi cted pH woul d be 7.48 and the predi cted [HCO
-
3
] would be 22 mEq/L (see Tabl e 9-
6).
4. A metabol ic acidosi s appears to be present.
5. The question of compensation is not perti nent duri ng general anesthesi a wi th control l ed
mechani cal venti l ation, given that PaCO
2
is not determined by the pati ent' s venti l atory
control . However, spontaneous hypocapnia of thi s magnitude woul d represent sl i ght
overcompensation (see Tabl e 9-2) and shoul d prompt a search for a reason for pri mary
respiratory al kal osi s.
6. Duri ng prol onged anesthesi a and surgery, one mi ght assume the presence of l actic
aci dosi s and provi de addi ti onal fl ui d therapy or otherwise attempt to i mprove perfusion.
However, serum electrolytes reveal an anion gap that i s sli ghtl y l ess than normal (see
Tabl e 9-8), indi cati ng that the metaboli c aci dosi s i s probabl y the resul t of dil uti on of the
extracel lul ar volume with a hi gh-chlori de fl uid.
5
Correction of the anion gap for the serum
al bumin of 2.0 g/dl only increases the ani on gap to 10 to 11 mEq/L, agai n consi stent wi th
a hyperchloremic metabol i c aci dosi s.
10
A random urine sample coul d hel p confi rm thi s
eti ol ogy (Tabl e 9-9).
8
Hyperchl oremi c aci dosis secondary to i nfusion of hi gh-chlori de fl uid
requi res no treatment. The arteri al bl ood gases and serum electrolytes are compati bl e
with the cli nical picture.
TABLE 9-9 Evaluation of Hyperchloremic Acidosis
URINARY SOLUTES
NH
4
+
Cl
-
A
-
Na
+
GI tract HCO
3
-
loss
(a) (b) (c)
Generated/i ngested organi c
acids (a) (d) (e)
HCI i ntake or equi val ent
a

(a) (f) (e)
Inadequate renal HCO
3
-

(g)
Example #2
A 35-year-ol d mal e, 3 days after appendectomy, devel ops nausea wi th recurrent emesi s
persisting for 48 hours. An arterial blood gas reveals the resul ts shown i n the mi ddl e col umn of
Tabl e 9-10.
1. The pH of 7.50 requi res no immedi ate i ntervention.
Renal HCO
3
-
loss
(g)
a
NH
4
Cl, chl oride salts of amino aci ds or di luti onal aci dosi s;
desi gnates normal: (a)

NH
4
+
>1 mmol /kg dai l y; (b) FE
Cl
<1 mmol /kg dai l y. FE = fractional excreti on of a
solute. Urinary unmeasured ani on concentrati on (sum of uri nary K
+
, NH
4
+
, and Na
+

less Cl
-
) estimates sum of urinary sulphate and organic ani on concentrati ons.

From Gl uck SL: Aci d-base. Lancet 352:474, 1998.
TABLE 9-10 Metabolic Alkalosis Secondary to Nausea and Vomiting with Subsequent
Lactic Acidosis Secondary to Hypovolemia
NORMAL METABOLIC
ALKALOSIS
METABOLIC
ACIDOSIS
Bl ood gases pH 7.40 7.50 7.40
PaCO
2

(mmHg)
40 46 40
[HCO
-
3
]
(mEq/L)
24 35 24
Serum
el ectrol ytes
Na
+
(mEq/L) 140 140 140
Cl
-
(mEq/L) 105 94 94
CO
2
(mEq/L)
25 36 25
Ani on gap
(mEq/L)
10 10 21
2. The pH i s al kal emi c, suggesti ng a pri mary alkal osi s.

3. An acute PaCO
2
of 46 mmHg woul d yi el d a pH of approximatel y 7.37; therefore, thi s is
not si mpl y an acute venti l atory disturbance.
4. The pati ent has a pri mary metabol i c al kal osi s as suggested by the [HCO
3
-
] of 35 mEq/L.
5. The l imi ts of respi ratory compensati on for metabol ic al kal osi s are wi de and di fficul t to
predi ct for indi vi dual patients. The rul es of thumb, summari zed i n Tabl e 9-2, suggest that
[HCO
3
-
] + 15 should equal the last two di gi ts of the pH and that the PaCO
2
shoul d
increase 5 to 6 mmHg for every 10 mEq/L change i n serum [HCO
3
-
], that i s, pH = 7.50
and PaCO
2
= 46 mmHg.
6. The ani on gap i s 12 mEq/L.
7. The di agnosi s of a pri mary metabol ic al kal osi s wi th compensatory hypoventi l ati on i s
consi stent wi th the hi story of recurrent vomi ti ng. Consider how the arterial bl ood gases
would change if vomiting were sufficiently severe to produce hypovolemic shock and lacti c
acidosis (thi rd column, Tabl e 9-10).
Thi s sequence il l ustrates the i mportant concept that the fi nal pH, PaCO
2,
and [HCO
3
-
] represent
the resul t of all of the vectors operating on acid-base status. Compl ex, or tri pl e di sturbances,
can onl y be i nterpreted usi ng a thorough, stepwi se approach.
FLUID MANAGEMENT
P hysi ol ogy
Body Fluid Compartments
Accurate replacement of fluid defici ts necessitates an understandi ng of the di stri buti on spaces
of water, sodi um, and coll oi d. Intracel l ul ar vol ume (ICV), whi ch consti tutes 40% of total body
weight, and extracel l ul ar vol ume (ECV), which consti tutes 20% of body wei ght, comprise total
body water (TBW), whi ch therefore consti tutes 60% of total body wei ght. Pl asma volume (PV)
equal s about one-fifth of ECV, the remai nder of whi ch is intersti tial fl ui d vol ume (IFV). Red cel l
vol ume, approxi matel y 2 li ters, i s part of ICV.
The di stri buti on vol ume of sodi um-free water is TBW. The distri buti on vol ume of infused sodi um
is ECV, whi ch contai ns equal sodi um concentrati ons ([Na
+
]) i n the PV and IF. Pl asma [Na
+
] i s
approxi mately 140 mEq/L. The predominant intracel lul ar cati on, potassi um, has an intracel l ul ar
concentration ([K
+
]) approxi mati ng 150 mEq/L. Albumi n, the most important oncoti cal l y acti ve
consti tuent of ECV, is unequal l y di stri buted i n PV (~4 g/dL) and IFV (~1 g/dL). The IFV
concentration of al bumin vari es greatl y among ti ssues; however, ECV i s the di stri buti on vol ume
for col loi d sol uti ons.
Distribution of Infused Fluids
Conventi onal l y, cl ini cal predi cti on of pl asma vol ume expansi on (PVE) after fl ui d i nfusion
assumes that body fl ui d spaces are static. Ki netic anal ysi s of PVE repl aces the stati c
assumpti on wi th a dynami c descri pti on. As an exampl e of the static approach, assume that a
70-kg pati ent has suffered an acute bl ood l oss of 2,000 mL, approxi matel y 40% of the
predi cted 5-l i ter bl ood vol ume. The formul a descri bi ng the effects of replacement with 5%
dextrose i n water (D5W), l actated Ri nger' s soluti on, or 5% or 25% human serum albumi n is as
fol l ows:

Rearrangi ng the equati on yi el ds the foll owing:
P.181

To restore bl ood vol ume usi ng D5W requi res 28 l i ters:

where 2 l iters i s the desired PV i ncrement, 42 l i ters = TBW in a 70-kg person, and 3 l iters i s
the normal esti mated PV.
To restore bl ood vol ume usi ng l actated Ri nger's soluti on requi res 9.1 l iters:

where 14 li ters = ECV in a 70-kg person.
If 5% al bumi n, whi ch exerts coll oid osmoti c pressure si mil ar to pl asma, were i nfused, the
infused vol ume ini ti al l y would remai n i n the PV, perhaps attracti ng addi tional i ntersti tial fl ui d
intravascul arl y. Twenty-five percent human serum albumi n, a concentrated col loid, expands PV
by approxi matel y 400 mL for each 100 mL i nfused.
However, in ki neti c terms, these anal yses are si mpl istic. Infused fl ui d does not si mpl y
equil i brate throughout an assumed di stributi on vol ume, but i s added to a hi ghl y regul ated
system that attempts to mai ntain i ntravascular, intersti tial , and i ntracell ul ar vol ume. Kineti c
model s of i ntravenous flui d therapy al low cl i ni ci ans to predi ct more accuratel y the ti me course
of vol ume changes produced by infusi ons of fl ui ds of vari ous composi ti ons. Ki neti c anal ysi s
permi ts estimati on of peak vol ume expansion and rates of cl earance of i nfused fl ui d and
compl ements analysi s of pharmacodynami c effects, such as changes in cardi ac output or
cardi ac fil l i ng pressures.
Fi gure 9-1 il l ustrates the conceptual kineti c model proposed by Svensn and Hahn.
24
A practi cal
physi ol ogi c tracer for

kineti c analysi s shoul d permi t frequent measurements to defi ne cl earance curves more
compl etel y. Svensn and Hahn
24
eval uated three endogenous tracersbl ood water
concentration, serum al bumi n concentration, and hemogl obi n concentrati on [Hb]in volunteers
who recei ved i nfusions of acetated Ri nger' s sol ution, 6% dextran 70, or 7.5% sal i ne. Although
much less tedi ous than bl ood water cal culations, [Hb] provi ded simil ar estimates of volumes of
di stri bution and el iminati on rate constants. After i nfusing the test fluids, Svensn and Hahn
fitted the results to one-vol ume and two-vol ume-of-flui d-space (VOFS) model s. The two-
compartment VOFS model i s most l i kel y to be superi or to the one-compartment model when
uri nary excreti on i n response to i nfusi on i s small .
25

P.182
Fi gure 9-2 shows the mean pl asma volume dil uti on curves obtained wi th the i nfusi on of
Ri nger' s sol ution or dextran 70. Al l dextran i nfusions were consi stent wi th a one-VOFS model ,
suggesti ng that the col l oid i nfusi on remai ned i n the PV. Hypertoni c crystall oid, li ke i sotoni c
crystal loi d, was associ ated i n i ndi vi dual i nstances wi th a mixture of one- and two-VOFS model s
FIGURE 9-1. Schemati c drawi ng of the ki neti c model used to cal cul ate the si ze of the
body fl ui d spaces expanded by intravenous i nfusions of fluid in humans. Data are fi tted to
a one-vol ume or two-vol ume-of-flui d-space (VOFS) model . The assumpti ons underl yi ng the
one-compartment VOFS model (top) are as fol l ows: (1) during fl ui d i nfusi on, fl ui d enters
an expandable space of volume v at a constant rate k
i
; (2) the expandabl e fl ui d space has
a target vol ume V, whi ch the body stri ves to maintai n; (3) vol ume v changes by fluid
bei ng eli mi nated from the fl uid space at a basal rate, k
b
(perspi rati on and basal di uresi s),
and at a controll ed rate. The control led rate i s proporti onal by a constant k
r
to the rel ative
deviation of v from the target volume V. The assumptions behind the two-compartment
VOFS model (bottom) are si mi l ar: (1) duri ng fl ui d i nfusi on, fl ui d enters an expandabl e
space of volume v
1
at a constant rate k
i
; (2) there i s a secondary expandable fl ui d space
of vol ume v
2
exchangi ng fl ui d wi th the pri mary fl ui d space; (3) vol ume v
1
changes through
exchange wi th the secondary fl ui d space and as a resul t of fl ui d bei ng el i mi nated from the
pri mary fl ui d space at a basal rate, k
b
(perspi rati on and basal di uresi s), and at a
control led rate; (4) the pri mary and secondary fl uid spaces have target vol umes V
1
and
V
2
, which the system strives to mai ntai n by acting on the control led el i mi nati on
mechanism k
r
, which is proporti onal to the rel ati ve devi ati on from the target vol ume of
the pri mary fl ui d space, and by acti ng on the fl ui d exchange mechanism; (5) the net rate
of fl ui d exchange between the two spaces is proporti onal to the di fference in relative
deviati ons from the target vol umes by a constant k
t
. (From Svensn C, Hahn RG: Vol ume
kineti cs of Ringer soluti on, dextran 70, and hypertoni c sal i ne i n male volunteers.
Anesthesi ol ogy 87: 204, 1997.)
Usi ng thi s approach, the effects of common physi ol ogi c and pharmacol ogi c i nfl uences can be
examined i n experi mental animal s or humans. For exampl e, i n chroni cal ly i nstrumented sheep,
isoflurane anesthesia was associ ated wi th simi lar ki netics of PV expansi on after fluid infusi on,
but reduced uri nary output in anestheti zed i n comparison to conscious sheep, demonstrated
that expansion of extravascul ar vol ume was actual l y greater duri ng anesthesia
26
; subsequent
experi ments demonstrated that thi s effect was attri butabl e to i soflurane and not to mechanical
ventil ati on duri ng anesthesi a.
27
Isofl urane is associated wi th extravascul ar flui d accumul ati on,
al though these observations must be confirmed in anestheti zed humans and other anesthetics
must be exami ned.
Regulation of Extracellular Fluid Volume
Total body water content i s regul ated by the i ntake and output of water. Water intake incl udes
ingested l iquids pl us an average of 750 mL i ngested in sol i d food and 350 mL that i s generated
metaboli cal l y. Insensi ble losses are normal l y 1 L/day and GI l osses are 100 to 150 mL/day.
Thi rst, the primary mechani sm of controll i ng water i ntake, i s tri ggered by an i ncrease i n body
fl ui d toni ci ty or by a decrease in extracell ul ar vol ume.
Reabsorpti on of fi l tered water and sodi um i s enhanced by changes medi ated by the hormonal
factors anti di ureti c hormone (ADH), atrial natri ureti c pepti de (ANP), and al dosterone. Renal
water handl i ng has three i mportant components: (1) del i very of tubul ar flui d to the di l uti ng
segments of the nephron; (2) separati on of solute and water i n the di l uti ng segment; and (3)
vari abl e reabsorpti on of water in the coll ecti ng ducts. In the descendi ng loop of Henl e, water is
reabsorbed whi le sol ute is retai ned to achi eve a final osmol al i ty of tubul ar flui d of
approxi mately 1,200 mOsm/kg (Fi g. 9-3). Thi s concentrated fl ui d i s then di l uted by the active
reabsorpti on of electrolytes i n the ascendi ng l i mb of the loop of Henl e and i n the di stal tubul e,
both of whi ch are rel ati vely i mpermeabl e to water. As fl ui d exi ts the di stal tubule and enters
the col lecting duct, osmol al i ty i s approximatel y 50 mOsm/kg. Wi thin the coll ecti ng duct, water
reabsorpti on i s modul ated by ADH (al so cal l ed vasopressi n). Vasopressin bi nds to V
2
receptors
al ong the basolateral membrane of the coll ecti ng duct cel l s, then stimul ates the synthesis and
FIGURE 9-2. Ki neti c curves obtai ned after i nfusi on i n adul t mal e vol unteers of 25 mL/kg
of acetated Ringer' s sol uti on (Ri nger) or 5 mL/kg of dextran 70 over 30 mi nutes. Dil uti on
of plasma vol ume is cal cul ated from changes i n hemogl obi n concentration (B-hemoglobi n),
bl ood water (B-water) concentrati on, and serum albumi n (S-al bumin) concentration. (From
Svensn C, Hahn RG: Vol ume ki netics of Ringer soluti on, dextran 70, and hypertoni c
sali ne in mal e vol unteers. Anesthesi ology 87: 204, 1997.)
inserti on of the aquapori n-2 water channel i nto the l uminal membrane of coll ecti ng duct cel ls.
28

Pl asma hypotonici ty suppresses ADH release, resul ting i n excreti on of di lute uri ne.
Hypertoni ci ty stimul ates ADH secreti on, which increases the permeabi li ty of the col lecti ng duct
to water and enhances water reabsorpti on. In response to changi ng plasma [Na
+
], changing
secretion of ADH can vary urinary osmolal ity from 50 to 1,200 mOsm/kg and urinary vol ume
from 0.4 to 20 L/day (Fi g. 9-4). Other factors that sti mul ate ADH secreti on, though none as
powerful l y as pl asma tonici ty, i ncl ude hypotensi on, hypovol emi a, and nonosmoti c sti muli such
as nausea, pai n, and medi cati ons, including opiates.
FIGURE 9-3. Renal fil tration, reabsorpti on, and excreti on of water. Open arrows
represent water and soli d arrows represent el ectrol ytes. Water and electrolytes are
fil tered by the glomerul us. In the proxi mal tubule (1), water and el ectrol ytes are absorbed
isotoni cal ly. In the descendi ng loop of Henl e (2), water is absorbed to achi eve osmoti c
equil i bri um wi th the intersti tium whi le el ectrol ytes are retained. The numbers (300, 600,
900, and 1,200) between the descendi ng and ascendi ng l i mbs represent the osmolal ity of
the intersti tium i n mOsm/kg. The deli very of sol ute and fl ui d to the di stal nephron i s a
functi on of proxi mal tubul ar reabsorption; as proxi mal tubul ar reabsorpti on i ncreases,
del i very of sol ute to the medull ary (3a) and corti cal (3b) di l uti ng si tes decreases. In the
di l uti ng si tes, el ectrol yte-free water is generated through sel ecti ve reabsorpti on of
el ectrol ytes whil e water i s retai ned in the tubul ar l umen, generating a di l ute tubul ar fl ui d.
In the absence of vasopressin, the col lecting duct (4a) remai ns rel ati vel y impermeabl e to
water and a di lute uri ne is excreted. When vasopressi n acts on the col l ecti ng ducts (4b),
water is reabsorbed from these vasopressi n-responsi ve nephron segments, al l owing the
excreti on of a concentrated uri ne. (From Fri ed LF, Pal evsky PM: Hyponatremi a and
hypernatremi a. Med Cl i n North Am 81(3):585, 1997.)
Two powerful hormonal systems regul ate total body sodi um. The natri ureti c pepti des, ANP,
brai n natri ureti c pepti de, BNP, and C-type natri ureti c pepti de, defend agai nst sodi um
overload
29
and the reni n-angiotensi n-al dosterone axi s defends agai nst sodi um depl eti on and
hypovolemia. ANP, rel eased from the cardi ac atri a in response to increased atri al stretch,
exerts vasodil atory effects and increases the renal excretion of sodi um and water. ANP
secretion is decreased during hypovol emi a. Even i n patients with chroni c (nonoli guri c) renal
insuffi ciency, i nfusi on of ANP in l ow, nonhypotensi ve doses i ncreased sodi um excretion and
augmented uri nary l osses of retai ned solutes.
30

Aldosterone is the final common pathway i n a compl ex response to decreased effective arteri al
vol ume, whether decreased effecti ve arterial vol ume i s true or rel ati ve (edematous states or
hypoal bumi nemi a). In thi s pathway, decreased

stretch i n the baroreceptors of the aortic arch and caroti d body and stretch receptors i n the
great veins, pul monary vascul ature, and atria result i n increased sympatheti c tone. Increased
FIGURE 9-4. Top: Rel ati onshi p between pl asma osmol al i ty and pl asma vasopressi n (AVP;
al so referred to as ADH). Bottom: Rel ati onshi p between pl asma AVP and uri nary
osmolal ity. (From Fri ed LF, Palevsky PM: Hyponatremi a and hypernatremi a. Med Cl i n North
Am 81(3):585, 1997.)
P.183
sympatheti c tone, in combinati on wi th decreased renal perfusion, l eads to reni n rel ease and
formation of angiotensi n I from angi otensinogen. Angi otensi n-converting enzyme (ACE)
converts angiotensi n I to angi otensi n II, whi ch sti mul ates the adrenal cortex to synthesize and
rel ease aldosterone.
31, 32
Acti ng pri mari l y i n the distal tubul es, hi gh concentrati ons of
al dosterone cause sodi um reabsorpti on and may reduce uri nary excreti on of sodium nearl y to
zero. Intrarenal physi cal factors are al so important i n regulating sodi um bal ance. Sodi um
loadi ng decreases col loi d osmotic pressure, thereby i ncreasing the glomerul ar fil trati on rate
(GFR), decreasing net sodium

reabsorpti on and i ncreasing di stal sodium deli very, whi ch, i n turn, suppresses renin secreti on.
Fl ui d Repl acement Ther apy
Maintenance Requirements for Water, Sodium, and Potassium
Two si mpl e formul as are used i nterchangeabl y to esti mate maintenance water requirements
(Tabl e 9-11). In healthy adults, suffici ent water i s required to bal ance gastrointestinal l osses of
100 to 200 mL/day, i nsensi bl e losses of 500 to 1,000 mL/day (hal f of whi ch is respi ratory and
half is cutaneous), and uri nary l osses of 1,000 mL/day. Uri nary losses exceeding 1,000 mL/day
may represent an appropri ate physiol ogi c response to ECV expansi on or an inabi l ity to conserve
salt or water.
Dai l y requi rements for sodi um and potassi um are approxi mately 75 mEq/L and 40 mEq/L,
respectively, although wi der ranges of sodi um i ntake than potassi um intake are physi ol ogicall y
tol erated because renal sodi um conservati on and excreti on are more effi cient than potassi um
conservati on and excreti on. Therefore, heal thy, 70-kg adul ts requi re 2,500 mL/day of water
contai ning a [Na
+
] of 30 mEq/L and a [K
+
] of 15 to 20 mEq/L. Intraoperati vely, fl ui ds
contai ning sodi um-free water (i .e., [Na
+
] <130 mEq/L) are rarel y used in adul ts, because of
the necessi ty for repl acing isotoni c l osses and the ri sk of postoperati ve hyponatremi a.
Dextrose
Traditi onal l y, gl ucose-contai ning i ntravenous fl ui ds have been given i n an effort to prevent
hypogl ycemi a and l i mi t protein catabol ism. However, because of the hyperglycemi c
response associated wi th surgi cal stress, only i nfants and patients recei vi ng i nsuli n or drugs
that interfere wi th gl ucose synthesi s are at ri sk for hypogl ycemi a. Iatrogeni c hypergl ycemi a can
li mi t the effectiveness of flui d resuscitati on by induci ng an osmotic di uresi s and, i n ani mals,
may aggravate i schemi c neurologi c injury.
33
Al though associ ated with worse outcome after
subarachnoi d hemorrhage
34
and traumati c brain injury
35
in humans, hyperglycemia may al so
P.184
TABLE 9-11 Maintenance Water Requirements
WEIGHT (kg) mL/kg/hr mL/kg/d
110 4 100
1120 2 50
21n 1 20
consti tute a hormonal l y mediated response to more severe i njury. In criti cal ly il l pati ents,
evidence strongl y suggests that ti ght control of pl asma gl ucose (mai ntenance of pl asma glucose
between 80 and 110 mg/dL) i s associated wi th reduced mortal i ty and morbidi ty.
36, 37, 38, 39

Evi dence also suggests that glucose control i mproves outcome i n surgi cal pati ents.
40

Surgical Fluid Requirements
Water and Electrolyte Composition of Fluid Losses. Surgical pati ents requi re repl acement
of PV and ECV l osses secondary to wound or burn edema, asci tes, and gastrointestinal
secreti ons. Wound and burn edema and asciti c flui d are protein rich and contai n el ectrol ytes in
concentrations si mi lar to pl asma. Although gastroi ntesti nal secreti ons vary greatl y in
composi tion, the composi ti on of replacement flui d need not be closel y matched if ECV is
adequate and renal and cardiovascular functi ons are normal. Substanti al l oss of gastroi ntesti nal
flui ds requi res more accurate replacement of electrolytes (i.e., potassi um, magnesi um,
phosphate). Chroni c gastri c losses may produce hypochl oremi c metabol ic alkal osi s that can be
corrected wi th 0.9% sal ine; chroni c di arrhea may produce hyperchloremic metabol i c aci dosi s
that may be prevented or corrected by i nfusi on of flui d contai ni ng bi carbonate or bicarbonate
substrate (e.g., l actate). If cardiovascular or renal functi on is impai red, more precise
repl acement may requi re frequent assessment of serum electrolytes.

Fluid Shifts During Surgery. Repl acement of i ntraoperati ve fl ui d l osses must i ncl ude
consi derati on of fl uid that accumul ates extravascul arl y in surgicall y mani pul ated tissue.
Therefore, gui deli nes have been devel oped for replacement of fluid losses duri ng surgi cal
procedures. The si mpl est formula provides, i n addi ti on to mai ntenance fl ui ds and repl acement
of esti mated bl ood l oss, 4 mL/kg/h for procedures i nvol vi ng mi nimal trauma, 6 mL/kg/h for
those i nvol vi ng moderate trauma, and 8 mL/kg/h for those involving extreme trauma.
However, formulas for intraoperative fl ui d repl acement wi ll no doubt undergo consi derable
debate and reformulation over the next few years. Cli ni cal tri als suggest that
peri operative fl ui d management may strongly i nfl uence both minor and major morbidi ty and
that the i nfluence may be speci fi c to the type of surgery and to the types of fl ui d used.
Yogendran et al
41
randomi zed 200 ASA IIII, ambul atory surgi cal patients to receive either 20
mL/kg or 2 mL/kg of Pl asmal yte as a bol us over 30 minutes before surgery; patients recei vi ng
the hi gher dose had less postoperati ve thi rst, drowsi ness, dizzi ness, and nausea. Holte et al
42

randomi zed 48 ASA III pati ents undergoi ng l aparoscopi c chol ecystectomy to recei ve ei ther 15
mL/kg or 40 mL/kg of l actated Ringer' s sol uti on intraoperati vely; the hi gher dose of fl ui d was
associated wi th improved postoperati ve pul monary functi on and exercise capaci ty, reduced
neurohumoral stress response, and i mprovements in nausea, general sense of wel l -bei ng,
thirst, di zziness, drowsiness, fati gue, and bal ance functi on. In marked contrast, Brandstrup et
al
43
randomi zed 172 electi ve colon surgery patients to ei ther restri cti ve perioperative fl ui d
management or standard peri operati ve fl ui d management with the pri mary goal of maintai ni ng
preoperati ve body wei ght i n the fl ui d-restri cted group. By desi gn, the fl ui d-restri cted group
recei ved less peri operati ve fl uid and acutel y gai ned <1 kg in contrast to >3 kg in the standard
therapy group.
More importantl y, total postoperati ve compli cati ons were si gni fi cantl y fewer in the fluid-
restricted group (Tabl e 9-12). Cardi opulmonary and ti ssue-heal i ng compl i cati ons were also
si gni fi cantl y reduced i n association wi th fl ui d restriction.
P.185
TABLE 9-12 Number of Patients with Complications (Per-protocol Analysis)
BLINDED ASSESSMENT UNBLINDED ASSESSMENT
RESTRICTED STANDARD P RESTRICTED STANDARD P
Mobilization of Expanded Interstitial Fluid
An i mportant corol l ary of peri operati ve IFV expansion is the mobil i zati on and return of
accumul ated fl ui d to the ECV and the PV, col loqui all y termed deresusci tation. In most
patients, mobi l izati on occurs on approxi matel y the thi rd postoperative day. If the
cardi ovascul ar system and kidneys cannot effecti vel y transport and excrete mobil i zed fl uid,
such as in the pati ent with borderl i ne cardi ac function, hypervol emi a and pul monary edema
may occur.
Col l oi ds, Cr yst al l oi ds, and Hyper t oni c Sol ut i ons
Physiology and Pharmacology
Osmoti cal l y acti ve parti cl es attract water across semipermeable membranes unti l equi l ibri um is
attai ned. The osmolarity of a solution refers to the number of osmoti cal l y active particl es per
li ter of sol vent; osmolal ity, a measurement of the number of osmoti cal ly active particl es per
ki logram, can be esti mated as foll ows:

where osmol al i ty i s expressed i n mOsm/kg, [Na
+
] i s expressed i n mEq/L, serum gl ucose i s
expressed i n mg/dL, and BUN i s bl ood urea ni trogen expressed i n mg/dL. Sugars, al cohol s, and
GROUP GROUP value GROUP GROUP val
Overal l
compl i cati ons
21 40 0.003 21 43 0.0
Major
compl i cati ons
a
8 18 0.040 8 19 0.0
Mi nor
compl i cati ons
a
15 36 0.000 15 37 0.0
Ti ssue-heal i ng
compl i cati ons
a
11 22 0.040 10 24 0.0
Cardiopulmonary
compl i cati ons
a
5 17 0.007 4 18 0.0
n = 69 in restri cted group and n = 72 i n standard group.
a
Number of pati ents i n subgroups does not add up to number of overall compl icati ons because som
patients had more than one compl icati on.
From Brandstrup B, Tonnesen H, Bei er-Hol gersen R et al : Effects of i ntravenous fl ui d restri cti on on
postoperative compl i cations: Compari son of two peri operati ve fl uid regi mensA randomi zed
assessor-bl i nded multi center tri al . Ann Surg 238:641, 2003.
radi ographi c dyes i ncrease measured osmolal ity, generating an i ncreased osmolal gap
between the measured and cal cul ated val ues.
A hyperosmol ar state occurs whenever the concentrati on of osmotical l y acti ve parti cl es i s hi gh.
Both uremi a (i ncreased BUN) and hypernatremi a (increased serum sodium) i ncrease serum
osmolal ity. However, because urea di stri butes throughout TBW, an increase i n BUN does not
cause hypertoni ci ty. Sodi um, l argel y restri cted to the ECV, causes hypertonici ty, that i s,
osmoti cal l y mediated redi stributi on of water from ICV to ECV. The term toni city is also used
coll oqui al l y to compare the osmotic pressure of a parenteral sol ution to that of plasma.
Although onl y a smal l proporti on of the osmoti cal l y acti ve particl es i n blood consi st of pl asma
protei ns, those parti cl es are essential i n determi ni ng the equi li brium of fl ui d between the
intersti ti al and pl asma compartments of ECV. The refl ection coeffi cient () descri bes the
permeabi l i ty of capi l l ary membranes to i ndividual sol utes, wi th 0 representi ng free permeabi li ty
and 1.0 representi ng compl ete impermeabi li ty. The reflection coeffi cient for al bumi n ranges
from 0.6 to 0.9 i n vari ous capi l l ary beds. Because capi l l ary protei n concentrations exceed
intersti ti al concentrations, the osmotic pressure exerted by pl asma protei ns (termed coll oid
osmoti c pressure or oncoti c

pressure) i s hi gher than intersti ti al oncotic pressure and tends to preserve PV. The fi ltration
rate of flui d from the capi ll ari es into the interstiti al space is the net resul t of a combi nation of
forces, i ncl udi ng the gradi ent from i ntravascular to i nterstiti al col l oi d osmotic pressures and
the hydrostati c gradi ent between i ntravascular and intersti tial pressures. The net fl uid fil tration
at any poi nt wi thi n a systemi c or pulmonary capil l ary i s represented by Starl ing' s law of
capil l ary fil tration, as expressed i n the equation:

where Q = fl uid fil tration, k = capi ll ary fi ltrati on coeffi cient (conductivity of water), A = the
area of the capillary membrane, P
c
= capi l l ary hydrostati c pressure, P
i
= i nterstiti al hydrostatic
pressure, = refl ecti on coeffici ent for al bumin,
i
= i nterstiti al col loi d osmotic pressure, and
c

= capi l lary col l oi d osmoti c pressure.
The IFV is determined by the rel ati ve rates of capi ll ary fi l trati on and l ymphati c drai nage. P
c
,
the most powerful factor promoti ng fl ui d fi l trati on, i s determi ned by capill ary fl ow, arteri al
resistance, venous resi stance, and venous pressure. If capi ll ary fi ltrati on i ncreases, the rates
of water and sodi um fil trati on usual l y exceed protei n fi l trati on, resul ti ng in preservation of
c
,
di l uti on of
i
, and preservati on of the oncoti c pressure gradi ent, the most powerful factor
opposi ng fl ui d fi l trati on. When coupl ed wi th i ncreased l ymphati c drai nage, preservati on of the
oncoti c pressure gradi ent l imits the accumul ati on of IF. If P
c
increases at a ti me when
lymphatic drai nage i s maxi mal , then IFV accumulates, forming edema.
Clinical Implications of Choices Between Alternative Fluids
If membrane permeabi l ity is i ntact, coll oi ds such as albumi n or hydroxyethyl starch
preferential ly expand PV rather than IFV. Concentrated col loi d-contai ning sol uti ons (e.g., 25%
al bumin) exert suffici ent oncoti c pressure to transl ocate substanti al vol umes of IFV into the PV.
Pl asma volume expansion unaccompani ed by IFV expansi on offers apparent advantages: l ower
fl ui d requi rements, l ess peri pheral and pulmonary edema accumulation, and reduced concern
about the cardi opulmonary consequences of l ater fl ui d mobil i zati on.
However, exhaustive research has fai led to establi sh the superi ori ty of ei ther coll oid-contai ning
or crystal l oi d-contai ning fl ui ds (Tabl e 9-13). Systematic revi ews of avai l abl e compari sons of
coll oid versus crystall oid
44
and albumi n versus crystal l oi d
45
suggest unchanged mortal i ty
associated wi th col l oi d use, al though crystal loi d may be superi or i n mul tipl y traumatized
patients.
46
Despi te the l ack of compel l ing evi dence suggesti ng that perioperative use of col l oi d
infl uences mortali ty, Moretti et al
47
reported that pati ents who were randomized to recei ve 6%
hetastarch had l ess postoperati ve nausea and vomi ting than those who recei ved l actated
Ri nger' s sol ution wi thout col loi d. In addi ti on, col l oi d admi nistrati on appears to have been an
P.186
essential component of peri operati ve management strategies that demonstrated i mproved
morbi dity after col on surgery
43
and after major surgery i n conjunction wi th goal -di rected fl ui d
chal l enges.
48, 49

Although hydroxyethyl starch, the most commonl y used syntheti c col loi d, i s less expensi ve than
al bumi n, l arge doses (exceedi ng 20 mL/kg/d) produce l aboratory evidence of coagulopathy.
50

Recentl y, a new hydroxyethyl starch formulati on has been i ntroduced that contains a different
mi x of mol ecul ar sizes and i s di ssol ved i n a base consi sti ng of a bal anced sal t soluti on rather
than 0.9% sal i ne. Proposed advantages of the new formul ati on i ncl ude l ess risk of induci ng
coagulopathy and of hyperchl oremi c metabol ic aci dosi s.
51
However, l ower mol ecular wei ght
hetastarch formul ati ons appear to i nfl uence coagul ati on l ess.
50
Further refi nement is li kel y to
occur in the di sti nctions among vari ous cl i ni cal l y avail able col loi ds.
52

Implications of Crystalloid and Colloid Infusions on Intracranial
Pressure
Because the cerebral capi ll ary membrane, the blood-brai n barri er, i s hi ghl y i mpermeable to
sodi um, abrupt changes i n serum osmol al i ty produced by changes i n serum sodi um produce
reciprocal changes in brai n water. In anestheti zed rabbi ts, reduci ng pl asma osmol al i ty from 295
mOsm/kg to 282 mOsm/kg (whi ch decreases plasma osmoti c pressure by ~250 mmHg)
increased cortical water content and ICP; i n contrast, reduci ng col loi d osmotic pressure from 20
to 7 mmHg produced no si gni fi cant change i n ei ther vari abl e.
53
Si mi lar independence of brai n
TABLE 9-13 Claimed Advantages and Disadvantages of Colloid vs. Crystalloid
Intravenous Fluids
SOLUTION ADVANTAGES DISADVANTAGES
Col l oi d Small er infused vol ume Greater cost
Prolonged i ncrease i n pl asma
vol ume Greater peri pheral edema
Less cerebral edema
Coagul opathy (dextran > HES)
Pul monary edema (capil l ary l eak
states)
Decreased GFR
Osmoti c di uresi s (l ow mol ecul ar
weight dextran)
Crystal l oi d Lower cost Transient hemodynamic
improvement
Greater urinary flow Peri pheral edema (protei n
di l uti on)
Repl aces i ntersti tial fl ui d Pul monary edema (protei n
di l uti on pl us hi gh PAOP)
HES, hydroxyethyl starch; GFR, glomerul ar fi ltration rate; PAOP, pulmonary arterial
occl usi on pressure.
water and ICP from col l oi d osmotic pressure has been demonstrated wi th prolonged
hypoal bumi nemi a
54
and i n animal s after forebrai n ischemi a
55
and focal cryogeni c injury.
56
In
contrast, after fl ui d percussi on brai n i njury, i ncreasing col l oi d oncoti c pressure wi th hetastarch
reduced brai n water i n compari son to i nfusion of 0.9% sal i ne (Fi g. 9-5).
57

Clinical Implications of Hypertonic Fluid Administration
An i deal al ternati ve to conventi onal crystall oid and col l oi d fl ui ds woul d be i nexpensi ve, woul d
produce mi ni mal peri pheral or pul monary edema, woul d generate sustai ned hemodynami c
effects, and would be effective even if admini stered i n small vol umes. Hypertoni c,
hypernatremi c sol utions appear to ful fi l l some of these criteri a (Tabl e 9-14).
FIGURE 9-5. The percentage of water content (mean SD; wet-dry method) of the
percussed (ri ght) hemi sphere and in the contral ateral (left) hemi sphere i n ani mals that
underwent i sovol emi c exchange with whol e blood, hetastarch, normal sal ine, or half-
normal sal ine. Wi thin each group, the water content of the percussed hemisphere was
greater than the water content of the contral ateral hemisphere. *P <0.05 versus the
correspondi ng hemi sphere in the whol e bl ood and hetastarch groups. (From Drummond JC,
Patel PM, Cole DJ et al : The effect of the reducti on of coll oi d oncotic pressure, wi th and
without reduction of osmol al i ty, on post-traumati c cerebral edema. Anesthesi ol ogy
88:993, 1998.)
P.187
TABLE 9-14 Hypertonic Resuscitation fluids: Advantages and Disadvantages
SOLUTION ADVANTAGES DISADVANTAGES
Hypertoni c crystal loi d Inexpensive Hypertoni ci ty
Promotes uri nary fl ow Subdural hemorrhage
Small i ni tial volume Transient effect
Current enthusi asm for hypertoni c resuscitati on was sti mulated by the work of Vel asco et al
58

who successful l y used small vol umes (6.0 mL/kg) of 7.5% hypertonic sal i ne as the sol e
resusci tati ve measure in dogs after severe hemorrhage. Hypertoni c sol uti ons exert favorabl e
effects on cerebral hemodynami cs, in part because of the reci procal rel ati onshi p between
pl asma osmol al i ty and brai n water.
53
ICP i ncreased during resuscitati on from hemorrhagi c
shock with lactated Ringer' s sol ution but remained unchanged i f 7.5% sal ine was i nfused i n a
suffi ci ent vol ume to comparably i mprove systemi c hemodynami cs.
59
However, improvements in
ICP gradual ly are l ost. Del ayed increases i n ICP were reported after hypertonic resuscitati on
from hypovolemic shock accompani ed by an i ntracrani al mass lesi on.
60
In additi on, systemic
hemodynamic improvement produced by hypertoni c resusci tati on i s short l i ved.
59
Strategi es to
prolong the therapeutic effects beyond 30 to 60 mi nutes i ncl ude continued i nfusion of
hypertoni c sal i ne, subsequent i nfusion of blood or conventi onal fl uids, or addi tion of coll oid to
hypertoni c resuscitati on.
Despi te concerns about central nervous system dysfuncti on because of hypertonici ty and
hypernatremi a associ ated wi th hypertoni c sal ine, acute increases i n serum sodi um from 155 to
160 mEq/L produced no apparent harm i n humans resusci tated wi th hypertonic sali ne.
61
Central
ponti ne myel inol ysi s, whi ch fol l ows rapid correcti on of severe, chroni c hyponatremia, has not
been observed i n cl ini cal tri al s of hypertonic resuscitati on. Despi te theoreti cal consi derations
favoring the use of hypertoni c sal ine i n resusci tati on of pati ents wi th traumati c brain i njury, a
randomi zed tri al fai led to demonstrate an i mprovement i n outcome.
62

Wi l l cl i ni cians routi nel y use hypertonic or combi nation hypertonic/hyperoncotic fl uids for
resusci tati on i n the future? Pending further precl inical work, the theoreti cal advantages of such
fl ui ds appear most attracti ve i n the acute resusci tation of hypovol emi c patients who have
decreased intracrani al compl iance.
63

Improved myocardi al
contracti l ity?
Arteri ol ar di l ati on
Reduced peri pheral
edema
Lower i ntracrani al
pressure
Hypertoni c crystal l oi d pl us
coll oid (i n compari son to
hypertoni c crystal l oi d alone)
Sustai ned
hemodynamic
response
Reduced subsequent
vol ume requi rements
Added expense
Coagul opathy
(dextran > HES)
Osmoti c di uresi s
Impai red crossmatch
(dextran)
Hypertoni ci ty
HES, hydroxyethyl starch.
From Prough DS, Johnston WE: Fl ui d resuscitati on i n septi c shock: No sol ution yet.
Anesth Anal g 69:699, 1989.
Fl ui d St at us: Assessment and Moni t or i ng
Assessment of Hypovolemia and Tissue Hypoperfusion
For most surgical pati ents, conventional cl i ni cal assessment of the adequacy of intravascul ar
vol ume i s appropri ate. For high-ri sk pati ents, goal -di rected hemodynami c management may be
superi or.
Conventional Clinical Assessment. Cl i ni cal quanti fi cati on of bl ood vol ume and ECV begi ns
with recogni ti on of defi ci t-generati ng settings, such as bowel obstruction, preoperati ve bowel
preparati on, chroni c diuretic use, sepsi s, burns, and trauma. Physi cal si gns that suggest
hypovolemia i ncl ude ol iguri a, supi ne hypotensi on, and a positi ve ti l t test. Ol i guria

impli es hypovol emi a, al though hypovol emi c pati ents may be nonol i guric and normovol emi c
patients may be oli guri c because of renal fai lure or stress-induced endocri ne responses.
64

Supi ne hypotensi on i mpl i es a blood vol ume defi ci t exceedi ng 30%, al though arteri al bl ood
pressure withi n the normal range coul d represent rel ati ve hypotensi on in an el derl y or
chroni cal l y hypertensi ve pati ent.
In the til t test, a posi tive response is defi ned as an i ncrease i n heart rate 20 beats/mi n and a
decrease i n systol ic bl ood pressure 20 mmHg when the subject assumes the upright positi on.
However, young, healthy subjects can wi thstand acute l oss of 20% of bl ood volume whi l e
exhi biti ng onl y postural tachycardi a and vari abl e postural hypotensi on. In contrast, orthostasis
may occur i n 20 to 30% of elderl y pati ents despi te normal bl ood vol ume.
65
In vol unteers,
withdrawal of 500 mL of bl ood
66
was associated wi th a greater i ncrease i n heart rate on
standi ng than before bl ood wi thdrawal but no si gni fi cant di fference i n the response of bl ood
pressure or cardiac index.
Laboratory evi dence that suggests hypovol emi a or ECV depleti on includes azotemi a, low uri nary
sodium, metaboli c alkal osi s (i f hypovolemia i s mi l d), and metabol ic acidosi s (if hypovol emi a is
severe). Hematocri t is vi rtual ly unchanged by acute hemorrhage unti l fl ui ds are admi ni stered or
unti l fl ui d shi fts from the i ntersti tial to the intravascul ar space. BUN, normal ly 8.0 to 20 mg/dL,
is i ncreased by hypovol emi a, high protei n i ntake, gastroi ntesti nal bl eedi ng, or accel erated
cataboli sm and decreased by severe hepati c dysfuncti on. Serum creatini ne (SCr), a product of
muscle cataboli sm, may be misl eadi ngl y l ow in el derl y adul ts, femal es, and debi l i tated or
malnouri shed pati ents. In contrast, i n muscul ar or acutely catabol ic pati ents, SCr may exceed
the normal range (0.5 to 1.5 mg/dL) because of more rapi d muscl e breakdown. A rati o of
BUN:SCr exceedi ng the normal range (10 to 20) suggests dehydrati on. In prerenal ol i guria,
enhanced sodi um reabsorption should reduce uri nary [Na
+
] to
20 mEq/L and enhanced water

reabsorpti on shoul d i ncrease urinary concentrati on (i .e., uri nary osmolal ity >400; uri ne/pl asma
creati ni ne rati o >40:1). However, the sensiti vi ty and speci fi city of measurements of uri nary
vari ables may be mi sleading. Although hypovol emi a does not generate metaboli c al kal osi s, ECV
depl etion i s a potent stimul us for the mai ntenance of metabol i c al kal osis. Severe hypovolemia
may result i n systemi c hypoperfusi on and l actic aci dosi s.
Intraoperative Clinical Assessment. Vi sual esti mation, the simplest techni que for
quanti fyi ng i ntraoperati ve bl ood loss, assesses the amount of bl ood absorbed by gauze squares
and l aparotomy pads and adds an esti mate of blood accumul ati on on the floor and surgi cal
drapes and in suction contai ners. Both surgeons and anesthesi ologists tend to underesti mate
losses.
Assessment of the adequacy of i ntraoperati ve fl uid resusci tati on integrates mul ti pl e cl i ni cal
vari abl es, i ncluding heart rate, bl ood pressure, urinary output, arteri al oxygenation, and pH.
Tachycardi a i s an insensiti ve, nonspeci fi c i ndi cator of hypovol emi a. In patients recei vi ng potent
inhalational agents, mai ntenance of a satisfactory bl ood pressure i mpl i es adequate
intravascul ar vol ume. Preservation of bl ood pressure, accompani ed by a CVP of 6 to 12 mmHg,
more strongl y suggests adequate repl acement. During profound hypovol emi a, i ndi rect
measurements of bl ood pressure may significantly underesti mate true bl ood pressure. In
P.188
patients undergoi ng extensi ve procedures, direct arterial pressure measurements are more
accurate than i ndi rect techni ques and provi de convenient access for obtai ni ng arteri al bl ood
sampl es. An addi tional advantage of di rect arteri al pressure monitori ng may be recogni tion of
increased systol ic bl ood pressure variation accompanying posi tive pressure venti lation in the
presence of hypovol emi a.
67, 68

Uri nary output usual l y decli nes preci pi tousl y duri ng moderate to severe hypovol emi a.
Therefore, in the absence of gl ycosuria or diureti c admini stration, a urinary output of 0.5 to 1.0
mL/kg/h duri ng anesthesi a suggests adequate renal perfusi on. Arterial pH may decrease onl y
when ti ssue hypoperfusi on becomes severe. Cardi ac output can be normal despi te severel y
reduced regi onal bl ood fl ow. Mi xed venous hemogl obi n desaturati on, a specific indi cator of poor
systemi c perfusi on, refl ects average perfusi on in mul ti pl e organs and cannot suppl ant regi onal
moni tors such as uri nary output.
Oxygen Delivery as a Goal of Management. No i ntraoperati ve moni tor is suffi ci entl y
sensi ti ve or speci fi c to detect hypoperfusi on in all patients. One key variabl e that has been
associated wi th improved outcome in high-ri sk surgical patients and cri ti cal ly i ll patients i s a
systemi c oxygen del i very (Do
2
)
600 mL O
2
/m
2
/min (equival ent to a CI of 3.0 L/m
2
/min, a
[Hgb] of 14 g/dL, and 98% oxyhemogl obi n saturati on). Boyd et al randomi zed 107 pati ents to
conventi onal treatment or fl ui d pl us dopexami ne to mai ntai n oxygen del i very 600 mL
O
2
/m
2
/mi n and demonstrated a decrease i n mortal i ty and i n the number of compli cati ons in the
pati ents managed at the higher l evel of oxygen del i very.
69
Based on these resul ts, the authors
calculated that the cost of obtai ni ng a survi vor was 31% lower in the protocol group.
70
Wil son
et al randomi zed 138 pati ents undergoi ng major el ecti ve surgery into three groups.
71
One
group recei ved routine peri operati ve care; one recei ved fl ui d and dopexami ne preoperati vel y,
i ntraoperati vel y, and postoperati vely to mai ntain oxygen deli very
600 mL O
2
/m
2
/min; and the
third recei ved fl uid pl us epi nephri ne preoperativel y, intraoperatively, and postoperati vel y to
achi eve the same end poi nts. In the two groups i n whi ch oxygen del i very was supported, onl y 3
of 92 died, compared to 8 of 46 control pati ents. However, the compl i cation rate was
si gni fi cantl y lower in the dopexami ne group than i n the epi nephri ne group. In contrast, Hayes
et al , who randomi zed 109 pati ents to conventi onal treatment or oxygen del i very 600 mL
O
2
/m/min usi ng a combi nati on of vol ume and dobutami ne, demonstrated an increase i n
mortal i ty i n the treatment group maintai ned at the higher l evel s and speculated that aggressive
el evati ons i n Do
2
actuall y may have been harmful .
72

At present, avai l abl e data are consi stent wi th several i nferences. Fi rst, there i s no apparent
benefi t for pati ents other than surgi cal pati ents
73
and pati ents undergoi ng i ni tial resuscitati on
from septic shock i n the emergency room.
74
In surgical pati ents, early i ni ti ati on of goal -
di rected resusci tati on i s associ ated with better outcome than del ayed ini ti ati on.
75
Second,
outcome may be strongl y infl uenced by the choice of i notropi c agents. Thi rd, i ncreased fl ui d
gi ven as part of goal -oriented resusci tation has been associ ated with an i ncreased incidence of
abdomi nal compartment syndrome i n trauma pati ents.
76

Several studi es have reported improved outcome based on adjustment of peri operati ve fluids
through the use of an esophageal Doppl er monitor that esti mates descending aorti c bl ood fl ow
and quanti fi es the duration of systole.
77
Usi ng the esophageal Doppl er to gui de admi ni strati on
of col l oi d bol uses, Venn et al
48
and Gan et al
49
have reported shortened length of hospi tal stay
after hi p surgery and major surgery, respectively. Horowi tz and Kumar
78
have specul ated that
the infusi on of coll oi d and not the moni tor-dri ven al gori thm were responsi bl e for the i mproved
resul ts.
ELECTROLYTES
Sodi um
Physiologic Role
Na
+
, the princi pal extracel lul ar cati on and sol ute, i s essenti al for generati on of acti on
potential s in neurol ogi c and cardiac ti ssue. Di sorders (pathol ogi cal i ncreases or decreases) of
total body sodi um are associ ated with correspondi ng increases or

decreases of ECV and PV. Di sorders of sodi um concentration, that i s, hyponatremi a and
hypernatremi a, usual ly resul t from rel ati ve excesses or defi ci ts, respecti vely, of water.
Regulation of total body sodi um and [Na
+
] i s accompl ished pri maril y by the endocri ne and renal
systems (Tabl e 9-15). Secreti on of al dosterone and ANP control total body sodi um. ADH, which
is secreted in response to i ncreased osmol al i ty or decreased bl ood pressure, pri mari l y regul ates
[Na
+
].

P.189
TABLE 9-15 Regulation of Electrolytes
ELECTROLYTE REGULATED BY
Sodium Al dosterone
ANP
[Na
+
] al tered by ADH
Potassium Al dosterone
Epi nephri ne
Insuli n
Intrinsic renal mechani sms
Calcium PTH
Vitamin D
Phosphorus Pri mari l y renal mechani sms
Mi nor: PTH
Magnesi um Pri mari l y renal mechani sms
Mi nor: PTH, vi tamin D
ANP, atri al natri ureti c pepti de; [Na
+
], sodium concentration;

ADH, anti diuretic hormone; PTH, parathyroi d hormone.
Hyponatremia
Hyponatremi a, defi ned as [Na
+
] <130 mEq/L, is the most common electrolyte di sturbance i n
hospi tal ized pati ents. In the majority of hyponatremic, hospi tal ized pati ents, total body sodi um
is normal or i ncreased. The most common cl inical associ ations with hyponatremi a i ncl ude the
postoperative state, acute i ntracrani al di sease, mal i gnant di sease, medi cations, and acute
pul monary disease. Hyponatremi a is associ ated with substanti al l y increased mortal i ty,
79
both as
a di rect effect of hyponatremia and because hyponatremia i s associ ated wi th severe systemi c
di sease.
The signs and symptoms of hyponatremi a depend on both the rate and severi ty of the decrease
in pl asma [Na
+
]. Symptoms that can accompany severe hyponatremia ([Na
+
] <120 mEq/L)
incl ude loss of appetite, nausea, vomi ti ng, cramps, weakness, altered level of consci ousness,
coma, and sei zures.
Acute CNS mani festations relate to brai n overhydrati on. Because the blood-brain barrier i s
poorl y permeabl e to sodi um but freel y permeabl e to water, a rapi d decrease i n pl asma [Na
+
]
promptly i ncreases both extracel l ul ar and i ntracel lular brai n water. Because the brai n rapi dl y
compensates for changes in osmol ali ty, acute hyponatremi a produces more severe symptoms
than chronic hyponatremi a. The symptoms of chroni c hyponatremi a probabl y rel ate to depl etion
of brain el ectrol ytes. Once brai n volume has compensated for hyponatremi a, rapi d i ncreases i n
[Na
+
] may l ead to abrupt brai n dehydrati on.

Hyponatremi a is cl assified as pseudohyponatremi a or true hyponatremi a. Pseudohyponatremi a
was an arti fact associated wi th the use of flame photometry, now an obsol ete techni que, to
measure pl asma [Na
+
] in severel y hyperprotei nemic or hyperl ipi demi c pati ents. The current
anal ytic method, di rect potenti ometry, di rectly measures [Na
+
] and is uninfl uenced by
nonaqueous components such as protei ns and l i pi ds.
In true hyponatremi a, serum osmolal ity may be normal, high, or low (Fi g. 9-6). Hyponatremi a
with a normal or hi gh serum osmol al i ty resul ts from the presence of a nonsodium solute, such
as gl ucose or mannitol, whi ch hol ds water wi thi n the extracel l ul ar space and resul ts i n
di l uti onal hyponatremi a. The presence of a nonsodi um sol ute (or of facti tious hyponatremia)
may be i nferred if measured osmolal ity exceeds cal cul ated osmol al i ty by >10 mOsm/kg. For
exampl e, pl asma [Na
+
] decreases approximatel y 2.4 mEq/L for each 100-mg/dL ri se i n gl ucose
concentration, wi th perhaps even greater decreases as glucose concentrati on >400 mg/dL.
80
In
anesthesia practice,

a common cause of hyponatremi a associ ated wi th a normal osmolal ity is the absorpti on of l arge
vol umes of sodi um-free irrigati ng sol utions (contai ni ng manni tol , gl yceri ne, or sorbi tol as the
solute) during transurethral resecti on of the prostate.
81
Neurol ogi c symptoms are mi nimal i f
manni tol i s empl oyed because the agent does not cross the bl ood-brai n barrier and i s excreted
with water i n the urine. In contrast, as gl ycine or sorbi tol i s metabol ized, hypoosmol ali ty wi l l
gradual l y devel op and cerebral edema may appear as a l ate compl icati on, that is,
hypoosmol al i ty i s more i mportant i n generati ng symptoms than hyponatremi a per se.
81
True
hyponatremi a wi th a normal or el evated serum osmol ali ty al so may accompany renal
insuffi ciency. BUN, included in the calcul ati on of total osmol al i ty, di stri butes throughout both
ECV and ICV. Calculation of effecti ve osmol al i ty (2[Na
+
] + gl ucose/18) excl udes the
contri buti on of urea to toni city and demonstrates true hypotonici ty.
P.190
True hyponatremi a wi th l ow serum osmol ali ty may be associ ated with a hi gh, low, or normal
total body sodi um and PV. Therefore, hyponatremia with hypoosmol ali ty (see Fi g. 9-6) i s
eval uated by assessi ng total body sodi um content, BUN, SCr, uri nary osmol al i ty, and uri nary
[Na
+
]. Hyponatremi a wi th i ncreased total body sodi um i s characteri sti c of edematous states,
that i s, congestive heart fai lure, ci rrhosi s, nephrosi s, and renal fai l ure. Aquapori n 2, the
vasopressi n-regul ated water channel , i s upregul ated i n experi mental congesti ve heart fai l ure
82

and ci rrhosi s
83
and decreased by chronic vasopressi n sti mul ati on.
84
In pati ents wi th renal
insuffi ciency, reduced urinary dil uti ng capaci ty can lead to hyponatremi a i f excess free water is
gi ven.
The underl yi ng mechani sm of hypovol emi c hyponatremi a i s secreti on of ADH in response to
vol ume contracti on in associ ati on with ongoi ng oral or intravenous i ntake of hypotoni c fl ui d.
85

Angi otensi n II al so decreases renal free water clearance. Thi azide di ureti cs, unli ke l oop
di uretics, promote hypovol emi c hyponatremi a by i nterferi ng wi th urinary dil uti on i n the distal
tubul e.
85
Hypovolemic hyponatremi a associ ated wi th a uri nary [Na
+
]
20 mmol /L suggests
mi neral ocorticoid defici ency, especi all y if serum [K
+
], BUN, and SCr are i ncreased.
85

The cerebral sal t-wasting syndrome i s an often severe, symptomati c sal t-losi ng diathesis that
appears to be medi ated by brai n natri ureti c pepti de
86
and i s i ndependent of the syndrome of
i nappropri ate anti di ureti c hormone (SIADH) secreti on; patients at ri sk i ncl ude those wi th
cerebral lesions as a resul t of trauma, subarachnoid hemorrhage, tumors, and i nfection.
87, 88, 89

Euvol emi c hyponatremia most commonly i s associ ated wi th nonosmotic vasopressin secreti on,
for exampl e, gl ucocorti coi d defi ci ency, hypothyroi di sm, thi azi de-induced hyponatremia, SIADH,
and the reset osmostat syndrome. Total body sodi um and ECV are rel atively normal and edema
is rarely evi dent. SIADH may be i diopathi c but also i s associ ated wi th di seases of the central
nervous system and wi th pulmonary disease (Tabl e 9-16). Euvol emi c hyponatremia i s usual ly
FIGURE 9-6. Al gorithm by whi ch hyponatremia can be eval uated.
associated wi th exogenous ADH admini stration, pharmacologi c potentiation of ADH acti on,
drugs that mi mi c the acti on of ADH i n the renal tubul es or excessi ve ectopic ADH secreti on.
Ti ssues from some smal l -cel l lung cancers, duodenal cancers, and pancreatic cancers i ncrease
ADH production in response to osmoti c sti mulation.
90

TABLE 9-16 Causes of the Syndrome of Inappropriate Secretion of Antidiuretic
Hormone (SIADH)
Neoplasms
Bronchogeni c carci noma
Pancreati c carci noma
Carci noma of the duodenum
Prostate carci noma
Thymoma
Lymphoma
Mesothel i oma
Central nervous system diseases
Head trauma
Subdural hematoma
Subarachnoid hemorrhage
Cerebrovascular accident
Meningiti s
Encephal i ti s
Brai n abscess
Hydrocephalus
Brain tumors
Guil l ai n-Barr
Acute intermi ttent porphyri a
Del i ri um tremens
Pul monary diseases
Tubercul osi s
Pneumoni a
Bronchi ectasi s
Aspergi l l osi s
Cysti c fi brosi s
Posi ti ve pressure venti l ati on
Medi cati ons
Opiates
Chl orpropami de
Carbamazepine
Phenothiazi nes
Tricycl ic anti depressants
Clofi brate
Vi ncri sti ne
Cyclophosphami de
Oxytoci n
Mi scel l aneous
General surgery
Pai n
Nausea
Psychosi s
At l east 4% of postoperati ve patients devel op pl asma [Na
+
] <130 mEq/L.
91
Al though
neurol ogic manifestati ons usual ly do not accompany postoperati ve hyponatremia, si gns of
hypervol emi a are occasional ly present.
91
Much less frequently, postoperati ve hyponatremi a is
accompani ed by mental status changes sei zures and transtentori al herni aton,
92
attri butable i n
part to intravenous admi ni strati on of hypotonic fl ui ds, secreti on of ADH, and other factors,
i ncl udi ng drugs and al tered renal functi on, that i nfl uence peri operati ve water bal ance.
93

Menstruati ng women may be parti cul arly vul nerabl e to brai n damage secondary to
postoperative hyponatremia.
94
Smal l er pati ents change pl asma [Na
+
] more i n response to
si mi l ar vol umes of hypotoni c fl ui ds. In an editori al accompanying a report
95
of apparent
postoperative SIADH i n a 30-kg, 10-year-ol d gi rl , Ari eff
96
suggested that chi ldren recei ve no
sodium-free water peri operati vel y. Postoperati ve hyponatremi a can devel op even with infusi on
of isotoni c fl ui ds if ADH is persi stentl y increased. Twenty-four hours after surgery, mean
pl asma [Na
+
] i n 22 women (mean age 42 years) undergoi ng uncompl i cated gynecologic surgery
had decreased from 140 1 mEq/L to 1360.5 mEq/L.
97
Al though the patients retai ned sodi um
peri operatively, they retai ned proporti onatel y more water (an average of 1.1 L of electrolyte-
free water). Careful postoperati ve attenti on to fl ui d and electrolyte bal ance may minimize the
occurrence of symptomati c hyponatremia.
If both [Na
+
] and measured osmolal ity are below the normal range, hyponatremi a i s further
eval uated by first assessing volume status usi ng physi cal fi ndi ngs and l aboratory data. In
hypovolemic pati ents or edematous pati ents, the rati o of BUN to SCr shoul d be >20:1. Urinary
[Na
+
] i s general l y <15 mEq/L i n edematous states and vol ume depl etion is >20 mEq/L i n
hyponatremi a secondary to renal sal t wasting or renal fai lure wi th water retenti on.
The cri teri a for the di agnosi s of SIADH i ncl ude hypotoni c hyponatremia; urinary osmol al ity
>100 to 150 mOsm/kg; absence of extracel l ul ar vol ume depletion; normal thyroi d and adrenal
functi on; and normal cardiac, hepati c, and renal functi on. Uri nary [Na
+
] shoul d be >30 mEq/L
unl ess fl ui ds have been restricted. Arieff
96
has argued that the di agnosi s of SIADH may be
inaccurately appli ed to functi onal l y hypovol emi c postoperati ve pati ents i n whom, by defi niti on,
ADH secreti on woul d be appropri ate.
Treatment of hyponatremia associ ated with a normal or hi gh serum osmol al i ty requires
reduction of the elevated concentrati ons of the responsibl e sol ute. Uremi c pati ents are treated
by free water restri cti on or dial ysis. Treatment of edematous (hypervol emi c) patients
necessitates restri cti on of both sodi um and water (Fi g. 9-7). Therapy i s di rected toward
i mprovi ng cardi ac output and renal perfusi on and usi ng diuretics

to i nhi bi t sodi um reabsorpti on. In hypovol emi c, hyponatremi c pati ents, bl ood vol ume must be
restored, usuall y by infusi on of 0.9% sali ne, and excessi ve sodi um l osses must be curtai led.
Correction of hypovolemia usual l y resul ts i n removal of the sti mul us for ADH rel ease,
accompanied by a rapi d water di uresi s.
From Fri ed LF, Pal evsky PM: Hyponatremia and hypernatremi a. Med Cl i n North Am 81
(3):585, 1997.
P.191
The cornerstone of SIADH management i s free water restri cti on and eli mi nation of preci pitati ng
causes. Water restri cti on, suffici ent to decrease TBW by 0.5 to 1.0 L/d, decreases ECV even i f
excessive ADH secretion conti nues. The resul tant reducti on i n GFR enhances proxi mal tubul ar
reabsorpti on of sal t and water, thereby decreasi ng free water generati on, and sti mul ates
al dosterone secreti on. As l ong as free water losses (i.e., renal , ski n, gastrointestinal ) exceed
free water intake, serum [Na
+
] wil l i ncrease. Duri ng treatment of hyponatremia, i ncreases in
pl asma [Na
+
] are determi ned both by the compositi on of the i nfused fl ui d and by the rate of
renal free water excretion.
98
Free water excreti on can be i ncreased by admi ni steri ng
furosemi de.
Neurologi c symptoms or profound hyponatremia ([Na
+
] <115 to 120 mEq/L) requires more
aggressi ve therapy. Hypertoni c (3%) sali ne is most clearl y indicated i n pati ents who have
sei zures or pati ents who acutel y devel op symptoms of water i ntoxi cation secondary to
intravenous fl ui d admini stration. In such cases, 3% sal ine may be administered at a rate of 1
to 2 mL/kg/h, to i ncrease plasma [Na
+
] by 1 to 2 mEq/L/h; however, thi s treatment shoul d not
conti nue for more than a few hours. Three percent sal i ne may onl y transi entl y i ncrease pl asma
[Na
+
] because ECV expansion resul ts in i ncreased uri nary sodi um excreti on. Intravenous
furosemi de, combi ned wi th quanti tative repl acement of uri nary sodi um losses wi th 0.9% or
3.0% sal ine, can rapi dly increase pl asma [Na
+
], i n part by i ncreasi ng free water cl earance.

The rate of treatment of hyponatremi a continues to generate controversy, extendi ng from too
fast, too soon to too sl ow, too l ate. Although del ayed correcti on may resul t in neurol ogi c
i njury, i nappropri atel y rapi d correcti on may resul t i n abrupt brai n dehydrati on (Fi g. 9-8) or
permanent neurol ogic sequel ae (i .e., osmoti c demyel i nati on syndrome),
99
cerebral hemorrhage,
or congestive heart fai lure. The symptoms of the osmoti c demyel i nati on syndrome vary from
mi ld (transi ent behavi oral disturbances or sei zures) to severe (i ncl udi ng pseudobul bar pal sy
and quadri paresi s).
100

FIGURE 9-7. Hyponatremi a i s treated according to the eti ology of the di sturbance, the
level of serum osmol al i ty, and a cli nical estimati on of total body sodi um.
The pri nci pal determi nants of neurologi c i njury appear to be the magni tude and chroni ci ty of
hyponatremi a and the rate of correcti on. The osmoti c demyel i nati on syndrome i s more li kel y
when hyponatremia has persi sted >48 hours.
101
Most pati ents in whom the osmoti c
demyel inati on syndrome i s fatal have undergone correcti on of pl asma [Na
+
] of more than 20
mEq/L/day. Other risk factors for the development of the osmoti c demyel inati on syndrome
incl ude al cohol ism, poor nutri ti onal status, l i ver disease, burns, and hypokal emi a.
The cli nici an faces formi dabl e di ffi cul ti es i n predicting the rate at whi ch pl asma [Na
+
] wil l
increase because increases i n pl asma [Na
+
] are determi ned both by the compositi on of the
i nfused fl ui d and by the rate of renal free water excreti on.
98
The expected change i n pl asma
[Na
+
] resul ti ng from 1 l iter of sel ected i nfusate can be esti mated usi ng the fol l owing
equati on:
102

where [Na
+
]
s
= the change in the patient' s serum [Na
+
], [Na
+
]
i nf
= [Na
+
] of the infusate,
[Na
+
]
s
= the patient' s serum [Na
+
], TBW = the pati ent' s estimated total body water i n l i ters,
and 1 = a factor added to take i nto account the vol ume of infusate.
Treatment shoul d be i nterrupted or sl owed when symptoms improve. Frequent determi nati ons
FIGURE 9-8. Brai n water and sol ute in concentrati ons i n hyponatremi a. If normal pl asma
sodium (Na) (A). suddenl y decreased, the i ncrease in brai n water theoreti cal l y would be
proporti onal to the decrease in pl asma Na (B). However, because of adapti ve l oss of
cerebral intracel l ul ar sol ute, cerebral edema i s mi nimized i n chroni c hyponatremi a (C).
Once adaptati on has occurred, a rapi d return of plasma Na concentration toward a normal
l evel resul ts i n brai n dehydrati on (D). (From Sterns RH: Vi gnettes in cl i ni cal
pathophysi ol ogy. Neurol ogical deteri oration fol l owing treatment for hyponatremi a. Am J
Ki dney Dis 13:434, 1989.)
of [Na
+
] are i mportant to prevent correcti on at a rate >10 mEq/L/24hr.
101
Ini ti al l y, plasma
[Na
+
] may be i ncreased by 1 to 2 mEq/L/hr; however, pl asma [Na
+
] should not be i ncreased
more than 10 mEq/L in 24 hours or 25 mEq/L i n 48 hours.
100
Another proposed sequence for
treating symptomati c hyponatremi a i s to i ncrease [Na
+
] promptl y by about 10 mmol , then to
proceed more slowl y. The rational e i s that cerebral water i s i ncreased by approximatel y 10% i n
chroni c hyponatremia.
85
Hypernatremi a shoul d be avoi ded. Once the pl asma [Na
+
] exceeds 120
to 125 mEq/L, water restri cti on alone is usual l y suffi cient to normali ze [Na
+
]. As acute
hyponatremi a i s corrected, CNS si gns and symptoms usual l y i mprove wi thin 24 hours, al though
96 hours may be necessary for maximal recovery.
For pati ents who require l ong-term pharmacologic therapy of hyponatremi a, demecl ocycl i ne i s
now the drug of choi ce.
85
Al though better tol erated than l i thium, demeclocycl i ne may i nduce
nephrotoxi ci ty, a particular concern i n patients with hepati c dysfuncti on. Hemodi alysi s i s
occasional ly necessary i n severel y hyponatremic pati ents who cannot be adequatel y managed
with drugs or hypertoni c sal ine. Once hyponatremia has

improved, careful flui d restri cti on i s necessary to avoid recurrence of hyponatremi a. In the
future, vasopressi n receptor antagoni sts may be used to treat hyponatremia.
103

Hypernatremia
Hypernatremi a ([Na
+
] >150 mEq/L) i ndi cates an absolute or rel ati ve water defici t. Normall y,
sl i ght i ncreases i n toni city or [Na
+
] stimul ate thi rst and ADH secreti on. Therefore, severe,
persistent hypernatremi a occurs onl y i n patients who cannot respond to thirst by voluntary
ingestion of fl ui d, that i s, obtunded pati ents, anesthetized pati ents, and i nfants.
Hypernatremi a produces neurol ogic symptoms (including stupor, coma, and seizures),
hypovolemia, renal insuffi ci ency (occasi onal l y progressi ng to renal fai lure), and decreased
uri nary concentrati ng abi l ity.
104, 105
Because hypernatremi a frequentl y results from di abetes
i nsi pi dus (DI) or osmoticall y induced l osses of sodium and water, many pati ents are
hypovol emi c or bear the sti gmata of renal di sease. Postoperati ve neurosurgical pati ents who
have undergone pi tui tary surgery are at parti cul ar risk of devel opi ng transi ent or prol onged DI.
Pol yuri a may be present for onl y a few days wi thi n the first week of surgery, may be
permanent, or may demonstrate a tri phasic sequence: early DI, return of uri nary concentrati ng
abi li ty, then recurrent DI.
The cli nical consequences of hypernatremia are most seri ous at the extremes of age and when
hypernatremi a devel ops abruptl y. Geri atri c patients are at i ncreased ri sk of hypernatremi a
because of decreased renal concentrati ng abi l ity and thi rst.
106
Brai n shri nkage secondary to
rapi dl y devel opi ng hypernatremi a may damage deli cate cerebral vessel s, l eadi ng to subdural
hematoma, subcorti cal parenchymal hemorrhage, subarachnoi d hemorrhage, and venous
thrombosi s. Polyuria may cause bl adder di stenti on, hydronephrosi s, and permanent renal
damage. At the cel lul ar l evel, restorati on of cel l vol ume occurs remarkabl y qui ckly after tonici ty
is altered (Fi g. 9-9).
107
Al though the mortali ty of hypernatremi a is 40 to 55%, it i s unclear
whether hypernatremia is the cause or a marker of severe associated disease.
P.192
Surpri si ngl y, i f pl asma [Na
+
] i s i ni ti all y normal , moderate acute i ncreases i n plasma [Na
+
] do
not appear to preci pi tate central ponti ne myel inol ysi s. However, larger acci dental i ncreases in
pl asma [Na
+
] have produced severe consequences i n chil dren. In experi mental ani mals, acute
severe hypernatremia (acute i ncrease from 146 to 170 mEq/L) caused neuronal damage at 24
hours, suggestive of earl y central pontine myel i nolysi s.
108

By definiti on, hypernatremia i ndi cates an absol ute or relative water defi ci t and i s always
associated wi th hypertoni ci ty. Hypernatremia can be generated by hypotoni c fl ui d l oss, as i n
burns, GI losses, di ureti c therapy, osmotic di uresi s, renal disease, mineral ocorticoi d excess or
defici ency, and iatrogeni c causes, or can be generated by i sol ated water l oss, as in central or
nephrogeni c DI (Fi g. 9-10). The acquired form of nephrogeni c DI i s more common and usuall y
less severe than the congenital form. As chroni c renal fai l ure advances, most pati ents have
defective concentrati ng abi l ity, resul ting i n resi stance to ADH associated wi th hypotoni c uri ne.
Because hypovol emi a accompani es most pathologi c water loss, si gns of hypoperfusi on al so may
FIGURE 9-9. Acti vati on of mechani sms regulating cel l vol ume i n response to acute
osmoti c stress. Regul atory vol ume decrease and regul atory vol ume increase refer to
compensatory l osses and gai ns of solutes. Al though the course of these regulatory vol ume
decreases and i ncreases varies wi th the type of cel l and experi mental conditi ons, typicall y
the responses occur over a peri od of mi nutes. Returni ng vol ume-regul ated cel ls to
normotonic condi ti ons causes shri nkage or swell i ng. (From McManus ML, Churchwi l l KB,
Strange K: Regul ati on of cel l vol ume in heal th and di sease. N Engl J Med 333:1260,
1995.)
be present. In many patients, before the devel opment of hypernatremia, an increased vol ume
of hypotonic uri ne suggests an abnormal ity in water bal ance. Al though uncommon as a cause of
hypernatremi a, i solated sodi um gai n occasi onal l y occurs in pati ents who recei ve l arge
quantiti es of sodium, such as treatment of metabol ic aci dosi s wi th 8.4% sodium bi carbonate, i n
whi ch [Na
+
] i s approximatel y 1,000 mEq/L, or perioperative or prehospi tal treatment wi th
hypertoni c sal i ne resusci tation solutions.
Hypernatremi c pati ents can be separated i nto three groups, based on cl i ni cal assessment of
ECV (see Fi g. 9-10). Note that plasma [Na
+
] does not refl ect total body sodi um, which must be
esti mated separatel y based on signs of the adequacy of ECV. In polyuric, hypernatremi c
patients, the next di fferential di agnosti c decisi on i s between sol ute di uresi s and DI.
Measurement of uri nary sodi um and osmolal ity can help to differenti ate the

vari ous causes. A uri nary osmol ali ty <150 mOsm/kg i n the setti ng of hypertonici ty and polyuria
is di agnostic of DI.
Treatment of hypernatremia produced by water l oss consi sts of repl eti on of water as wel l as
associated defi ci ts i n total body sodium and other electrolytes (Tabl e 9-17). Common errors i n
treating hypernatremi a i nclude excessi vel y rapi d correction as wel l as fai l i ng to appreci ate the
magni tude of the water defi ci t and fai l i ng to account for ongoi ng mai ntenance requirements and
conti nued flui d l osses i n planning therapy.
FIGURE 9-10. Severe hypernatremi a is eval uated by fi rst separati ng patients i nto
hypovol emic, euvol emic, and hypervol emi c groups based on assessment of extracel lular
vol ume (ECV). Next, potential etiologi c factors are di agnosticall y assessed. [Na
+
], serum
sodium concentration; U
Na
, uri nary sodi um concentrati on; U
OSm
, uri nary osmol al i ty.
P.193
TABLE 9-17 Hypernatremia: Acute Treatment
Sodium depletion (hypovolemia)
Hypovol emi a correcti on (0.9% sal i ne)
Hypernatremi a correcti on (hypotonic fl ui ds)
Sodium overload (hypervolemia)
Enhance sodi um removal (loop di ureti cs, di al ysi s)
Repl ace water defi ci t (hypotoni c fl ui ds)
Normal total body sodium (euvolemia)
The fi rst step in treati ng hypernatremi a is to esti mate the TBW defi ci t, which can be
accompl i shed by i nserti ng the measured plasma [Na
+
] i nto the equation:

where 140 is the mi ddle of the normal range for [Na
+
].

Hypernatremi a must be corrected sl owl y because of the ri sk of neurologi c sequel ae such as
sei zures or cerebral edema (Fi g. 9-11).
109
At the cel l ul ar l evel , restorati on of cel l vol ume
occurs remarkabl y qui ckly after tonici ty i s al tered; as a consequence, acute treatment of
hypertoni city may result i n overshooting the ori ginal , normotonic cel l vol ume.
107, 109
The water
defici t should be repl aced over 24 to 48 hours, and the plasma [Na
+
] shoul d not be reduced by
more than 1 to 2 mEq/L/h. Reversi bl e underl yi ng causes should be treated. Hypovol emi a shoul d
be corrected promptl y wi th 0.9% sal i ne. Although the [Na
+
] of 0.9% sal ine is 154 mEq/L, the
solution i s effective in treati ng vol ume defi ci ts and wi l l reduce [Na
+
] that exceeds 154 mEq/L.
Once hypovol emi a i s corrected, water can be repl aced oral ly or with intravenous hypotoni c
flui ds, depending on the abi l ity of the pati ent to tolerate oral hydrati on. In the occasi onal
sodi um-overl oaded pati ent, sodi um excreti on can be accelerated usi ng loop diureti cs or
di alysi s.
Repl ace water defi ci t (hypotoni c fl ui ds)
Control di abetes i nsi pi dus
Central di abetes i nsi pi dus:
DDAVP, 1020 g intranasal ly; 24 g sc
Aqueous vasopressi n, 5 U q 24 hours im or sc
Nephrogeni c di abetes i nsi pi dus:
Restri ct sodi um, water i ntake
Thi azi de di ureti cs
FIGURE 9-11. A. The concentrati on of sodi um i s refl ected i n the intensity of the
The management of hypernatremia secondary to DI vari es accordi ng to whether the eti ol ogy i s
central or nephrogenic (see Tabl e 9-17). The two most sui tabl e agents for correcting central DI
(an ADH defi ci ency syndrome) are desmopressin (DDAVP) and aqueous vasopressi n. DDAVP,
gi ven subcutaneously in a dose of 1 to 4 g or i ntranasal l y i n a dose of 5 to 20 g every 12 to
24 hours, is effective i n the vast majori ty of pati ents. DDAVP is less l ikel y than vasopressi n to
produce vasoconstri cti on and abdomi nal crampi ng.
110
Incomplete ADH defici ts (partial DI) often
are effecti vel y managed wi th pharmacol ogi c agents that sti mulate ADH rel ease or enhance the
renal

response to ADH. Chl orpropami de, whi ch potenti ates the renal effects of vasopressin, and
carbamazepi ne, whi ch enhances vasopressin secreti on, have been used to treat parti al central
DI, but are associ ated wi th cl inicall y important side effects. In nephrogeni c DI, sal t and water
restriction or thi azide diuretics i nduce contracti on of ECV, thereby enhanci ng fl ui d reabsorpti on
in the proxi mal tubules. If l ess fi ltrate passes through i nto the col lecting ducts, less water wi l l
be excreted.
P ot assi um
Physiologic Role
Potassium pl ays an i mportant rol e i n cel l membrane physi ology, especi al l y i n mai ntai ni ng
resti ng membrane potenti al s and i n generating acti on potenti al s in the central nervous system
and heart. Potassi um i s actively transported i nto cell s by a Na/K ATPase pump, whi ch mai ntai ns
an i ntracel l ul ar [K
+
] that i s at l east 30-fol d greater than extracel l ul ar [K
+
]. Intracel lular
potassium concentration ([K
+
]) i s normal l y 150 mEq/L, whi le the extracel l ul ar concentrati on i s
only 3.5 to 5.0 mEq/L. Serum [K
+
] measures about 0.5 mEq/L higher than plasma [K
+
] because
of cel l lysi s duri ng cl otting. Total body potassi um i n a 70-kg adul t is approxi matel y 4,256 mEq,
of whi ch 4,200 mEq i s i ntracel l ul ar; of the 56 mEq i n the ECV, only 12 mEq i s located i n the PV.
The rati o of intracel l ul ar to extracel lul ar potassi um contri butes to the resting potenti al
di fference across cel l membranes and therefore to the i ntegrity of cardi ac and neuromuscul ar
transmi ssi on. The pri mary mechani sm that mai ntai ns potassi um inside cel ls i s the negative
vol tage created by the transport of three sodi um ions out of the cel l for every two potassi um
ions transported i n (Fi g. 9-12).
111
Both i nsul i n and -adrenergi c agonists promote potassi um
entry into cell s.
111, 112
In contrast, -adrenergi c agonists impai r cel l ul ar potassi um uptake.
113

Metabol ic acidosis tends to shift potassium out of cel l s, whil e metabol ic al kalosis favors
movement i nto cel l s.
stippl i ng: the upper fi gure, representi ng extracel l ul ar vol ume (smal ler circle) and
intracel lular volume (l arger ci rcl e), is more heavi l y sti ppl ed, that is, serum sodi um i s
hi gher. B. In response to an acute i ncrease i n serum sodium resul ti ng from water l oss,
both intracel l ul ar and extracel lular volume substantiall y decrease. The brai n
(schemati cal l y i l lustrated) shri nks in proporti on to the reduction in intracel l ul ar vol ume in
other ti ssues. C. However, owing to the producti on of idi ogenic osmoles, the brai n rapi dl y
restores i ts i ntracel lular volume, despi te the persistent reducti on i n intracel l ul ar vol ume in
other ti ssues and i n extracel lular volume. D. With excessively rapi d correcti on of
hypernatremi a (the reduction in serum sodium i s reflected in the decrease in the intensity
of sti ppl i ng), the brai n expands to greater than i ts origi nal si ze. The resulti ng i ncrease i n
cerebral edema and i ntracrani al pressure can cause severe neurologic damage. (Modi fi ed
from Fei g PU: Hypernatremia and hypertoni c syndromes. Med Cli n North Am 65:271,
1981.)
P.194
Usual potassium i ntake i s between 50 and 150 mEq/day. Freel y fi ltered at the gl omerulus, most
potassium excreti on i s uri nary, wi th some fecal eli mi nation. Most fi l tered potassi um is
reabsorbed; usual l y, excreti on i s approximatel y equal to dai ly i ntake. As l ong as GFR i s >8
mL/kg, di etary potassi um intake, unless greater than normal , can be excreted. Assuming a
pl asma [K
+
] of 4.0 mEq/L and a normal GFR of 180 L/day, 720 mEq of potassium is fil tered
dai ly, of whi ch 85 to 90% i s reabsorbed i n the proxi mal convol uted tubul e and l oop of Henl e.
The remai ning 10 to 15% reaches the distal convoluted tubul e, whi ch i s the major si te at which
potassium excreti on i s regulated. Excreti on of potassi um i ons is a function of open potassi um
channel s and the electri cal dri vi ng force i n the corti cal col l ecting duct.
111

The two most i mportant regul ators of potassi um excreti on are the plasma [K
+
] and al dosterone,
al though there i s some evidence to suggest i nvol vement of the central nervous system and of
an enteri c refl ex medi ated by potassi um-ri ch meal s.
114
Potassi um secreti on i nto the distal
convol uted tubul es and cortical coll ecti ng ducts i s i ncreased by hyperkal emi a, al dosterone,
al kalemia, i ncreased del ivery of Na
+
to the di stal tubul e and col lecti ng duct, hi gh uri nary fl ow
rates, and the presence i n l umi nal flui d of nonreabsorbable anions such as carbeni ci l li n,

phosphates, and sul fates. As sodi um reabsorpti on i ncreases, the electri cal dri vi ng force
opposi ng reabsorpti on of potassi um is i ncreased. Al dosterone i ncreases sodium reabsorpti on by
inducing a more open confi gurati on of the epithel i al sodi um channel
115
; potassi um-spari ng
di uretics (amil ori de and tri amterene) and tri methropri m bl ock the epi theli al sodium channel ,
thereby increasi ng potassium reabsorpti on.
116
Magnesi um depl eti on contributes to renal
potassium wasting.
Hypokalemia
Uncommon among heal thy persons, hypokal emi a ([K
+
] <3.0 mEq/L) i s a frequent compl icati on
of treatment with diureti c drugs and occasi onal l y compl icates other di seases and treatment
regi mens (Tabl e 9-18).
113
As a general rule, a chroni c decrement of 1.0 mEq/L i n the pl asma
[K
+
] corresponds to a total body defici t of approximatel y 200 to 300 mEq. In uncompl i cated
hypokalemia, the potassium defici t exceeds 300 mEq i f pl asma [K
+
] i s <3.0 mEq/L and 700
mEq i f pl asma [K
+
] i s <2.0 mEq/L. Pl asma [K
+
] poorl y refl ects total body potassi um;
hypokalemia may occur wi th normal , l ow, or hi gh total body potassi um.
FIGURE 9-12. Hormones shi fti ng potassi um into cel ls. Major hormones i nvol ved are: (A)
insuli n and (B) -2 adrenergic agents. (From Hal peri n ML, Kamel KS: Potassi um. Lancet
352:135, 1998.)
P.195
Hypokal emi a causes muscl e weakness and, when severe, may even cause paralysi s. With
chroni c potassi um loss, the ratio of i ntracell ular to extracel l ul ar [K
+
] remai ns rel ati vel y stabl e;
in contrast, acute redi stributi on of potassium from the extracel l ul ar to the intracel l ul ar space
substantial ly changes resti ng membrane potenti al s.
Cardi ac rhythm di sturbances are among the most dangerous compl i cations of potassium
defici ency. Acute hypokal emi a causes hyperpol ari zation of the cardiac cel l and may l ead to
ventri cul ar escape activity, re-entrant phenomena, ectopic tachycardi as, and del ayed
conducti on. In pati ents taki ng di goxi n, hypokal emia i ncreases toxi ci ty by increasi ng myocardial
di goxi n bi ndi ng and pharmacol ogi c effecti veness. Hypokal emi a contributes to systemi c
hypertensi on, especi all y when combined wi th a hi gh-sodium diet.
117
In di abeti c patients,
hypokalemia i mpai rs i nsul i n secreti on and end-organ sensiti vi ty to i nsul i n. Although no cl ear
threshol d has been defi ned for a l evel of hypokal emi a bel ow whi ch safe conduct of anesthesia is
compromised, [K
+
] <3.5 mEq/L has been associ ated wi th an increased i nci dence of
peri operative dysrhythmias, especi al l y atri al fi bri l lation/fl utter, i n cardi ac surgi cal pati ents.
118

Potassium depl eti on al so i nduces defects in renal concentrati ng abi l ity, resul ting i n pol yuri a and
a reduction i n GFR. Potassium repl acement improves GFR, al though the concentrati ng defi ci t
may not i mprove for several months after treatment. If hypokalemia i s suffici ently prol onged,
chroni c renal intersti tial damage may occur. In experi mental ani mals, hypokalemia was
associated wi th i ntrarenal vasoconstri cti on and a pattern of renal injury si mil ar to that
produced by i schemi a.
119

TABLE 9-18 Causes of Renal Potassium Loss
Drugs Diuretics
Thi azi de di ureti cs
Loop diuretics
Osmotic diuretics
Anti bi oti cs
Peni ci l l i n and peni ci l l i n anal ogues
Amphotericin B
Aminoglycosides
Hormones
Al dosterone
Gl ucocorti coid-excess states
Bicarbonaturi a
Di stal renal tubul ar aci dosi s
Treatment of proxi mal renal tubular aci dosi s
Correction phase of metabol ic alkal osi s
Magnesi um defi ci ency
Other less common causes
Cisplatin
Carboni c anhydrase inhi bi tors
Leukemia
Di ureti c phase of acute tubular necrosis
Intrinsi c renal transport defects
Barter' s syndrome
Gitelman' s syndrome
Modified from Weiner ID, Wi ngo CS: Hypokal emi a consequences, causes, and
correcti on. J Am Soc Nephrol 8:1179, 1997.
Hypokalemia may result from chroni c depl eti on of total body potassium or from acute
redi stri buti on of potassi um from the ECV to the ICV. Redi stri buti on of potassi um into cel ls
occurs when the activity of the sodi umpotassium ATPase pump i s acutel y i ncreased by
extracel lul ar hyperkal emi a or i ncreased intracel l ul ar concentrati ons of sodi um, as well as by
insuli n, carbohydrate loading (whi ch stimul ates rel ease of endogenous insul in),
2
-adrenergi c
agoni sts, and al dosterone.
111
Both metabol ic and respiratory alkal osi s lead to decreases in
pl asma [K
+
].
111, 117

Causes of chroni c hypokal emi a i ncl ude those eti ologi es associated wi th renal potassium
conservati on (extrarenal potassi um losses; low urinary [K
+
]) and those wi th renal potassium
wasting (Fig. 9-13).
111, 117
A l ow uri nary [K
+
] suggests inadequate dietary intake or extrarenal
depl etion (i n the absence of recent diuretic use). Di ureti c-induced uri nary potassium losses are
frequently associ ated wi th hypokal emi a, secondary to i ncreased al dosterone secretion,
al kalemia, and increased renal tubul ar fl ow. Al dosterone does not cause renal potassi um
wasting unless sodi um i ons are present; that i s, aldosterone pri mari l y control s sodium
reabsorpti on, not potassi um excretion. Renal tubul ar damage because of nephrotoxi ns such as
aminogl ycosi des or amphoteri ci n B may also cause renal potassi um wasti ng.
Initi al eval uati on of hypokalemia i ncl udes a medi cal hi story (e.g., di arrhea, vomi ti ng, di ureti c
or l axative use), physi cal exami nation (e.g., hypertensi on, cushi ngoi d features, edema),

measurement of serum electrolytes (e.g., magnesi um), arteri al pH assessment, and eval uation
of the electrocardi ogram (ECG). A majori ty of trauma pati ents devel op hypokal emi a that
returns to normal wi thin 24 hours wi thout speci fi c therapy.
113
Measurement of 24-hour urinary
excreti on of sodi um and potassi um may di sti ngui sh extrarenal from renal causes. Magnesi um
defici ency, associated wi th aminogl ycosi de and ci spl ati n therapy, can generate hypokal emi a
that i s resistant to replacement therapy. Pl asma reni n and al dosterone l evel s may be helpful i n
the differenti al diagnosi s. Characteri sti c el ectrocardiographi c changes associ ated wi th
FIGURE 9-13. Approach to managi ng hypokal emi a. Causes for excessi ve excreti on of
potassium (>15 mmol/day) despi te hypokal emi a are too hi gh a flow rate i n the corti cal
collecting duct ([CCD], l eft l i mb) and/or too hi gh a concentrati on of potassi um [K+] in
lumen of the CCD (right limb). Both flow rate and CCD [K+] should be eval uated. Fi nal
consi derati ons are shown by bull ets. A rel ati vel y sl ower Cl
-
reabsorpti on i n CCD i s
suggested by hi gh pl asma reni n activity and NaCl wasting despi te l ow extracel l ul ar fl uid
vol ume; the converse appli es for relatively faster Na
+
reabsorpti on. (From Halperin ML,
Kamel KS: Potassi um. Lancet 352:135, 1998.)
P.196
hypokalemia i ncl ude flat or i nverted T waves, promi nent U waves, and ST segment depressi on.
The treatment of hypokal emi a consi sts of potassi um repletion, correcti on of al kalemi a, and
removal of offendi ng drugs (Tabl e 9-19). Hypokal emi a secondary onl y to acute redi stri buti on
may not requi re treatment. There is no urgent need for potassi um repl acement therapy i n mi l d
to moderate hypokalemia (3 to 3.5 mEq/L), especi al l y i f it i s a chroni c state and the pati ent
has no symptoms. If total body potassium i s decreased, oral potassi um supplementati on i s
preferabl e to i ntravenous repl acement. Potassi um i s usual ly repl aced as chl oride sal t because
coexi sti ng chl ori de defi ci ency may li mit the abi li ty of the kidney to conserve potassi um.
Potassium repl eti on must be performed cauti ousl y (i.e., usually at a rate 10 to 20 mEq/h)
because the magnitude of potassium defici ts i s unpredi ctable. The pl asma [K
+
] and the ECG
must be moni tored duri ng rapi d repl eti on (10 to 20 mEq/h) to avoi d hyperkal emi c
compl i cati ons.
113, 120
The pl asma [K
+
] and ECG shoul d be moni tored to detect i nadvertent
hyperkalemia. Parti cular care shoul d be taken i n patients who have concurrent aci demi a, type
IV renal tubul ar acidosis, or diabetes mell i tus, or i n those pati ents receiving nonsteroidal anti-
infl ammatory agents, ACE i nhi bitors, or -bl ockers, all of whi ch del ay movement of
extracel lul ar potassi um i nto cel l s.
However, in pati ents wi th l ife-threatening dysrhythmias secondary to hypokal emi a, serum [K
+
]
must be rapi dl y i ncreased. Assumi ng that PV i n a 70-kg adul t is 3.0 L, admini stration of 6.0
mEq/L of potassi um i n 1.0 mi nute wil l i ncrease serum [K
+
] by no more than 2.0 mEq/L because
redi stri buti on i nto intersti tial fl ui d wi l l decrease the quanti ty remaini ng i n the pl asma
volume.
111

Hypokal emi a associ ated with hyperal dosteronemi a (e.g., pri mary al dosteroni sm, Cushi ng
syndrome) usual l y responds favorabl y to reduced sodi um i ntake and i ncreased potassi um
intake. Hypomagnesemia, i f present, aggravates the effects of hypokalemia, i mpai rs potassi um
conservati on, and shoul d be treated. Potassi um suppl ements or potassi um-sparing diureti cs
should be given cauti ousl y to pati ents who have di abetes mel li tus or renal insuffici ency, whi ch
li mi t compensation for acute hyperkal emi a. In pati ents, such as those who have diabetic
ketoaci dosi s, who are both hypokalemic and aci demi c, potassium admini stration should precede
correcti on of aci dosi s to avoid a precipi tous decrease i n plasma [K
+
] as pH i ncreases.

In pati ents wi th normal serum potassi um accompani ed by symptoms of potassium depletion
(e.g., muscle fati gue), history of potassi um l oss or insuffici ent intake, or i n patients i n whom
potassi um depl eti on may be of speci al threat, for exampl e, pati ents on di ureti cs, di gi tal i s, or -
2 adrenergic agoni sts, muscle bi opsy wi th measurement of muscle potassium concentrati on may
be a useful procedure to detect and quanti fy potassi um depl eti on.
TABLE 9-19 Hypokalemia: Treatment
Correct precipitating factors
Increased pH
Decreased [Mg
2+
]

Drugs
Mild hypokalemia ([K
+
] >2.0 mEq/L)

Intravenous KCl infusi on 10 mEq/h
Severe hypokalemia ([K
+
]
2.0 mEq/L, paral ysi s, or electrocardiographi c [ECG]

changes)
Intravenous KCl infusi on 40 mEq/h
Conti nuous ECG moni toring
If li fe threatening, 56 mEq bol us
Hyperkalemia
The most lethal manifestati ons of hyperkal emi a ([K
+
] >5.0 mEq/L) i nvol ve the cardiac
conducti ng system and i ncl ude dysrhythmi as, conducti on abnormal i ti es, and cardi ac arrest. In
anesthesia practice, the cl assi c exampl e of hyperkal emi c cardi ac toxi ci ty i s associ ated wi th the
administrati on of succi nyl choli ne to parapl egi c, quadripl egi c, or severel y burned
121
pati ents. If
pl asma [K
+
] is <6.0 mEq/L, cardi ac effects are negli gi ble. As the concentrati on i ncreases
further, the electrocardi ogram shows tal l , peaked T waves, especial ly i n the precordi al l eads.
Wi th further i ncreases, the PR i nterval becomes prol onged, fol l owed by a decrease i n the
ampli tude of the P wave. Finall y, the QRS compl ex wi dens i nto a pattern resembli ng a si ne
wave, as a prelude to cardi ac standsti ll (Fi g. 9-14).
122
Hyperkalemic cardi otoxici ty i s enhanced
by hyponatremi a, hypocal cemia, or aci dosi s. Because progressi on to fatal cardiotoxi city is
unpredictabl e and often swift, the presence of hyperkal emi c ECG changes mandates i mmedi ate
therapy. The li fe-threatening cardiac effects usuall y requi re more urgent treatment than other
mani festati ons of hyperkal emi a. However, ascendi ng muscle weakness appears when pl asma
[K
+
] approaches 7.0 mEq/L, and may progress to fl acci d paralysi s, i nabil i ty to phonate, and
respiratory arrest.
FIGURE 9-14. El ectrocardi ographic changes as a result of hyperkalemia occurring in a 42-
year-ol d woman undergoing pl acement of an arteri ovenous fi stula for permanent
hemodial ysis access to treat end-stage renal di sease. A. Duri ng di ssecti on of the brachi al
artery under local anesthesi a, her cardi ac rhythm converted from normal sinus rhythm to
compl ete heart bl ock with ventri cul ar escape (approxi matel y 25 beats per mi nute). Two
ampul es of cal ci um gl uconate (9.2 mEq) were admi nistered intravenousl y. B. An
The most important di agnosti c issues are medi cal history, emphasizing recent drug therapy,
and assessment of renal function. Although the ECG may provi de the first suggestion of
hyperkal emi a i n some pati ents, and despi te the wel l -descri bed effects of hyperkalemia on
cardi ac conducti on and rhythm, the ECG i s an insensiti ve and nonspeci fic method of detecti ng
hyperkalemia.
123
If hyponatremia i s also present, adrenal function should be evaluated.

Hyperkal emi a may occur wi th normal, hi gh, or l ow total body potassium stores. A defi ci ency of
al dosterone, a major regulator of potassi um excretion, leads to hyperkal emi a i n adrenal
insuffi ciency and hyporeni nemic hypoaldosteronism, a state associated wi th di abetes mell i tus,
renal insuffici ency, and advanced age. Because the ki dneys excrete potassium, severe renal
insuffi ciency commonl y causes hyperkal emi a. Pati ents wi th chroni c renal insuffici ency can
maintain normal plasma [K
+
] despi te markedl y decreased GFR because uri nary potassi um
excreti on depends on tubul ar secretion rather than gl omerular fi ltration if GFR exceeds 8
mL/min.
Drugs are now the most common cause of hyperkal emi a, especi al l y i n elderly pati ents.
124
Drugs
that may li mi t potassi um excretion incl ude nonsteroi dal anti -infl ammatory drugs, ACE
inhi bitors, cycl ospori n, and potassium-spari ng diureti cs such as tri amterene. Drug-induced
hyperkalemia most commonly occurs in pati ents wi th other predi sposing factors, such as
di abetes mel l itus, renal i nsuffici ency, advanced age, or hyporeni nemic hypoal dosteroni sm. ACE
inhi bitors are parti cul arly l ikely to produce hyperkal emi a i n patients who have congesti ve heart
fai l ure.
125

In pati ents who have normal total body potassi um, hyperkalemia may accompany a sudden
shift of potassium from the ICV to the ECV because of aci demi a, increased catabol i sm, or

rhabdomyol ysis. Metabol ic aci dosi s and respi ratory aci dosi s tend to cause an i ncrease i n pl asma
[K
+
]. However, organi c aci doses (i .e., l acti c acidosis, ketoaci dosi s) have li ttl e effect on [K
+
],
whereas mi neral aci ds cause signi ficant cell ul ar shi fts. In response to i ncreased hydrogen i on
acti vi ty because of addi tion of aci ds, potassi um wi ll i ncrease i f the ani on remai ns i n the
extracel lul ar volume.
111
Nei ther lactate nor ketoaci ds remai n in the extracel lular fl ui d.
Therefore, hyperkal emi a i n these ci rcumstances refl ects ti ssue i njury or lack of i nsuli n.
111

Pseudohyperkal emi a, whi ch occurs when potassium is released from cel l s i n bl ood col lection
tubes, can be di agnosed by compari ng serum and pl asma K
+
l evel s from the same bl ood
sampl e. Hyperkal emi a usuall y accompanies mal ignant hyperthermi a.
The treatment of hyperkal emi a is ai med at el i mi nating the cause, reversing membrane
hyperexci tabi l ity, and removing potassi um from the body (Fi g. 9-15).
111, 125
Emergent
management of severe hyperkalemia i s li sted in detai l in Tabl e 9-20.
125
Mi neral ocorti coi d
defici ency can be treated wi th 9--fludrocorti sone (0.025 to 0.10 mg/day). Hyperkalemia
secondary to di gital i s intoxi cati on may be resistant to therapy because attempts to shift
potassium from the ECV to the ICV are often ineffecti ve. In thi s si tuati on, use of digoxi n-
specific anti bodi es has been successful .
el ectrocardi ogram reveal ed si nus tachycardi a wi th profound prol ongati on of the QRS
interval (l eft bundle-branch morphol ogy), first-degree atrioventricular block, and peaked
T waves. The serum potassium concentration was 8.6 mmol /L. C. After reducti on of the
serum potassi um concentrati on, the el ectrocardiogram showed sinus rhythm wi th
normal izati on of the PR and QRS i nterval s. Anteroseptal ST wave and T wave changes
were noted on subsequent electrocardi ograms. A cardi ac exercise imagi ng study di d not
show ischemia. (From Kuvin JT: El ectrocardiographi c changes of hyperkal emi a. N Engl J
Med 338:662, 1998.)
P.197
Membrane hyperexci tabi l i ty can be antagoni zed by translocating potassi um from the ECV to the
ICV, removing excess potassi um, or (transi entl y) by i nfusing cal ci um chloride to depress the
membrane threshol d potenti al . Pendi ng definiti ve treatment, rapi d i nfusion of cal ci um chl ori de
(one gram of CaCl
2
over 3 mi nutes, or two to three ampules of 10% cal ci um gluconate over 5
mi nutes) may stabi li ze cardi ac rhythm (see Fi g. 9-14). Cal cium should be given cautiousl y i f
FIGURE 9-15. Treatment of pati ent wi th hyperkalemi a. If an emergency i s present
(usual l y cardi ac), intravenous Ca
2+
must be gi ven. Thi s treatment shoul d be gi ven
promptly. Efforts are al so taken to shi ft potassi um i nto cel l s with insul in wi th or wi thout
NaHCO
3
. Longer term strategi es are to li mit i ntake of potassi um, prevent i ts absorpti on i n
the gastrointestinal tract, and promote i ts excreti on; the l atter incl udes measuri ng uri ne
[K
+
] and fl ow rate to deci de l everage for therapy. (From Halperin ML, Kamel KS:
Potassium. Lancet 352:135, 1998.)
TABLE 9-20 Severe Hyperkalemia:
a
Treatment

Reverse membrane effects
Cal cium (10 mL of 10% cal ci um chloride IV over 10 mi n)
Transfer extracel l ul ar [K
+
] i nto cel l s

Gl ucose and insul in (D10W + 510 U regular insul in per 2550 g glucose)
Sodi um bicarbonate (50 to 100 mEq over 510 mi n)
-2 agoni sts
Remove potassium from body
Di uretics, proxi mal or loop
Potassi um-exchange resi ns (sodi um pol ystyrene sul fonate)
Hemodi al ysi s
Moni tor ECG and serum [K
+
] l evel
a
Potassium concentration ([K
+
]) >7.0 mEq/L or el ectrocardi ographi c (ECG) changes.
di gi tal is i ntoxi cation is li kel y. Acute al kali nizati on usi ng sodium

bi carbonate (50 to 100 mEq over 5 to 10 mi nutes i n a 70-kg adul t) transi entl y promotes
movement of potassium from the ECV to the ICV. Bi carbonate can be admi ni stered even if pH
exceeds 7.40; however, i t should not be administered to pati ents wi th congestive cardiac
failure or hypernatremi a. Insulin, in a dose-dependent fashi on, causes cell ul ar uptake of
potassium by i ncreasi ng the acti vi ty of the sodi um/potassium ATPase pump. However, when
used al one, bi carbonate i s rel ati vel y i neffecti ve and i s no longer favored.
125
Insul in i ncreases
cel lul ar uptake of potassi um best when hi gh i nsuli n levels are achi eved by intravenous injecti on
of 5 to 10 U of regular insul in, accompani ed by 50 mL of 50% gl ucose.
125
-2 adrenergic drugs
such as sal butamol and al buterol also increase potassium uptake by skeletal muscle and reduce
pl asma [K
+
], an action that may expl ai n hypokal emi a with severe, acute il l ness. -2 agoni sts
have been used to treat hyperkalemia.
126
Sal butamol, a sel ecti ve -2 agoni st, decreases serum
potassium acutely when gi ven by i nhalati on or intravenousl y. In 15 pediatri c pati ents with
baseli ne serum [K
+
] of 6.6 mEq/L, a si ngl e i nfusi on of salbutamol (5 g/kg over 15 minutes)
reduced serum [K
+
] to 5.7 mEq/L after 30 minutes and 4.9 mEq/L after 120 mi nutes.
127
When
using -2 adrenergic agents to reduce serum [K
+
], the potenti al for generating cardi ac
dysrhythmi as should be recogni zed.
128

Potassi um may be removed from the body by the renal or gastrointestinal routes. Furosemide
promotes kal iuresi s i n a dose-dependent fashion. Sodi um polystyrene sul fonate resi n
(Kayexal ate), which exchanges sodi um for potassium, can be given orall y (30 g) or as a
retention enema (50 g i n 200 mL of 20% sorbi tol ). However, sodi um overl oad and hypervolemia
are potenti al ri sks. Rarel y, when tempori zing measures are insuffi cient, emergency
hemodial ysis may remove 25 to 50 mEq/h. Peri toneal dial ysis i s l ess effi cient.
Cal ci um
Physiologic Role
Cal cium is a di valent cati on found pri mari ly i n the extracel l ul ar fl ui d. The free calci um
concentration [Ca
2+
] i n ECV is approxi mately 1 mM, whereas the free [Ca
2+
] i n the ICV
approxi mates 100 mM, a gradi ent of 10,000 to 1. Circul ati ng calci um consi sts of a protein-
bound fracti on (40%), a chelated fracti on (10%), and an i oni zed fracti on (50%), whi ch i s the
physi ol ogi cal l y acti ve and homeostati cal ly regulated component.
129
Acute aci demi a increases
and acute al kalemi a decreases ionized cal ci um. Because mathematical formulae that correct
total cal ci um measurements for al bumin concentrati on are i naccurate i n criti cal ly il l pati ents,
130

ioni zed calci um shoul d be di rectl y measured.
In general , calci um is essential for al l movement that occurs i n mammal i an systems. Essenti al
for normal exci tati on-contracti on coupl ing, cal cium is al so necessary for proper functi on of
muscle ti ssue, cil i ary movement, mi tosis, neurotransmitter release, enzyme secretion, and
hormonal secreti on. Cycl i c AMP (cAMP) and phosphoi nosi tides, which are major second
messengers regulating cel l ul ar metabol i sm, function pri mari l y through the regulation of cal ci um
movement. Activati on of numerous intracel l ul ar enzyme systems requi res cal ci um. Cal cium i s
important both for generation of the cardiac pacemaker activity and for generati on of the
cardi ac acti on potential , and therefore i s the pri mary i on responsi ble for the pl ateau phase of
the action potential . Calci um al so plays vi tal functions i n membrane and bone structure.
Serum [Ca
2+
] i s regul ated by mul tipl e factors (Fi g. 9-16),
131
including a cal ci um receptor
132, 133

and several hormones. Parathyroid hormone (PTH) and cal citriol, the most important
neurohumoral mediators of serum [Ca
2+
]
134
(see Tabl e 9-15), mobi l i ze cal cium from bone,
increase renal tubul ar reabsorption of cal ci um, and enhance i ntesti nal absorpti on of cal cium.
Vitami n D, after ingesti on or cutaneous manufacture under the sti mul us of ul travi ol et l ight, is
25-hydroxyl ated to calci diol i n the li ver and then i s 1-hydroxyl ated to cal ci tri ol, the active
metaboli te, i n the kidney. Even in the absence of dietary cal ci um i ntake, PTH and vi tamin D can
maintai n a normal ci rculating [Ca
2+
] by mobi l i zi ng cal ci um from bone.

P.198
Hypocalcemia
Hypocal cemia (ioni zed [Ca
2+
] <4.0 mg/dL or <1.0 mmol /L) occurs as a resul t of fai l ure of PTH
or cal citri ol acti on or because of cal ci um chel ati on or precipi tation, not because of cal ci um
defici ency al one. PTH defi ci ency can resul t from surgi cal damage or removal of the parathyroi d
gl ands or from suppressi on of the parathyroi d gl ands by severe hypo- or hypermagnesemi a.
Burns, sepsi s, and pancreati ti s may suppress parathyroid functi on and i nterfere with vi tami n D
acti on.

Vitami n D defici ency may result from l ack of dietary vitamin D or vitamin D malabsorption in
patients who l ack sunl ight exposure. Hyperphosphatemi a-induced hypocal cemi a may occur as a
consequence of overzeal ous phosphate therapy, from cel l l ysis secondary to chemotherapy, or
as a resul t of cel l ul ar destruction from rhabdomyol ysis. Precipi tati on of CaHPO
4
compl exes
occurs with hyperphosphatemi a. However, i onized [Ca
2+
] onl y decreases approximatel y 0.019
mM for each 1.0 mM i ncrease in phosphate concentration. In massive transfusi on, citrate may
produce hypocal cemi a by chel ati ng calci um; however, decreases are usual l y transi ent and
produce no cardi ovascul ar effects. A healthy, normothermic adul t who has i ntact hepati c and
renal functi on can metabol i ze the ci trate present in 20 uni ts of blood per hour wi thout
becomi ng hypocal cemic.
135
However, when citrate clearance i s decreased (e.g., by hepati c or
renal di sease or hypothermi a) and when bl ood transfusi on rates are rapi d (e.g., >0.5 to 2
mL/kg/mi n), hypocalcemi a and cardi ovascul ar compromi se may occur. Al kal emi a resul ti ng from
hyperventi lation or sodi um bicarbonate injecti on can acutel y decrease [Ca
2+
].

The hal lmark of hypocal cemi a i s i ncreased neuronal membrane irritabi l ity and tetany (Tabl e 9-
FIGURE 9-16. Schemati c representati on of the regulatory system mai ntai ning Ca
2+
o

homeostasi s. The soli d arrows and li nes del i neate effects of parathyroi d hormone and 1,25
(OH)
2
D
3
on thei r target ti ssues; dashed arrows and li nes show exampl es of how
extracel lul ar Ca
2+
or phosphate ions act di rectly on ti ssues regul ati ng mi neral i on
metabol i sm. Ca, cal ci um; PO
4
, phosphate; ECF, extracel l ul ar fl ui d; PTH, parathyroi d
hormone; 1,25 (OH)
2
D
3
, 1,25 di hydroxyvi tamin D; 25(OH)D, 25-hydroxyvi tamin D;
negati ve si gns i ndi cate i nhi bitory acti ons and pl us si gns i ndicate stimul atory effects.
(From Brown EM, Pol l ak M, Hebert SC: The extracell ular cal ci um-sensi ng receptor: Its rol e
in heal th and disease. Annu Rev Med 49:15, 1998.)
P.199
21). Earl y symptoms include sensations of numbness and tingli ng involving fi ngers, toes, and
the ci rcumoral regi on. In frank tetany, tonic contracti on of respi ratory muscl es may lead to
laryngospasm, bronchospasm, or respiratory arrest. Smooth muscl e spasm can resul t i n
abdomi nal crampi ng and urinary frequency. Mental status al terati ons i nclude i rritabil i ty,
depressi on, psychosi s, and dementia. Hypocal cemia may i mpair cardi ovascul ar functi on and has
been associ ated wi th heart fai lure, hypotensi on, dysrhythmi as, insensi tivity to di gitali s, and
impai red -adrenergi c acti on.
Reduced ioni zed serum cal cium occurs i n as many as 88% of cri ti cal l y i l l pati ents, 66% of less
severely i ll ICU pati ents, and 26% of hospitali zed non-ICU pati ents.
136
Pati ents at parti cular
ri sk i nclude pati ents after multi ple trauma and cardi opul monary bypass. In most such pati ents,
ioni zed hypocal cemi a is cl inicall y mi ld ([Ca
2+
] 0.8 mmol /L to 1.0 mmol /L).

Initi al di agnostic eval uation should concentrate on hi story and physi cal exami nation, laboratory
eval uation of renal function, and measurement of serum phosphate concentration. Latent
hypocal cemi a can be di agnosed by tappi ng on the faci al nerve to el i ci t Chvostek' s si gn or by
i nfl ati ng a sphygmomanometer to 20 mmHg above systol ic pressure, whi ch produces radi al and
ul nar nerve ischemia and causes carpal spasm known as Trousseau' s sign. The differenti al
di agnosi s of hypocalcemi a can be approached by addressi ng four issues: age of the pati ent,
serum phosphate concentrati on, general cl i ni cal status, and durati on of hypocal cemia.
137
High
phosphate concentrati ons suggest renal fail ure or hypoparathyroi dism. In renal insuffici ency,
reduced phosphorus excreti on resul ts i n hyperphosphatemia, whi ch down-regul ates the 1-
hydroxyl ase responsibl e for the renal conversion of cal ci di ol to cal ci tri ol . Thi s, in combinati on
wi th decreased producti on of cal ci tri ol secondary to reduced renal mass, causes reduced
intesti nal absorpti on of cal ci um and hypocal cemi a.
134
Low or normal phosphate concentrati ons
TABLE 9-21 Hypocalcemia: Clinical Manifestations
Cardiovascular
Dysrhythmi as
Digi tal i s insensiti vi ty
ECG changes
Heart failure
Hypotensi on
Neuromuscular
Tetany
Muscl e spasm
Papi ll edema
Sei zures
Weakness
Fati gue
Respiratory
Apnea
Laryngeal spasm
Bronchospasm
Psychiatric
Anxi ety
Dementi a
Depressi on
Psychosis
ECG, electrocardi ographi c.
imply vitamin D or magnesium deficiency. An otherwi se healthy pati ent wi th chroni c
hypocal cemia probabl y i s hypoparathyroi d. Chroni cal ly i ll adul ts with hypocal cemi a often have
di sorders such as malabsorpti on, osteomal aci a, or osteobl astic metastases. Cli ni cal di agnosi s of
hypocal cemia i n the pati ent recei vi ng mul tipl e transfusi ons, because of ci trate excess, i s often
di fficul t. The only manifestation may be hypotensi on as a resul t of poor cardi ac functi on, whi ch
i s di ffi cul t to di fferentiate from hypotension as a result of hypovol emi a.
The defi ni tive treatment of hypocal cemi a necessitates identi fi cati on and treatment of the
underlying cause (Tabl e 9-22). Symptomati c hypocal cemi a usuall y occurs when serum i onized
[Ca
2+
] i s <0.7 mM. The cl i ni cian should careful ly consi der whether mi l d, asymptomatic i oni zed
hypocal cemia requi res therapy, particul arl y in ischemic and septic states in which experi mental
evidence suggests that calci um may i ncrease cell ul ar damage.
Unnecessary offendi ng drugs shoul d be discontinued. Hypocal cemi a resul ting from
hypomagnesemi a or hyperphosphatemi a i s treated by repl eti on of magnesium or removal of
phosphate. Treatment of a pati ent who has tetany and hyperphosphatemia requi res
coordi nati on of therapy to avoid the consequences of metastati c soft ti ssue cal cificati on.
138

Potassium and other el ectrol ytes shoul d be measured and abnormali ties shoul d be corrected.
Hyperkal emi a and hypomagnesemia potenti ate hypocal cemia-induced cardiac and
neuromuscul ar i rri tabil i ty. In contrast, hypokal emia protects agai nst hypocal cemi c tetany;
therefore, correcti on of hypokal emi a wi thout correcti on of hypocal cemia may provoke tetany.
Mi l d, i oni zed hypocalcemi a shoul d not be overtreated. For instance, in most pati ents after
cardi ac surgery, admi ni strati on of cal ci um only i ncreases blood pressure
139
and actual ly
attenuates the -adrenergi c effects of epi nephri ne.
139
In normocalcemi c dogs, calci um chl oride
pri mari l y acts as a peri pheral vasoconstri ctor, wi th transi ent reducti on of myocardi al
contracti l ity; i n hypocal cemi c dogs, cal cium infusi on signi fi cantl y i mproves contracti l e
performance and bl ood pressure (Tabl e 9-23).
140
Therefore, cal cium infusi ons should be of

li mi ted value i n surgi cal pati ents unless there i s demonstrable evidence of hypocal cemi a.
140

Cal cium sal ts appear to confer no benefit to pati ents al ready recei vi ng inotropi c or vasoacti ve
agents.
TABLE 9-22 Hypocalcemia: Acute Treatment
Admi ni ster cal ci um
IV: 10 mL 10% cal ci um gl uconate
a
over 10 min, foll owed by el emental cal ci um 0.3
2.0 mg/kg/h
Oral : 500100 mg el emental calci um q 6 hours
Administer vitamin D
Ergocal ci ferol , 1,200 g/day (T
1/2
= 30 days)
Di hydrotachysterol , 200400 g/day (T
1/2
= 7 days)
1,25-di hydroxychol ecal ci ferol , 0.251.0 g/day (T
1/2
= 1 day)
Moni tor electrocardi ogram
a
Cal cium gluconate contains 93 mg elemental cal cium per 10-mL vi al. T
1/2
, hal f-li fe.
P.200
TABLE 9-23 Serum Ionized [Ca
2+
] Concentration and Hemodynamic Variables One
Minute after Calcium Administration (5 mg/kg Intravenous Bolus) in Normocalcemic
and Hypocalcemic (Produced by CPD Administration) Dogs
The cornerstone of therapy for confi rmed, symptomatic, i oni zed hypocal cemi a ([Ca
2+
] <0.7
mM) is calci um admi ni stration. In pati ents who have severe hypocalcemi a or hypocalcemi c
symptoms, calci um shoul d be admi ni stered intravenously. In emergency si tuati ons, i n an
averaged-si zed adult, the rul e of 10s advi ses infusi on of 10 mL of 10% cal cium gl uconate (93
mg el emental cal ci um) over 10 minutes, foll owed by a continuous i nfusion of elemental
calci um, 0.3 to 2 mg/kg/h (i .e., 3 to 16 mL/h of 10% cal ci um gl uconate for a 70-kg adul t).
Cal cium sal ts shoul d be di l uted i n 50 to 100 mL D5W (to li mit venous irri tati on and
thrombosi s), should not be mi xed wi th bi carbonate (to prevent preci pi tati on), and must be
NORMOCALCEMIC HYPOCALCEMIC
BASELINE 1 MIN BASELINE CPD 1 MIN
Ca
2+
(mmol/L) 1.24 0.04 1.47
0.06
a
1.24 0.03 0.76
0.03
a
1.42
0.22
b
E
1ves

(mmHg/mL)
4.06 1.00 2.16
0.90
a
5.03 0.47 3.76
0.61
a
4.87
0.64
b
HR (beats/mi n) 159 8 260 9 154 6 144
7
a
148
6
a
PAOP (mmHg) 9 2 9 1 7 1 10 2 9 2
MAP (mmHg) 120 6 137
8
a
157 6 131
6
a
154
6
b
SVR
(dyne/s/cm)
3,858
458
4,347
596
a
4,067
550
3,697
479
4,548
904
CO (L/min) 2.7 0.4 2.7
0.4
3.4 0.2 3.0
0.3
3.1
0.4
Val ues are mean SEM (n = 6); E
l ves
, slope of the l eft ventricular end-systol i c
pressurevol ume rel ati onshi p; CPD, ci trate-phosphate-dextrose; HR, heart rate;
PAOP, pul monary arteri al occl usi on pressure; MAP, mean arteri al pressure; SVR,
systemi c vascul ar resistance; CO, cardi ac output.
a
P <0.05 vs. basel i ne.
b
p <0.05 vs CPD.
From Mathru M, Rooney MW, Gol dberg SA et al : Separation of myocardi al versus
peri pheral effects of cal ci um admi ni strati on i n normocal cemi c and hypocal cemi c states
using pressure-vol ume (conductance) rel ati onships. Anesth Anal g 77:250, 1993.
gi ven cauti ousl y to di gi tal i zed pati ents because cal cium increases the toxici ty of di goxi n.
Conti nuous ECG moni toring during i ni tial therapy wil l detect cardiotoxici ty (e.g., heart bl ock,
ventri cul ar fi bril l ati on). During cal cium repl acement, the cl i ni cian should moni tor serum
cal ci um, magnesi um, phosphate, potassium, and creati nine. Once the ioni zed [Ca
2+
] i s stabl e in
the range of 4 to 5 mg/dL (1.0 to 1.25 mM), oral cal ci um suppl ements can substitute for
parenteral therapy. Uri nary cal ci um shoul d be moni tored i n an attempt to avoi d hypercal ciuri a
(>5 mg/kg per 24 hours) and uri nary tract stone formati on.
When suppl ementation fai l s to mai ntain serum calci um wi thin the normal range, or i f
hypercal ci uri a develops, vi tami n D may be added. Al though the pri nci pal effect of vitami n D i s
to i ncrease enteri c cal ci um absorpti on, osseous calci um resorption is al so enhanced. When
rapid changes in dosage are anti ci pated or an immedi ate effect i s requi red (e.g., postoperative
hypoparathyroi di sm), shorter acti ng calci ferol s such as di hydrotachysterol may be preferable.
Because the effect of vitami n D i s not regul ated, the dosages of cal ci um and vitami n D shoul d
be adjusted to rai se the serum cal ci um i nto the l ow normal range.
Adverse reacti ons to calci um and vitami n D incl ude hypercal cemia and hypercal ci uri a. If
hypercal cemi a devel ops, cal ci um and vi tami n D shoul d be di sconti nued and appropri ate therapy
gi ven. The toxi c effects of vitami n D metabol ites persist i n proporti on to their bi ol ogi c hal f-
li ves (ergocal ci ferol , 20 to 60 days; dihydrotachysterol , 5 to 15 days; calci triol , 2 to 10 days).
Gl ucocorti coi ds antagoni ze the toxic effects of vi tamin D metabol ites.
Hypercalcemia
Al though i onized [Ca
2+
] most accuratel y demonstrates hypercal cemi a (i onized [Ca
2+
] >1.5
mmol /L or total serum cal ci um >10.5 mg/dL), hypercalcemi a customari l y i s defi ned i n terms of
total serum cal ci um. In hypoalbumi nemic pati ents, total serum cal ci um can be esti mated by
assumi ng an i ncrease of 0.8 mg/dL for every 1 g/dL of al bumi n concentrati on bel ow 4.0 g/dL.
Patients i n whom total serum calci um is l ess than 11.5 mg/dL are usual ly asymptomatic.
Patients with moderate hypercalcemi a (total serum calci um 11.5 to 13 mg/dL) may show
symptoms of lethargy, anorexi a, nausea, and polyuria. Severe hypercal cemia (total serum
calci um >13 mg/dL) i s associ ated wi th more severe neuromyopathi c symptoms, incl uding
muscle weakness, depressi on, i mpai red memory, emotional l abi l ity, lethargy, stupor, and coma.
The cardi ovascular effects of hypercalcemi a i nclude hypertensi on, dysrhythmias, heart bl ock,
cardi ac arrest, and di gitali s sensiti vi ty. Skel etal di sease may occur secondary to di rect
osteol ysi s or humoral bone resorpti on.
Hypercalcemi a i mpairs urinary concentrating abil i ty and renal excretory capaci ty for calci um by
irreversibl y precipi tating cal cium sal ts wi thin the renal parenchyma and by reduci ng renal bl ood
flow and GFR. In response to hypovolemia, renal tubul ar reabsorpti on of sodium enhances renal
calci um reabsorpti on. Effecti ve treatment of severe hypercal cemi a is necessary to prevent
progressi ve dehydrati on and renal fai l ure l eadi ng to further increases i n total serum cal cium,
because vol ume depl eti on exacerbates hypercal cemi a.
141
Hypercal cemia occurs when cal ci um
enters the extracell ul ar vol ume more rapidly than the kidneys can excrete the excess.
Cli nicall y, hypercal cemia most commonl y results from an excess of bone resorpti on over bone
formation, usuall y secondary to mal ignant disease, hyperparathyroi dism, hypocal ciuri c
hypercal cemia, thyrotoxi cosis, immobi li zati on, and granul omatous diseases. Granul omatous
di seases produce hypercal ciuri a and hypercal cemi a because of conversi on by granulomatous
ti ssue of cal ci di ol to cal ci tri ol.
134

Mal i gnancy may produce hypercal cemi a either through bone destructi on or secretion by
mali gnant ti ssue of hormones that promote hypercal cemi a.
142
Al though weakness, weight

loss, and anemi a associ ated wi th primary hyperparathyroi dism may suggest mal ignancy, these
may resul t si mpl y from the pri mary di sease process. Hypercal cemi a associated wi th
granulomatous di seases (e.g., sarcoi dosis) results from the producti on of cal citri ol by
granulomatous ti ssue. To compensate for increased gut absorpti on or bone resorption of
calci um, renal excreti on can readi l y i ncrease from 100 to more than 400 mg/day. Factors that
P.201
promote hypercalcemi a may be offset by coexi sti ng disorders, such as pancreatiti s, sepsi s, or
hyperphosphatemi a, that cause hypocalcemi a.
Although defi ni tive treatment of hypercal cemi a requi res correction of underl yi ng causes,
temporizing therapy may be necessary to avoi d compl i cations and to rel i eve symptoms. Total
serum cal ci um exceeding 14 mg/dL represents a medi cal emergency. General supporti ve
treatment i ncl udes hydration, correcti on of associ ated el ectrol yte abnormal i ti es, removal of
offendi ng drugs, dietary cal ci um restri cti on, and i ncreased physi cal activity. Because anorexia
and antagoni sm by cal ci um of ADH action invari ably l ead to sodi um and water depl eti on,
infusi on of 0.9% sal i ne wil l di lute serum cal ci um, promote renal excretion, and can reduce total
serum cal ci um by 1.5 to 3 mg/dL. Urinary output shoul d be mai ntai ned at 200 to 300 mL/h. As
GFR i ncreases, sodium ions i ncrease cal ci um excreti on by competing wi th calci um i ons for
reabsorpti on i n the proxi mal renal tubules and loop of Henl e.
Furosemide further enhances cal cium excreti on by increasi ng tubul ar sodi um. Pati ents who
have renal i mpai rment may requi re hi gher doses of furosemide. During sal i ne i nfusion and
forced diuresi s, careful moni toring of cardiopul monary status and el ectrol ytes, especial ly
magnesi um and potassi um, i s required. Intensive di uresi s and sal i ne admi ni strati on can achi eve
net cal ci um excretion rates of 2,000 to 4,000 mg per 24 hours, a rate eight ti mes greater than
sali ne al one, but sti ll somewhat l ess than the rate of removal achieved by hemodi al ysi s (i .e.,
6,000 mg every 8 hours). Pati ents treated wi th phosphates shoul d be wel l hydrated.
Bone resorption, the primary cause of hypercal cemia, can be minimized by i ncreasing physi cal
acti vi ty and initi ati ng drug therapy.
131, 143
Bi sphosphonates, currentl y the first-li ne therapy for
acute hypercal cemi a, inhi bi t osteoclast functi on and vi abil i ty. Bi sphosphonates are the pri ncipal
drugs for the management of hypercal cemi a medi ated by osteocl asti c bone resorption.
144

Pamidronate, unl ike earl ier biphosphonates, does not appear to worsen renal i nsuffi ci ency.
More recentl y rel eased bi phosphonates i nclude alendronate, ri sendronate, and zol ecroni c acid.
Ri sendronate has been associated wi th l ess gastroi ntesti nal morbi di ty than al endronate.
145, 146

Zol edroni c aci d has the most rapi d onset of acti on among the bi phosphonates and prol ongs the
durati on before rel apse of hypercal cemi a; however, zol edroni c aci d has been associated wi th
compromised renal function.
143

Other osteocl ast-inhi biti ng agents used to treat hypercalcemi a include mi thramycin and
calci toni n.
147
Mithramyci n, a cytotoxi c agent, lowers serum cal ci um primari ly by i nhi biti ng bone
resorpti on, probabl y because of toxi city to osteocl asts. The hypocalcemi c effect, usual ly seen
within 12 to 24 hours fol l owi ng a si ngl e i ntravenous dose of 25 g/kg, peaks at 48 to 72 hours,
and persi sts for 5 to 7 days. Major toxic effects of mithramyci n, more l i kely to occur in pati ents
with renal insuffici ency, i ncl ude thrombocytopeni a, nephrotoxi ci ty, and hepatotoxi ci ty.
Cal citoni n l owers serum cal ci um wi thi n 24 to 48 hours and i s more effecti ve when combi ned
with glucocorticoi ds.
143
Usuall y cal ci tonin reduces total serum cal cium by onl y 1 to 2 mg/dL.
Although cal citoni n is relatively nontoxic, more than 25% of pati ents may not respond. Thus,
calci toni n i s unsui tabl e as a fi rst-li ne drug during l ife-threatening hypercal cemi a.
Hydrocortisone i s effecti ve i n treati ng hypercal cemic pati ents wi th lymphati c mal i gnanci es,
vitami n D or A intoxi cation, and di seases associated wi th producti on by tumor or granulomas of
1,25(OH)
2
D or osteoclast-acti vating factor. Gl ucocorti coi ds rarel y improve hypercalcemi a
secondary to mal ignancy or hyperparathyroidi sm. In the near future, calci um receptor agoni sts
may become the treatments of choi ce for suppressi ng pri mary and secondary
hyperparathyroi dism. Currentl y undergoi ng i ni ti al cl i ni cal tri al s, these agents also reduce
i norgani c phosphate concentrati on (Pi) and the cal ci um phosphate produce.
148

Phosphates lower serum cal cium by causi ng deposi ti on of cal ci um in bone and soft ti ssue.
Because the ri sk of extraskel etal cal ci fi cation of organs such as the ki dneys and myocardi um is
less if phosphates are gi ven orall y, the intravenous route should be reserved for patients wi th
li fe-threatening hypercal cemi a or pati ents in whom other measures have fai led.
P hosphat e
Physiologic Role
Phosphorus, i n the form of i norgani c phosphate (Pi ), is di stributed in si mi lar concentrations
throughout i ntracel lular and extracell ul ar fl ui d. Of total body phosphorus, 90% exi sts i n bone,
10% i s i ntracell ul ar, and the remai nder, <1%, is found i n the extracel l ul ar fl uid. Phosphate
ci rculates as the free ion (55%), complexed ion (33%), and i n a protei n-bound form (12%).
Bl ood l evels vary widel y: the normal total Pi ranges from 2.7 to 4.5 mg/dL i n adults.
Control of Pi i s achieved by al tered renal excreti on and redi stri buti on withi n the body
compartments. Absorption occurs in the duodenum and jejunum and i s l argel y unregul ated.
Phosphate reabsorpti on i n the kidney i s pri mari l y regul ated by PTH, di etary intake, and insulin-
like growth factor.
149
Phosphate i s freel y fi ltered at the gl omerulus and i ts concentrati on i n the
gl omerul ar ultrafi l trate i s simil ar to pl asma. The fi ltered phosphate i s then reabsorbed i n the
proxi mal tubul e where i t is cotransported wi th sodi um.
149
Proxi mal tubul ar reabsorpti on of
phosphorus occurs by passi ve cotransport wi th sodi um.
150
Cotransport i s regul ated by
phosphorus i ntake and PTH.
151
Phosphate excreti on i s increased by vol ume expansi on and
decreased by respi ratory al kalosis.
Phosphates provi de the primary energy bond i n ATP and creati ne phosphate. Therefore, severe
phosphate depl eti on resul ts i n cel l ul ar energy depl eti on. Phosphorus i s an essential element of
second-messenger systems, including cAMP and phosphoi nosi tides, and a major component of
nucl eic acids, phosphol i pids, and cel l membranes. As part of 2,3-di phosphogl ycerate, phosphate
promotes rel ease of oxygen from the hemoglobi n mol ecul e. Phosphorus al so functi ons i n
protei n phosphoryl ati on and acts as a uri nary buffer.
Hypophosphatemia
Hypophosphatemi a i s characteri zed by low l evel s of phosphate-contai ning cel l ul ar components,
i ncl udi ng ATP, 2,3-di phosphogl ycerate, and membrane phosphol i pids. Serious l i fe-threatening
organ dysfuncti on may occur when the serum Pi fal l s bel ow 1 mg/dL. Neurol ogi c mani festations
of hypophosphatemi a i ncl ude paresthesias, myopathy, encephal opathy, del irium, sei zures, and
coma.
152
Hematol ogi c abnormal iti es i ncl ude dysfuncti on of erythrocytes, pl atel ets, and
leukocytes. Because hypophosphatemi a l imi ts the chemotactic, phagocytic, and bacteri ci dal
acti vi ty of granul ocytes, associ ated i mmune dysfuncti on may contribute to the susceptibi l ity of
hypophosphatemi c pati ents to sepsis.
153
Muscl e weakness and malai se are common. Respi ratory
muscle fai l ure and myocardi al dysfuncti on are potenti al problems of

parti cul ar concern to anesthesi ologi sts. Rhabdomyol ysi s is a compl icati on of severe
hypophosphatemi a.
154

Common i n postoperati ve and traumati zed pati ents, hypophosphatemi a (Pi <2.5 mg/dL) is
caused by three primary abnormali ties i n Pi homeostasi s: an i ntracell ul ar shift of Pi , an
increase i n renal Pi l oss, and a decrease i n gastrointestinal Pi absorpti on. Carbohydrate-
i nduced hypophosphatemia (refeedi ng syndrome),
155
medi ated by i nsul in-i nduced cel l ul ar Pi
uptake, is the type most commonl y encountered i n hospi tal i zed pati ents. Hypophosphatemi a
may also occur as catabol ic pati ents become anabol ic, and duri ng medi cal management of
di abeti c ketoaci dosi s. Acute alkal emi a, which may reduce serum Pi to 1 to 2 mg/dL, increases
intracel lular consumption of Pi by i ncreasing the rate of gl ycolysi s. Hyperventi lation
si gni fi cantl y reduces Pi and, i mportantly, the effect i s progressive after cessati on of
hyperventi lation.
156
Acute correcti on of respi ratory acidemia may al so resul t i n severe
hypophosphatemi a. Respi ratory al kalosis probabl y expl ains the hypophosphatemia associ ated
with gram-negati ve bacteremia and sal icyl ate poi soning. Excessive renal l oss of Pi expl ains the
hypophosphatemi a associ ated wi th hyperparathyroi di sm, hypomagnesemi a, hypothermi a,
di uretic therapy, and renal tubular defects i n Pi absorpti on. Excess gastroi ntesti nal l oss of Pi is
most commonl y secondary to the use of Pi -bi nding antaci ds or to mal absorpti on syndromes.
Measurement of uri nary Pi aids i n differenti ati on of hypophosphatemi a as a resul t of renal
losses from that because of excessi ve gastrointestinal l osses or redistri buti on of Pi into cel ls.
P.202
Extrarenal causes of hypophosphatemia cause avid renal tubular Pi reabsorpti on, reducing
uri nary excretion to <100 mg/day.
Pati ents who have severe (<1 mg/dL) or symptomati c hypophosphatemi a requi re i ntravenous
phosphate admi ni strati on (Tabl e 9-24).
152, 156
In chroni cal l y hypophosphatemic pati ents, 0.2 to
0.68 mmol /kg (5 to 16 mg/kg elemental phosphorus) shoul d be infused over 12 hours. For
moderatel y hypophosphatemic adul t pati ents suffering from cri tical il l ness, the use of 15 mmol
bol uses (465 mg) mi xed wi th 100 mL of 0.9% sodi um chl ori de and gi ven over a 2-hour peri od
safel y repl etes phosphate.
157
The dosage i s then adjusted as i ndi cated by the serum Pi l evel ,
because the cumulative defi ci t cannot be predi cted accuratel y. Oral therapy can be substi tuted
for parenteral Pi once the serum Pi l evel exceeds 2.0 mg/dL. Continued therapy wi th Pi
supplements i s requi red for 5 to 10 days to repl eni sh body stores.
Phosphate shoul d be admi ni stered cauti ously to hypocal cemi c pati ents because of the risk of
precipi tating more severe hypocal cemi a. In hypercal cemi c patients, Pi may cause soft-ti ssue
calci fi cation. Phosphorus must be given cautiousl y to pati ents with renal i nsuffi ci ency because
of impai red excretory abi li ty. Duri ng treatment, cl ose moni tori ng of serum Pi , cal cium,
magnesi um, and potassi um i s essenti al to avoid compl i cations.
Hyperphosphatemia
The cli nical features of hyperphosphatemi a (Pi >5.0 mg/dL) rel ate primari ly to the development
of hypocal cemi a and ectopi c cal cificati on. Hyperphosphatemi a i s caused by three basi c
mechani sms: i nadequate renal excretion, increased movement of Pi out of cell s, and i ncreased
Pi or vi tami n D i ntake. Rapi d cell l ysi s from chemotherapy, rhabdomyol ysi s, and sepsi s can
cause hyperphosphatemia, especi all y when renal function is i mpai red. Renal fai lure i s the most
common cause of hyperphosphatemi a.
151
Renal excreti on of Pi remains adequate until the GFR
fal l s below 20 to 25 mL/mi n.
Measurements of BUN, creati ni ne, GFR, and uri nary Pi are hel pful i n the di fferential diagnosis
of hyperphosphatemi a. Normal renal function accompani ed by hi gh Pi excretion (>1,500
mg/day) i ndi cates an oversupply of Pi. An el evated BUN, el evated creati ni ne, and low GFR
suggest i mpaired renal excretion of Pi. Normal renal functi on and Pi excreti on l ess than 1,500
mg/day suggest i ncreased Pi reabsorpti on (i .e., hypoparathyroi di sm).
Hyperphosphatemi a is corrected by el i mi nati ng the cause of the Pi elevation and correcti ng the
associated hypocal cemi a. Calci um supplementati on of hypocal cemi c pati ents shoul d be del ayed
unti l serum phosphate has fal l en bel ow 2.0 mmol /L (6.0 mg/dL).
134
The serum concentrati on of
Pi i s reduced by restri cti ng i ntake, increasi ng urinary excretion wi th sal i ne and acetazolami de
(500 mg every 6 hours), and i ncreasi ng gastrointestinal l osses by enteric admi ni strati on of
TABLE 9-24 Hypophosphatemia: acute treatment
Parenteral phosphate, 0.2 mM0.68 mM/kg (516 mg/kg) over 12 hours
Potassi um phosphate (93 mg/mL of phosphate)
Sodi um phosphate (93 mg/mL of phosphate)
al uminum hydroxi de (30 to 45 mL every 6 hours). Alumi num hydroxi de absorbs Pi secreted i nto
the bowel lumen and i ncreases Pi l oss even i f none i s i ngested. Hemodi al ysi s and peri toneal
di alysi s are effecti ve i n removi ng Pi i n pati ents who have renal fail ure.
Magnesi um
Physiologic Role
Magnesi um i s an important, multi functi onal , di val ent cation located pri maril y i n the
intracel lular space (intracel lul ar magnesi um ~2,400 mg; extracel l ul ar magnesi um ~280 mg).
Approxi matel y 50% of magnesi um i s l ocated i n bone, 25% i s found in muscl e, and l ess than 1%
of total body magnesi um ci rculates in the serum. Of the normal ci rcul ati ng total magnesi um
concentration (1.5 to 1.9 mEq/L or 0.75 to 0.95 mmol /L or 1.5 to 1.9 mg/dL),
151
there are
three components: protei n bound (30%), chelated (15%), and i oni zed (55%), of whi ch only
i oni zed magnesi um i s acti ve.
Magnesi um i s necessary for enzymatic reactions i nvol vi ng DNA and protei n synthesis, energy
metabol i sm, gl ucose uti l i zati on, and fatty acid synthesis and breakdown.
158, 159
As a primary
regul ator or cofactor in many enzyme systems, magnesi um i s important for the regul ati on of
the sodi um-potassium pump, Ca-ATPase enzymes, adenyl cycl ase, proton pumps, and sl ow
calci um channel s. Magnesi um has been cal led an endogenous cal ci um antagonist, because
regul ati on of slow calci um channel s contributes to maintenance of normal vascul ar tone,
preventi on of vasospasm, and perhaps to preventi on of cal cium overload in many ti ssues.
Because magnesi um parti al l y regul ates PTH secreti on and is i mportant for the maintenance of
end-organ sensi ti vi ty to both PTH and vi tami n D, abnormaliti es i n i onized magnesium
concentration ([Mg
2+
]) may resul t in abnormal calci um metabol ism. Magnesi um functi ons i n
potassium metaboli sm pri maril y through regulating sodi umpotassium ATPase, an enzyme that
control s potassi um entry into cel ls, especi all y in potassi um-depl eted states, and control s
reabsorpti on of potassi um by the renal tubul es. In addi ti on, magnesi um functi ons as a
regul ator of membrane exci tabi li ty and serves as a structural component in both cel l
membranes and the skel eton.
Because magnesi um stabi li zes axonal membranes, hypomagnesemia decreases the threshol d of
axonal sti mul ation and

increases nerve conduction velocity. Magnesi um also i nfl uences the rel ease of
neurotransmitters at the neuromuscul ar juncti on by competiti vel y i nhibi ting the entry of
calci um i nto the presynaptic nerve terminal s. The concentration of cal ci um requi red to tri gger
calci um rel ease and the rate at whi ch cal cium i s rel eased from the sarcoplasmi c reticulum are
inversel y related to the ambi ent magnesi um concentrati on. Thus, the net effect of
hypomagnesemi a is muscl e that contracts more i n response to sti muli and is tetany prone.
Magnesi um i s widel y avai labl e i n foods and i s absorbed through the GI tract, although di etary
consumpti on appears to have decreased over several decades.
159
The di stal tubul e i s the major
site of magnesium regul ati on. Pl asma [Mg
2+
] regul ates magnesi um reabsorpti on through the
Ca
2+
/Mg
2+
sensi ng receptor, located on the capil l ary si de of cell s i n the thick ascendi ng
li mb.
160
Whi l e both magnesi um and Pi are pri mari l y regul ated by i ntri nsi c renal mechani sms,
158

PTH exerts a greater effect on renal loss of Pi.
Magnesi um has been used to hel p manage an impressive array of cl i ni cal probl ems i n patients
who are not hypomagnesemi c.
161
Therapeuti c hypermagnesemi a is used to treat pati ents wi th
premature labor, preecl ampsia, and ecl ampsia. Because magnesi um blocks the release of
catechol amines from adrenergic nerve termi nals and the adrenal gl ands, magnesium has been
used to reduce the effects of catechol ami ne excess i n patients with tetanus and
pheochromocytoma. Magnesium administration may influence dysrhythmias by direct effects on
myocardial membranes, by al teri ng cel lul ar potassi um and sodi um concentrati ons, by inhi bi ti ng
cel lul ar cal ci um entry, by i mprovi ng myocardi al oxygen suppl y and demand, by prol ongi ng the
effecti ve refractory peri od, by depressi ng conducti on, by antagonizing catechol ami ne acti on on
P.203
the conducti ng system, and by preventi ng vasospasm. Admi ni strati on of magnesi um reduces
the incidence of dysrhythmi as after myocardi al i nfarcti on and i n patients with congestive heart
fai l ure.
162
In humans with ischemic myocardium, magnesi um prevented i schemi c i ncreases i n
acti on potential durati on and membrane repolarizati on.
163
After acute myocardi al infarction,
intravenous magnesi um admi ni stration decreased short-term mortal i ty.
164
In addi ti on,
magnesium may be useful as treatment for a torsades de poi ntes ventri cul ar dysrhythmi a, even
in normomagnesemic pati ents.
165

Hypomagnesemia
The cli nical features of hypomagnesemi a ([Mg
2+
] <1.8 mg/dL), li ke those of hypocalcemi a, are
characteri zed by increased neuronal irritabi l ity and tetany (Tabl e 9-25).
166
Symptoms are rare
when the serum [Mg
2+
] i s 1.5 to 1.7 mg/dL; in most symptomati c patients serum [Mg
2+
] i s
<1.2 mg/dL. Patients frequentl y compl ai n of weakness, lethargy, muscl e spasms, paresthesi as,
and depressi on. When severe, hypomagnesemi a may i nduce sei zures, confusi on, and coma.
Cardi ovascul ar abnormal iti es i ncl ude coronary artery spasm, cardi ac fai l ure, dysrhythmias, and
hypotensi on. Severe hypomagnesemi a may reduce the response of adenyl ate cyclase to
stimul ati on of the PTH receptor.
167
Hypomagnesemi a can aggravate di goxi n toxici ty and
congesti ve heart fail ure.
TABLE 9-25 Manifestations of Altered Serum Magnesium Concentrations
MAGNESIUM LEVEL
MANIFESTATION mg/dL mEq/L mmol/L
<1.2 <1 <0.5 Tetany
Sei zures
Arrhythmi as
1.21.8 1.01.5 0.50.75 Neuromuscul ar irritabi l ity
Hypocal cemi a
Hypokal emi a
1.82.5 1.52.1 0.751.05 Normal magnesi um l evel
2.55.0 2.14.2 1.052.1 Typically asymptomatic
5.07.0 4.25.8 2.12.9 Lethargy
Drowsi ness
Fl ushi ng
Nausea and vomi ti ng
Dimini shed deep tendon reflex
7.012 5.810 2.95 Somnol ence
Loss of deep tendon refl exes
Hypotensi on
ECG changes
Rarel y resul ti ng from i nadequate di etary i ntake, hypomagnesemi a most commonl y is caused by
inadequate gastroi ntesti nal absorption, excessive magnesium losses, or fai l ure of renal
magnesium conservation. Excessi ve magnesium loss i s associ ated with prolonged nasogastri c
sucti oning, gastrointestinal or bil i ary fistul as, and i ntestinal drains. Inabi l i ty of the renal
tubul es to conserve magnesi um compli cates a vari ety of systemi c and renal diseases, although
advanced renal disease with a decreased GFR may l ead to magnesium retention. Pol yuri a,
whether secondary to ECV expansi on or to pharmacol ogi c or pathol ogi c di uresi s, may resul t in
excessive urinary magnesium excretion. Vari ous drugs, incl udi ng ami noglycosi des,

ci s-pl ati num, cardiac glycosides, and diuretics, enhance urinary magnesium excreti on.
Intracel lular shi fts of magnesium as a resul t of thyroi d hormone or i nsul i n admini stration may
al so decrease serum [Mg
2+
].

Because the sodium-potassium pump i s magnesi um dependent, hypomagnesemi a i ncreases
myocardi al sensi ti vi ty to di gi tali s preparations and may cause hypokal emi a as a result of renal
potassium wasting. Attempts to correct potassium defici ts wi th potassium repl acement therapy
al one may not be successful wi thout simul taneous magnesi um therapy. Magnesium i s i mportant
in the regulation of potassium channel s. The i nterrel ationships of magnesi um and potassi um in
cardi ac ti ssue have probabl y the greatest cl i ni cal rel evance i n terms of arrhythmi as, di goxi n
toxi ci ty, and myocardi al i nfarction. Both severe hypomagnesemi a and hypermagnesemi a
suppress PTH secreti on and can cause hypocal cemi a. Severe hypomagnesemi a may also i mpair
end-organ response to PTH.
Hypomagnesemi a i s associ ated wi th hypokal emi a, hyponatremi a, hypophosphatemi a, and
hypocal cemia. The reported preval ence of hypomagnesemi a in hospi tal i zed and criti cal ly i ll
patients varies from 11 to 61%, wi th the vari abi l i ty attri butabl e to differences i n measurement
technique.
168
Devel opment of a speci fi c electrode to measure ioni zed [Mg
2+
] has demonstrated
an associ ati on between hypomagnesemi a, use of di uretics, and devel opment of sepsi s.
168

Patients who devel op hypomagnesemi a whi l e in intensive care have an i ncreased mortali ty.
168

Of al cohol i c patients admi tted to the hospital, 30% are hypomagnesemic.
169
Serum [Mg
2+
] may
not refl ect intracel l ul ar magnesi um content. Peri pheral l ymphocyte magnesi um concentrati on
correlates well with skel etal and cardi ac magnesi um content.
Measurement of 24-hour urinary magnesium excreti on i s useful in separating renal from
nonrenal causes of hypomagnesemi a. Normal kidneys can reduce magnesi um excreti on to less
than 1 to 2 mEq/day i n response to magnesi um depl eti on. Hypomagnesemi a accompani ed by
hi gh uri nary excreti on of magnesi um (>3 to 4 mEq/day) suggests a renal etiol ogy. In the
magnesium-loadi ng test, urinary Mg
2+
excretion is measured for 24 hours after an i ntravenous
magnesium load.
170

Magnesi um defi ci ency is treated by the admi ni strati on of magnesi um suppl ements (Tabl e 9-26).
One gram of magnesi um sul fate provi des approximatel y 4 mmol (8 mEq, or 98 mg) of el emental
>12 >10 >5 Compl ete heart bl ock
Cardi ac arrest
Apnea
Paral ysi s
Coma
From Topf JM, Murray PT: Hypomagnesemi a and hypermagnesemi a. Rev Endocr Metab
Disord 4:195, 2003.
P.204
magnesi um. Mi l d defi ci enci es can be treated wi th di et al one. Repl acement must be added to
dai ly magnesium requi rements (0.3 to 0.4 mEq/kg/day). Symptomati c or severe
hypomagnesemi a ([Mg
2+
] <1.0 mg/dL) shoul d be treated with parenteral magnesi um: 1 to 2 g
(8 to 16 mEq) of magnesium sulfate as an intravenous bolus over the fi rst hour, followed by a
conti nuous i nfusi on of 2 to 4 mEq/h. Therapy shoul d be gui ded subsequently by the serum
magnesium l evel . The rate of infusi on shoul d not exceed 1 mEq/mi n, even i n emergency
si tuati ons, and the pati ent shoul d recei ve continuous cardi ac monitori ng to detect
cardi otoxi ci ty. Because magnesi um antagoni zes cal ci um, bl ood pressure and cardiac functi on
shoul d be moni tored, al though blood pressure and cardi ac output usual ly change l i ttle during
magnesium i nfusi on. Treatment of hypomagnesemi a duri ng cardi opul monary bypass decreased
the incidence of postoperati ve ventricular tachycardia from 30 to 7% and i ncreased the
frequency of continuous si nus rhythm from 5 to 34%.
171

Duri ng repl eti on, patel l ar reflexes shoul d be moni tored frequentl y and magnesi um wi thhel d i f
they become suppressed. Pati ents who have renal insuffici ency have a di minished abi l ity to
excrete magnesium and require careful moni toring duri ng therapy. Repleti on of systemic
magnesium stores usuall y requires 5 to 7 days of therapy, after whi ch dail y maintenance doses
of magnesium should be provi ded. Magnesi um can be gi ven orall y, usual ly i n a dose of 60 to 90
mEq/day of magnesi um oxi de. Hypocal cemi c, hypomagnesemi c pati ents shoul d receive
magnesium as the chlori de salt, because the sulfate i on can chelate cal ci um and further reduce
the serum [Ca
2+
].

Hypermagnesemia
Most cases of hypermagnesemi a ([Mg
2+
] >2.5 mg/dL) are iatrogeni c, resul ting from the
administrati on of magnesi um i n antacids, enemas, or parenteral nutri tion, especial ly to patients
with impaired renal function. Other rarer causes of mi l d hypermagnesemi a are hypothyroi dism,
Addison' s disease, l i thi um intoxi cati on, and famil i al hypocal ci uri c hypercal cemia.
Hypermagnesemia i s rarely detected in routi ne el ectrol yte determi nations.
166, 172, 173

Hypermagnesemia antagonizes the rel ease and effect of acetyl choli ne at the neuromuscul ar
juncti on. The resul t is depressed skeletal muscle functi on and neuromuscul ar bl ockade.
Magnesi um potenti ates the acti on of nondepolarizing muscl e rel axants and decreases potassi um
rel ease i n response to succi nylchol ine. The cl inical features of progressive hypermagnesemi a
are li sted in Tabl e 9-25.
166

The neuromuscular and cardiac toxici ty of hypermagnesemi a can be acutel y, but transientl y,
antagoni zed by gi vi ng i ntravenous calci um (5 to 10 mEq) to delay toxi ci ty whi le more defi ni tive
therapy i s insti tuted.
166
Al l magnesi um-contai ning preparations must be stopped. Uri nary
excreti on of magnesi um can be i ncreased by expandi ng ECV and i nduci ng di uresi s wi th a
TABLE 9-26 Hypomagnesemia: Acute Treatment
Intravenous Mg
a
: 816 mEq (12 g MgSO
4
) bol us over 1 hour, fol lowed by 24 mEq/h
(250500 mg/h MgSO
4
) as conti nuous infusi on
Intramuscul ar Mg
a
: 10 mEq q 46 hours
a
MgSO
4
: 1 g = 8 mEq Mg; MgCl
2
: 1 g = 10 mEq Mg.
combi nation of sal ine and furosemi de. In emergency si tuati ons and i n pati ents wi th renal
fai l ure, magnesi um may be removed by di al ysi s.
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> Tabl e of Contents > Secti on II - Basi c Pri nci pl es of Anesthesi a Practi ce > Chapter 10 - Hemotherapy and
Hemostasi s
Chapter 10
Hemotherapy and Hemostasis
John C. Drummond
Charise T. Petrovitch
KEY POINTS
In terms of the transfusi on-transmi tted i nfecti ous diseases, the Ameri can bl ood
supply has never been safer than it is today.
The three leadi ng causes of transfusion-rel ated death i n the Uni ted States are
ABO incompatibi l i ty, transfusi on-rel ated acute l ung i njury (TRALI), and sepsis
caused by bacteri al infecti ons.
In the setti ng of massive transfusi on, assumi ng maintenance of i sovolemia,
criti cal di luti on of cl otting factors and platelets wi ll occur after an average
repl acement of 140% and 230% of bl ood volume, respectively.
Coagul ati on factor and pl atel et replacement shoul d be determi ned by l aboratory
assessment and/or observation of cl i ni cal coagul opathy and not EBL-driven
formulas.
The red bl ood cel l (RBC) transfusi on trigger for most patients wi l l li e between
hemoglobi n val ues of 7 and 10 g/dL.
Pl atel et admini stration thresholds rel evant to anesthesi ol ogi sts wil l l ie usuall y
between 50,000 and 100,000/uL.
Normal coagulation can be achi eved with cl otting factor l evel s of 20 to 30% of
normal . Those l evels can usual l y be achi eved by admi ni strati on of 10 to 15
mL/kg of fresh frozen plasma (FFP).
A pati ent who has recei ved 10 to 12 uni ts of group O RBCs shoul d not be
swi tched back to his or her own ABO group unl ess testi ng has been performed
to confi rm that si gni fi cant ti ters of Anti -A or Anti -B antibodi es are not present.
The classi cal , dual -cascade (intrinsic and extri nsic pathway) model of
coagulation is an inadequate representation of coagul ati on, as it occurs i n vivo.

The knowledge that the human immunodefi ci ency virus (HIV) i s transmi ssi bl e by bl ood generated
publ ic fear of transfusi on and l ed to dramati c changes in the approach to the pati ent requiri ng
bl ood products. Whil e the transfusi on-rel ated risk of acqui ri ng HIV i s now vanishi ngl y smal l , there
remai n numerous other hazards associ ated with blood products. The admi ni strati on of blood
products shoul d be undertaken onl y wi th a compl ete understandi ng of those hazards and of the
potential benefi ts. Accordi ngl y, this chapter begi ns with a revi ew of the ri sks associ ated with the
administrati on of bl ood products, foll owed by a di scussi on of the factors that determine the
necessity for the admini stration of the three most commonl y used components, packed red bl ood
cel l s (RBCs), fresh frozen pl asma (FFP), and pl atel ets, and then a di scussion of conservati on
techniques for minimizing the necessity for transfusi on.
The remai nder of the chapter presents a descri pti on of the preparati on of bl ood products, a
di scussi on of the physi ol ogy of hemostasi s, a description of tests of the hemostatic mechani sm,
and fi nall y a revi ew of common bleedi ng disorders, i ncl udi ng discussion of the effects of
pharmacol ogic agents on hemostasi s.
THE RISKS OF BLOOD PRODUCT ADMINISTRATION
The risks can be subdi vi ded i nto those of i nfecti ous and noni nfectious eti ol ogi es. An excell ent
revi ew has been provi ded by Kl einman et al.
1
Transfusi on-transmi ssi ble i nfecti ons, in particul ar
viral infecti ons, have had the hi ghest profi l e and wi l l therefore be addressed fi rst. However, i n
reali ty, the morbi dity and mortali ty associ ated wi th nonviral hazards i s far greater.
I nf ect i ous Ri sks Associ at ed wi t h Bl ood P r oduct Admi ni st r at i on
The potenti al l y transmi ttabl e di seases/agents are numerous and include several vi ruses: hepati tis
A, B, C, D, and E; the human T-cel l lymphotropi c viruses (HTLV-1, HTLV-2); the human
immunodefici ency viruses 1 and 2; cytomegalovi rus; West Ni l e vi rus (WNV); the Epstei n-Barr
virus; parvovi rus B19; the GBV-C vi rus (al so call ed hepatiti s G); transfusi on-transmi tted vi rus
(TTV); the SEN virus; pri ons (Creutzfel dt-Jakob and variant Creutzfeldt-Jakob); Lyme disease;
contami nati ng bacteri a; parasites (mal ari a, Chagas disease, ehrli chi osi s, babesi osi s); and
In vi vo, coagul ati on i s i ni ti ated pri ncipal ly by contact of factor VII with
extravascul ar ti ssue factor l eadi ng fi rst to pl atel et acti vation fol l owed by the
generati on of large amounts of thrombi n by acti vated cl otting factors acti ng on
the phospholipid surface provi ded by activated pl atel ets.
Von Wi l l ebrand' s di sease i s the most common heredi tary bl eedi ng di sorder and
some form of the disease, which may be subcli ni cal pri or to surgery, i s present
in approxi matel y 1% of the popul ati on.
Factors II, VII, IX, and X and Protei ns C and S are dependent on vitami n K for
thei r synthesi s. Vitami n K defi ciency occurs frequently i n hospi tal ized pati ents
because of di etary insuffici ency, gut steri l izati on, and mal absorpti on. A hi gh
index of suspici on shoul d be mai ntai ned.
As many as 5% of patients who receive hepari n therapy for 5 days wi l l devel op
hepari n-induced thrombocytopeni a/thrombosi s. The cl inical mani festations are
more often the resul t of thrombosi s and thromboembol ism than
thrombocytopeni a.
P.209
syphi li s.
1
Several of these wi ll not be considered further. Whi l e GBV-C, TTV, and SENV are
transmi tted by transfusion, they do not appear to cause cli ni cal di sease; the rate of transmi ssi on
of Parvovi rus B19 i s very low and cl i ni cal di sease i s extremel y infrequent;
1
there have been no
reported instances of transfusi on-transmi tted Lyme disease and only one i nstance of ehrli chi osi s.
2

Esti mates of the frequency of i nfecti ous agents i n the North Ameri can bl ood suppl y are
presented in Tabl e 10-1. The rate of viral i nfecti vi ty has decreased dramati cal ly i n the last
two decades. It is i n particul ar the advent of universal (i n the Uni ted States) nuclei c aci d testi ng
(NAT) for HIV and the hepatiti s C vi rus (HCV) that has reduced the frequency of transmission of
those agents to very l ow l evels, that i s, about one in two mi l li on. Hepatiti s B virus (HBV) remains
the greatest ri sk, currentl y about 1/350,000 donor exposures.
3
Al l of these esti mates are deri ved
from the observed rates of seroposi tivity among donors and the stati sti cal l ikel i hood of
administrati on of bl ood from donors whose infecti on i s i n the window peri od between contracting
the vi rus and detectabi l i ty by the avail able assays. Usi ng NAT testi ng, the wi ndow peri ods for HIV
and HCV are 13 and 12 days, respecti vel y.
1
For HBV, usi ng HbsAg testi ng, the wi ndow peri od i s 59
days. A NAT test for HBV i s avai l abl e
4
and wi l l probabl y be i mplemented by or before 2008.

Hepatitis C Virus
The signi ficance of HCV i s that, despite i ts commonly mi l d ini ti al presentati on, i n 85% of patients
it progresses to a chronic state wi th si gnifi cant associ ated morbidi ty and mortal i ty. Twenty
percent of chronic carri ers devel op ci rrhosis and 1 to 5% devel op hepatocel l ul ar carci noma.
6, 7

Hepatitis B Virus
It i s esti mated that onl y 35% of HBV-exposed pati ents wi l l devel op acute di sease,
8
al though
approxi mately 1% wi l l develop ful mi nant acute hepati tis. In approximatel y 85% of pati ents, the
di sease resol ves spontaneousl y, 9% develop chronic persi stent hepati tis, 3% devel op chroni c
acti ve hepati ti s, 1% devel op ci rrhosi s with or wi thout chronic acti ve hepati tis, and 1% develop
hepatocel l ul ar carcinoma.
9
The current esti mate of ri sk i n the Uni ted States is 1 HBV i nfecti on per
350,000 donor exposures.
TABLE 10-1 Estimates of the rate (per donor exposure) of transfusion-transmitted
infectious disease
Hepati ti s B
3
(HBV) 1/350,000
Hepati ti s C
3
(HCV) 1/2,000,000
Human immunodeficiency virus
3
(HIV) 1/2,000,000
Human T-cel l lymphotrophi c vi rus
5
(HTLV) 1/2,900,000
Bacteri al sepsis/endotoxi n reacti on
5
RBC 1/30,000
Pl atel ets 1/2,000
Hepatitis A Virus
Transmi ssi on of hepatitus A vi rus (HAV) by transfusi on has been very rare. Bl ood banks screen for
HAV by hi story only and there i s no carri er state for thi s vi rus. The i nfecti ous peri od i s l imited to 1
to 2 weeks. The diagnosis depends on hepati ti s anti body seroconversi on.
Human Immunodeficiency Virus
The most feared compli cati on of a bl ood transfusi on i s the transmi ssi on of HIV, the causati ve
agent of the acqui red immunodefici ency syndrome (AIDS). It i s a retrovi rus, so cal l ed because i ts
propagati on requi res translation of RNA to DNA. Current screeni ng tests are di rected at both HIV 1
and HIV 2, though the l atter has been an extremely i nfrequent cause of human disease. The
inci dence of transfusi on-rel ated HIV i nfection has fall en dramaticall y and progressivel y wi th the
implementation of a series of serol ogi c screeni ng tests of donors, i ncl udi ng, very recentl y, NAT
testi ng. The current esti mate of ri sk i n the Uni ted States is 1 HIV infecti on per 1.5 to 2 mi ll i on
donor exposures. For reference, that risk was approxi mately 1:100 i n the earl y 1980s and
1:400,000 in 1997.
10

Human T-Cell Lymphotropic Virus
HTLV-1 and HTLV-2 belong to the same retrovi rus fami l y as HIV. The incidence of cl i ni cal di sease
resul ti ng from

transmi tted vi rus appears to be very l ow. They are associ ated wi th T-cel l leukemi a and l ymphoma
rather than the general ized i mmunodefi ci ency of AIDS. In the Uni ted States, al l donor uni ts are
screened for the presence of antibody to HTLV-I and HTLV-2.
Cytomegalovirus
Transfusi on-associated CMV i nfecti ons are usual ly beni gn and sel f-li mi ted. However, CMV may
cause seri ous, even fatal, infecti ons i n the immunocompromi sed. Pati ents at ri sk i ncl ude
premature neonates, sol i d organ and bone marrow transpl ant recipi ents, and those pati ents wi th
severely depressed immune function. CMV pneumonia i s an i mportant infecti ous cause of death i n
al logeni c bone marrow transpl ant reci pients.
11
Leukoreducti on reduces, but does not prevent, CMV
transmi ssi on.
12
Restri cti on of i mmunocompromi sed pati ents to bl ood from CMV seronegative
donors is requi red i n many centers.
Parasitic Diseases
Transfusi on-transmi tted mal aria i s rel ati vel y common in regions where the di sease i s endemi c but
has been rare in the Uni ted States.
1
Because the parasi te resides wi thi n the red cel l, the hazard is
associated al most excl usi vel y with RBC transfusion. Chagas disease is caused by a protozoan
(Trypanosoma cruzi ) that i s endemi c to South and Central Ameri ca (i ncluding Mexi co). Si gni fi cant
cl i ni cal di sease has been rare in North Ameri ca and has occurred al most excl usively i n
immunocompromised transfusi on reci pients.
Bacterial Contamination of Blood Components
Bacteri al contaminati on occurs at a much hi gher frequency (Tabl e 10-1) than any of the other
infecti ons discussed in thi s section and i s associated wi th substanti al mortal i ty.
13
Fatal i ti es are
estimated to occur at the rate of between 1: 1-6,000,000 transfused uni ts
5
, wi th the rate bei ng
substanti al l y greater wi th pl atel et than RBC admini stration because the former are stored at room
temperature and because pl atelet admi ni strati on commonl y involves pools of 6 to 10 uni ts. A
psoral en-based photochemi cal process that inactivates the DNA and RNA of bacteria (as well as
viruses and protozoa) has recently shown effi cacy without causing materi al i mpai rment of pl atelet
functi on and may serve to address thi s probl em of bacterial contami nation of platelets.
14
The
source of the bacteri a can be donor bl ood, donor ski n flora, or contaminants i ntroduced duri ng
coll ecti on, processing, and storage. Numerous Gram-positi ve and -negati ve organi sms can occur i n
P.210
pl atel ets. Goodnough et al i dentifi ed the organisms i n order of frequency as Staphyl ococcus
aureus, Kl ebsi ell a pneumoni ae, Serrati a marcescens, and Staphyl ococcus epi dermidi s.
8
Only a
li mi ted number of bacteri a, including Yersi ni a enterocol iti ca and certain Serrati a and Pseudomonas
species can grow at RBC storage temperatures.
1

The pati ent who receives contami nated bl ood transfusi on wi l l rapi dl y experi ence some combinati on
of fever, chi ll s, tachycardi a, emesi s, and shock and may devel op di ssemi nated i ntravascular
coagulation (DIC) and acute renal fai lure. The reactions are vari abl e i n severity and an i ndex of
suspi cion shoul d be mai ntai ned in order to di sti nguish these reacti ons from other major and mi nor
transfusion reacti ons. The transfusion should be stopped i mmedi atel y and bl ood cul tures obtai ned.
West Nile Virus
WNV i s a mosqui to-borne fl avi vi rus (as is dengue fever) that became epidemic, pri ncipal ly i n
Mi dwestern states, i ncl udi ng Nebraska, Col orado, and Kansas, in 2002. Al though the majori ty of
infected i ndi vi dual s are either asymptomatic or develop onl y a mil d i l lness, encephal i ti s/meni ngi ti s
can occur and the death rate among confi rmed cases is 510%.
3, 15
Transmi ssi on by bl ood
transfusion and organ transpl antati on has been confi rmed. Fortunatel y, the wi ndow period
between infecti on and cl i ni cal symptoms i s short, at around 3 days, and the peri od of infecti vi ty
al so appears to be rel ati vel y bri ef. Indi vi dual donor NAT testi ng for WNV i s bei ng performed i n
areas of high incidence.
3

Prion-Related Diseases
Pri ons are the causative agents of Creutzfeldt-Jakob di sease (CJD) and variant Creutzfel dt-Jakob
di sease (vCJD). The latter i s the human di sease caused by the agent responsibl e for bovine
spongiform encephalitis (BSE). Al l three are fatal, degenerative neurologi c di seases caused by an
abnormall y fol ded vari ant of a protei n that i s consti tuti vel y present. Between the beginni ng of the
BSE epi demi c i n Engl and i n 1984 and February 2004, 156 cases of vCJD had been reported, wi th
al l but 10 occurring i n the Uni ted Ki ngdom.
16
The ri sk of transfusi on-rel ated vCJD i s undefi ned.
CJD has never been known to have been transmitted by transfusi on and there has been onl y a
si ngl e reported case of apparentl y transfusion rel ated vCJD.
17
However, the i ncubati on peri od of
vCJD may be as long as 6 years so the true transmi ssi on rate may be, as yet, underrecogni zed.
Nonethel ess, i t i s to be hoped that changes in ani mal husbandry practi ces combi ned wi th exclusion
of donors who have sojourned i n hi gh-ri sk areas wil l mi ni mi ze whatever ri sk exi sts.
Noni nf ect i ous Ri sks Associ at ed wi t h Bl ood P r oduct
Admi ni st r at i on
The noni nfecti ous ri sks associ ated wi th bl ood product admini stration, the majori ty of whi ch are
i mmunol ogi cal l y medi ated, and thei r approximate i nci dences are presented i n Tabl e 10-2.
TABLE 10-2 The Noninfectious Adverse Reactions Associated with Blood Product
Administration and Their Approximate Incidences
1, 5, 10

ADVERSE REACTION INCIDENCE
Acute hemolyti c transfusi on reactions 1/25,00050,000
Del ayed hemolyti c transfusi on reacti ons 1/2,500
Mi nor all ergi c reacti ons 1/200250
Immunologically Mediated Transfusion Reactions
Reacti ons to transfused blood products can occur as a resul t of the presence of antibodi es that are
ei ther constituti ve (e.g., Anti -A, Anti -B) or that have been formed as a resul t of pri or exposure to
donor RBCs, whi te bl ood cel l s, platel ets, and/or protei ns, or as a consequence of the effects of
transfused white cell s.
Reactions to RBC Antigens
Acute Hemolytic Transfusion Reactions. The most feared of the immune reacti ons i s the
immedi ate acute hemolyti c

transfusion reacti on (AHTR) agai nst foreign RBCs. Hemol ysi s of the donor RBCs often leads to
acute renal fai l ure, dissemi nated intravascul ar coagulati on, and death. There are more than 300
di fferent anti gens on human red cel ls, but many are weak i mmunogens that usual l y do not el i ci t a
cl i ni cal ly detectabl e antibody response. The antibodi es that fi x compl ement and commonl y produce
immedi ate i ntravascular hemol ysis i ncl ude anti -A, anti -B, anti -Kel l, anti -Ki dd, anti -Lewis, and
anti -Duffy.
18

The i nci dence of AHTRs is estimated to be on the order of 1 per 12,000 uni ts transfused.
1
ABO
incompatibi l ity is among the three leading causes of transfusion-rel ated deaths i n the Uni ted
States with a frequency i n recent years sli ghtl y l ess than TRALI and narrowl y greater than
bacteri al contami nation (L. Holness, MD, personal communi cati on, November 2004). In one
jurisdi cti on (Canada), cleri cal /care provider errors were responsibl e for the majori ty of the
incompatibl e bl ood transfusi ons that resul ted in pati ent death.
1
It is an uncomfortabl e irony that,
at the ti me of thi s writi ng, one of the pri nci pal hazards to the pati ent resi des not i n the bl ood
suppl y per se, but rather in the process that del i vers i t to the pati ent.
When i ncompati bl e bl ood i s administered, anti bodi es and complement in reci pi ent pl asma attack
the correspondi ng anti gens on donor RBCs. Hemolysi s ensues. The hemol ytic reaction may take
pl ace in the i ntravascul ar space and/or it may occur extravascularly wi thi n the endopl asmic
reticul um. The anti genanti body complexes acti vate Hageman factor (factor XII), whi ch i n turn
acts on the ki ni n system to produce bradyki ni n. The release of bradyki ni n increases capi l lary
permeabil i ty and di l ates arteri ol es, both of whi ch contribute to hypotensi on. Acti vation of the
compl ement system results i n the rel ease histamine and serotonin from mast cel ls, resul ti ng in
bronchospasm. Thi rty to fi fty percent of pati ents devel op DIC.
18

Hemolysi s rel eases hemogl obi n i nto the blood. Ini ti all y i t i s bound to haptogl obin and al bumin
unti l the bi ndi ng si tes are saturated, then i t ci rculates unbound i n the blood unti l i t i s excreted by
the ki dneys. Renal damage occurs for several reasons. Bl ood fl ow to the ki dneys i s reduced i n the
presence of systemi c hypotensi on and renal vasoconstri cti on. Free hemogl obi n i n the form of aci d
Anaphyl acti c/-toid reacti ons 1/25,00050,000
Febril e reacti ons 1/200
Transfusi on-rel ated acute l ung i njury (TRALI) 1/5,000
Graft-versus-Host Di sease Rare
Immunomodul ation (?) 1/1
P.211
hemati n or red cel l stroma may preci pi tate i n the renal tubul es causi ng mechani cal obstructi on.
18

Anti genanti body compl exes may be deposi ted i n the gl omerul i . If the pati ent devel ops DIC, fi bri n
thrombi wi l l al so be deposited i n the renal vasculature, further compromi si ng perfusi on.
The signs and symptoms of a hemol yti c transfusion reacti on i ncl ude fever, chi ll s, nausea,
vomi ti ng, di arrhea, and ri gors. The patient is hypotensive and tachycardic (bradykinin effects) and
may appear fl ushed and dyspnei c (histamine). Chest and back pains result from diffuse
intravascul ar occlusi on by aggluti nated red cel ls. The pati ent i s often restl ess and has a headache
and a sense of impendi ng doom. Hemogl obinuria wi l l occur as well as diffuse bl eeding wi th the
development of DIC. With renal fai lure, ol i guria develops. Duri ng general anesthesi a, many of the
si gns are masked. Hypotensi on and hemogl obi nuri a and di ffuse bleedi ng be may the onl y cl ues
that a hemol yti c transfusi on reacti on has occurred. However, hypotensi on and bl eeding are
nonspeci fi c and fai rl y common in the operating room envi ronment and the diagnosis may not be
suspected unti l hemogl obi nuri a i s observed. A reasonabl e index of suspi cion should be maintai ned
duri ng admi ni stration of RBCs to anestheti zed pati ents i n order to avoi d cri ti cal del ay i n di agnosi s.
If a reacti on i s suspected, the transfusi on shoul d be stopped and the i dentity of the pati ent and
the l abel i ng of the bl ood rechecked. Management has three mai n objectivesmaintenance of
systemi c bl ood pressure, preservation of renal function, and the preventi on of DIC. Systemi c bl ood
pressure shoul d be supported by admi ni strati on of vol ume, pressors, and i notropes as requi red.
Uri ne output should be promoted by admi ni strati on of fl ui ds and the use of diureti cs, ei ther
manni tol or furosemi de, or both. Sodi um bi carbonate can be admi ni stered to alkal ini ze the uri ne.
There currently i s no speci fi c therapy to prevent the devel opment of DIC. However, preventi ng
hypotensi on and supporti ng cardiac output to prevent stasis and hypoperfusi on, both of whi ch
contri bute to the evoluti on of DIC, are i mportant.
Laboratory tests shoul d i nclude (1) a repeat crossmatch and (2) a direct anti globul i n (Coombs)
test. The di rect antigl obul in test i s the defi ni ti ve test for an acute hemol yti c transfusion reacti on.
It exami nes reci pi ent RBCs for the presence of surface i mmunogl obul ins and complement. Pati ent
serum is al so exami ned for the presence of anti bodi es that react with the donor cel ls. Serum
haptoglobi n l evel , pl asma, and urine hemogl obin and bi l i rubi n assays are usual l y performed.
However, these are evidence only of hemol ysis, not specifi cal l y of an immune reaction.
18

Laboratory tests to establ ish basel ine coagul ati on status incl uding pl atelet count, PT, aPTT, TT,
fibri nogen l evel , and fibri n degradati on products shoul d be performed.
Exami nation of the pati ent' s pl asma after bri ef centrifugati on for the pi nki sh di scol orati on caused
by free hemogl obi n is a si mpl e, rapi d screeni ng test when a hemol yti c transfusi on reacti on i s
suspected.
18
Hemol ysis can be a result of other causes, including overheati ng prior to transfusion
or i nadvertent use of a hypotoni c sol ution as a di luent. However, hemolysi s shoul d be assumed to
indicate a hemol ytic transfusion reacti on unti l proven otherwi se.
Delayed Hemolytic Transfusion Reactions. Numerous instances have been reported i n whi ch
transfused red cel ls are rapi dly eli mi nated from the ci rcul ati on at a short interval (days) after an
apparentl y compati bl e crossmatch. Many of these events are del ayed hemol yti c transfusi on
reacti ons (DHTRs).
19
These reacti ons occur when the donor RBCs bear an anti gen to whi ch the
recipi ent has previ ousl y been exposed by either transfusi on or pregnancy. Over ti me, the recipi ent
anti bodi es fal l to l evel s too l ow to be detected by compati bi l i ty testi ng. When re-exposure occurs,
the recipi ent undergoes an anamnesti c response and produces more anti body that eventual ly l yses
the forei gn RBCs. Typi cal ly the anti body-coated RBC i s sequestered extravascul arl y and lysi s
occurs i n the spleen and reticuloendotheli al system. Because the red cell destructi on occurs
extravascul arl y, symptoms are less severe and the reacti on i s less li kel y to be fatal . Unl i ke AHTRs,
whi ch usual l y i nvol ve anti bodi es i n the ABO system, DHTRs commonl y i nvol ve anti bodi es against
Rhesus (Rh), Kel l, Duffy, and Ki dd anti gens. The frequency of del ayed hemol ytic reacti ons i s
reported to be 1 per 800 to 2,500 transfusi ons.
18, 20

Evi dence of hemol ysi s is usual l y detected by the fi rst or second week fol l owi ng transfusi on. The
reacti on may be undetected or may be i denti fi ed because of the combi nati on of a l ow-grade fever,
i ncreased bi l i rubi n wi th or wi thout mi ld jaundi ce, and/or an unexpl ained reducti on i n hemoglobi n
concentration. The di agnosi s is confi rmed by a posi ti ve di rect anti gl obul in test (Coombs test).
Serum haptogl obin i s al so decreased. The reaction is sel f-li mi ting and the cl i ni cal mani festations
resol ve as the transfused cel ls are removed from the circul ati on.
18

Reactions to Donor Proteins
Minor Allergic Reactions. Al lergic reacti ons to proteins i n donor pl asma cause urti carial
reacti ons i n 0.5% of all transfusi ons.
1, 5, 10
The reacti on i s al most al ways associ ated wi th the
transfusion of fresh frozen pl asma, but because there i s a small vol ume of donor pl asma present
in other blood products

(RBCs, platel ets), al lergic reactions can occur wi th transfusi on of these components as well . The
patient may have itchi ng, swel l i ng, and a rash as a resul t of the rel ease of histami ne. These mi l d
symptoms can be treated wi th di phenhydrami ne. Patients who experi ence severe urticari al
reacti ons may benefi t from the use of sal ine washed cel l s.
18

Anaphylactic Reactions. Infrequentl y a more severe form of all ergi c reacti on i nvol vi ng
anaphyl axi s wi l l occur i n whi ch the pati ent experi ences dyspnea, bronchospasm, hypotensi on,
laryngeal edema, chest pai n, and shock. Anaphylaxi s preci pi tated by a transfusi on i s a rare, but
potenti al l y fatal , event. It occurs when pati ents wi th heredi tary IgA defi ci ency who have been
sensi ti zed by previ ous transfusions or pregnancy are exposed to bl ood wi th foreign IgA protein.
Treatment consi sts of di scontinuation of the transfusi on and epi nephri ne and methyl predni sol one.
Washed red cel l s, frozen deglycerol i zed red cel l s, or red cel l s from IgA-defici ent donors shoul d
subsequently be used for these patients.
18

White CellRelated Transfusion Reactions
Febrile Reactions. Pati ents who recei ve multi ple transfusions of RBCs or pl atel ets often devel op
anti bodi es to the HLA anti gens on the passenger leukocytes i n these products. Duri ng subsequent
RBC transfusi ons, febri l e reacti ons may occur as a result of anti body attack on donor l eukocytes.
The febri l e response occurs i n about 1% of al l red bl ood cel l transfusi ons. Typi cal l y, the pati ent
experi ences a temperature i ncrease of more than 1 degree centigrade withi n 4 hours of a blood
transfusion and defervesces wi thin 48 hours.
18
Pati ents may experience fever only but they may
al so devel op chi ll s, respi ratory di stress, anxiety,
21
headache, myal gias, nausea, and a
nonproductive cough. Febri l e reacti ons can be treated with acetami nophen. A leukocyte-mediated
febri l e transfusi on reacti on shoul d be di sti ngui shed from a hemol ytic transfusi on reacti on (di rect
Coombs test). Leukoreducti on (see later) reduces or prevents these reacti ons.
Transfusion-Related Acute Lung Injury. Transfusi on-rel ated acute l ung i njury (TRALI) i s a
noncardiogeni c form of pul monary edema associ ated with blood product admini stration. It has
been associ ated wi th admi ni strati on of al l bl ood components but occurs most frequentl y wi th RBCs
(whol e bl ood or packed cel ls), FFP, and pl atelets. The incidence i s frequentl y esti mated to be
1:5,000 units transfused. However, it i s li kel y that TRALI i s both underrecognized and
underreported. TRALI, wi th a mortali ty of 5 to 8%, was the most common cause of transfusion-
rel ated death reported to the FDA for the years 2001 to 2003, although but i t was onl y narrowly
ahead of ABO incompatibi l ity and bacteri al contaminati on (L. Hol ness, MD, personal
communi cati on, November 2004).
Detail ed revi ews of TRALI are avai l abl e.
22, 23
In most i nstances, TRALI occurs when agents present
i n the pl asma phase of donor blood activate l eukocytes i n the host.
24
Those agents are probabl y
most often antil eukocyte antibodi es i n donor bl ood formed as a resul t of previous transfusi on or
pregnancy. In some i nstances, the opposi te reacti on, aggregati on of donor leukocytes and
reci pi ent anti bodi es, may be the cause when the reci pient has been all oi mmuni zed agai nst WBC
anti gens. Because anti granul ocyte anti bodi es can be demonstrated i n most but not al l instances of
TRALI, i t i s suspected that bi ol ogicall y active l i pi ds can al so be the i ni ti ator of the pul monary
insult. Those l i pids are thought to be deri ved from the breakdown over time of the membranes of
the cel l ul ar el ements i n stored bl ood products. It al so appears that TRALI requires the presence of
some preexi sti ng and predi sposi ng i nflammatory condi tion in the reci pi ent, for exampl e, sepsi s,
trauma, surgery.
P.212
The cli nical appearance i s very si mil ar to the adul t respiratory distress syndrome (ARDS), though
the mortal i ty rate i s substantial ly l ess than that associated wi th the l atter. Beginni ng wi thin 6
hours after transfusi on, and often more rapidl y, the pati ent devel ops dyspnea, chi l l s, fever, and
noncardiogeni c pul monary edema. Chest x-ray reveal s bi lateral infi ltrates. Severe pul monary
insufficiency can develop. Treatment is l argel y supporti ve. The transfusi on shoul d be stopped i f
the reacti on i s recognized i n ti me. The pati ent shoul d be gi ven suppl emental oxygen and
ventil atory support as necessary, ideal ly usi ng the same l ow ti dal vol ume lung protecti ve
strategi es that are empl oyed in ARDS.
25
The pulmonary edema is noncardi ogenic. Accordingl y,
di uretics are not warranted. Gl ucocorticoids have been admi ni stered but there are no data to
support that practi ce.
Patients who have experi enced this reaction previously may benefit from the use of washed
PRBCs. Mul ti parous femal e donors have been i denti fi ed as frequent sources of antil eukocyte
anti bodi es and i t has been proposed that these femmes fatal es
26
be excl uded from the donor
pool.
27

Graft-versus-Host Disease (GVHD). Packed RBCs and pl atel et concentrates both contai n a
si gni fi cant number of vi abl e donor lymphocytes. When transfused (transpl anted) into
immunocompromised patients, the donor l ymphocytes may become engrafted, prol i ferate, and
establ i sh an i mmune response agai nst the reci pient. In essence, the engrafted l ymphocytes reject
the host.
28

Pati ents at ri sk for GVHD i ncl ude organ transplant reci pi ents, neonates who have undergone a
bl ood-exchange transfusi on,
18
and pati ents i mmunocompromi sed by many other di sease processes.
GVHD typi cal l y progresses rapi dl y to pancytopeni a and the fatal i ty rate i s very high. Transfusion-
associated GVHD has al so been reported in apparentl y i mmunocompetent patients when a geneti c
rel ati onship exists between the donor and the recipi ent. In these circumstances, the recipi ent may
share HLA anti gen hapl otypes with the donor l ymphocytes. The pati ents, al though immunologi cal ly
competent, fai l to reject the transfused cel ls because they do not recognize them as forei gn. The
transfused donor l ymphocytes, however, recogni ze the host as foreign and a GVHD reacti on takes
pl ace.
29
Because of this phenomenon, the Ameri can Associ ati on of Blood Banks has recommended
that di rected donati ons from fi rst-degree rel ati ves be i rradi ated to i nacti vate donor lymphocytes.
GVHD has been reported only after the transfusion of cel l ul ar bl ood components. It has not
occurred fol lowi ng transfusion of FFP, cryopreci pitate, or frozen red cel l s.
29
Ideal ly, cel l ul ar
bl ood products i ntended for i mmunocompromi sed pati ents and di rected donor units from rel ati ves
shoul d al ways be i rradi ated.
21
Leukoreducti on may reduce the inci dence of GVHD, but i t does not
prevent i t.
1
Irradi ati on remai ns the only effecti ve means for preventi ng GVHD.
30

Immunomodulation. Alteration of immune function has been associated wi th all ogeni c
transfusion. The i niti al observati ons were of decreased rates of transpl ant rejection
31
and
decreased rates of spontaneous aborti on i n pati ents who had recei ved homol ogous transfusi ons.
Alteration i n i mmune surveil l ance was i nferred. Numerous adverse effects of transfusi on,
presumed to refl ect this attenuati on of i mmunocompetence, have been reported, i ncluding
increased mortal ity, accel erated recurrence of mali gnancy, i ncreased ri sk of infecti on, and more
rapi d progressi on of HIV/AIDS.
32
The studi es addressi ng cancer, i nfecti on, and mortali ty have
been very thoroughl y reviewed by Vamvakas et al. Those authors questi oned the val i dity of the
concl usions on the basi s of the fai lure, i n most reports, to control for compoundi ng vari ables.
33

The i ssue, in short, i s: pati ents with more severe il l ness are more li kel y to require transfusi on and
are at i ncreased ri sk of compl i cations i ndependent of the transfusi on. Subsequent reports of an
adverse effect of al l ogenic blood, with al l owance made for confoundi ng vari abl es, have
appeared.
34

Transfused whi te cel ls are thought to be the medi ators of the immuni ty attenuati ng effects,
al though the preci se mechani sms have not been defi ned. These observati ons have led to the
devel opment and appl i cation of techni ques for l eukocyte depl eti on of donor bl ood products.
Leukoreducti on. Many countries i ncl udi ng Canada, France, Portugal , and the Uni ted Ki ngdom and
P.213
certai n states and regi ons wi thin the Uni ted States have al ready adopted the practi ce of
leukoreduction of 100% of their blood suppl i es, and the enti re Uni ted States i s movi ng toward that
objecti ve. There are several wel l -confi rmed benefits of l eukoreducti on i ncludi ng reducti on i n the
development of al loi mmuni zation and pl atel et refractori ness,
35
reducti on i n the i nci dence of febri l e
nonhemol yti c transfusion reacti ons,
36
and reducti on i n (but not preventi on of
12
) the transmi ssi on
of CMV. However, selective leukoreduction coul d readi l y be appl i ed for the pati ents to whom these
benefi ts are rel evant. The advocacy of uni versal leukoreduction is based on the premi se that i t
mi ght serve to accompl ish the vari ous benefi ts li sted as Reported but unconfi rmed in Tabl e 10-3.
Whil e many of the putati ve benefi ts are unconfi rmed, addi tional reports of benefi ts attri butabl e to
leukoreduction are being added to the l i terature.
38, 40
Al though skeptici sm persi sts, the common
view i s that, i n spi te of the associ ated costs, because the hazards of l eukoreducti on are mi nimal ,
the possi bl e benefi ts justify proceeding wi th uni versal leukoreduction.
41, 42

Uni versal l eukoreducti on, when ful ly i mpl emented, wi l l empl oy prestorage depl eti on to prevent the
rel ease of medi ators from WBCs during storage. Thi s i s especial ly rel evant to platel ets, whi ch are
stored at room temperature. In the i nteri m, cl i ni cians usi ng bedsi de fi l tering shoul d appreci ate
that the avai lable fi lters are less effi ci ent at higher temperatures and fi l tering shoul d therefore
i deal l y be performed before bl ood warms to room temperature. Cli nici ans should al so be attenti ve
to the possi bil i ty of severe, apparentl y bradyki nin-medi ated, hypotensi on i n pati ents who receive
bedsi de fi ltered blood. The reaction appears to occur more frequentl y, though not exclusi vel y, in
patients recei vi ng angiotensin converti ng enzyme i nhi bi tors (whi ch reduce breakdown of
bradyki ni n).
43

Ot her Noni nf ect i ous Ri sks Associ at ed wi t h Tr ansf usi on
Massive Transfusion
The rapi d transfusi on of l arge vol umes of stored bl ood can have several consequences. Some of
these are functi ons of properti es of the blood itself, of the agents used to preserve and
anti coagul ate i t, and of the biochemi cal reactions that occur duri ng storage. There are other
compl i cati ons that are not uni que to bl ood transfusi ons, but whi ch may occur wi th the rapid
transfusion of any l arge vol ume of fl ui d.
Hypothermia. The admi ni strati on of one unit of PRBCs at 4 degrees centi grade wi l l reduce the
core temperature of a 70-kg pati ent approxi mately 0.25 degrees C. Hypothermi a slows coagul ati on
(as it does all enzymati cal ly medi ated reactions) and causes sequestrati on of platelets. At 29C
(at whi ch temperature the ri sk of cardiac dysrhythmias i s cri ti cal ), PT and aPTT wi l l increase
approxi mately 50% over normothermi c val ues and pl atel et count wi l l decrease by approxi matel y
TABLE 10-3 Benefits of Leukoreduction
CONFIRMED BENEFITS
Decreased al l oi mmunizati on/pl atel et refractori ness i n multi ply transfused leukemi cs
35

Prevention of febrile reacti ons to RBC transfusi ons
36

Reduction of CMV transmi ssi on
12

REPORTED BUT UNCONFIRMED BENEFITS
37

Decreased postoperati ve i nfections
Decreased postoperati ve mortali ty
38

Shortened hospi tal i zati on
Preventi on of transfusi on-rel ated HIV accel erati on
39

Preventi on of transfusi on-rel ated i ncrease in tumor recurrence
Reduced i nci dence/severi ty of GVHD
40%.
44
Dysrhythmias may be seen at higher core temperatures i f unwarmed bl ood i s admi ni stered
rapidl y, in particular through central access catheters. Whil e there is a general convi cti on that
cold pati ents bleed, there have been no quanti tati ve correl ati ons of temperature and bleedi ng in
the cl i ni cal setti ng. Temperatures of 33C are commonl y used i n elective neurosurgery wi thout
cl i ni cal ly apparent coagul opathy. However, Ferrara et al
45
revi ewed the cl i ni cal course of 45
patients who recei ved massi ve transfusion fol l owing trauma. The durati on of hypotension was
si mi l ar i n patients who survived and those who di d not. However, the degree of aci dosi s and
hypothermia was more extreme in the nonsurvi vors and the nonsurvi vors devel oped
coagulopathies despite adequate bl ood, pl asma, and platelet repl acement. In studi es of this
nature, i t i s difficult to separate the effects of the common cli ni cal concomitants of hypothermi a,
for exampl e, aci dosi s, shock, massi ve transfusi on, massi ve tissue i njury, from those of
hypothermia per se. Furthermore, the significance of hypothermi a may l i e i n the interacti on wi th
other vari ables. In spi te of the ambi gui ty, hypothermi a shoul d be careful l y avoi ded and
aggressi vel y corrected i n the pati ent recei vi ng massi ve transfusi on. Accordingly, transfusi ons
administered rapi dl y or in substanti al volume shoul d be warmed, to prevent hypothermi a. With
decreasing body temperature, cardi ac output decl ines, ti ssue perfusi on is i mpai red (as a
consequence of both vasoconstri cti on and a l eft shi fti ng of the O2-Hb dissoci ati on curve), and
metaboli c aci dosi s may devel op. Shi veri ng on emergence can increase oxygen consumpti on by
400%. Hypothermi a has been associated wi th increased postoperati ve morbi dity and mortali ty
incl udi ng increased rates of postoperati ve i nfection.
46, 47

Volume Overload. Ci rcul atory volume overload occurs when bl ood or fl ui d is transfused too
rapidl y for compensatory fl ui d redi stri buti on to take pl ace.
Dilutional Coagulopathy. Admi ni strati on of l arge vol umes of flui d defi ci ent i n platel ets and
cl otting factors wi l l predi ctably lead to the devel opment of a coagul opathy as a consequence
of dil uti on. There has been consi derabl e di scussi on of whether, in the face of massi ve transfusion
of bl ood products, pati ents wil l fi rst mani fest defi ci enci es of pl atel ets or cl otti ng factors. The
initi al conclusi on was that thrombocytopeni a woul d devel op fi rst. In retrospect, that cli nical
concl usion may have been the consequence of a wider use of whole bl ood than prevai ls today. In
spi te of the l abi l ity of factors V and VIII, sufficient concentrations of these factors probabl y
remai n i n banked whol e bl ood to mai ntai n coagulation function even in the face of very large
transfusions. The same i s probabl y not true when pati ents receive only the smal l residual plasma
vol ume present with packed RBCs. Investi gati ons of pati ents receiving large volume i sovol emi c
transfusions suggest that cl i ni cal ly significant dil uti on of fi bri nogen; factors II, V, and VIII; and
pl atel ets wil l occur after volume exchanges of approximately 140%, 200 to 230%, and 230% (i .e.,
1.4, 2, and 2.3 bl ood volumes), respecti vel y.
48
Resusci tati on from hypovolemia wi l l resul t i n
reaching these threshol ds at smal l er percentage vol ume exchanges. However, cal cul ati ons of thi s
nature shoul d not be used as a gui de to bl ood product admi ni strati on but merel y as a means of

anti cipati ng cli ni cal l y relevant occurrences. The deci sion to admi ni ster fresh frozen pl asma or
pl atel ets wil l depend on clini cal and l aboratory evidence of coagulopathy.
Decreases in 2,3-Diphosphoglycerate (2,3-DPG). Storage of red bl ood cell s i s associated wi th
a progressi ve decrease i n intracel lul ar ATP and 2,3-DPG wi th a resul tant left shi fti ng of the O2-Hb
di ssociation curve. Accordi ngl y, transfusi on of the 2,3-DPGdepl eted blood whi l e i ncreasing the
patient' s hemogl obin val ue wi l l resul t i n l ess effi ci ent oxygen del i very than would occur wi th
nati ve hemoglobi n at the same hematocrit. After transfusion, 2,3-DPG level s return toward normal
over 12 to 24 hours.
49

Acid-Base Changes. When CPD sol uti on i s added to a uni t of freshl y drawn bl ood, pH decreases
to approxi matel y 7.0 to 7.1. Further reduction of pH wi l l occur duri ng storage as a consequence of
ongoi ng metabol i sm of gl ucose to l actate. At the end of 21 days, the pH may be as l ow as 6.9, but
much of thi s is the resul t of the production of CO2 that i s rapi dly eli mi nated foll owi ng the
transfusion. Whether rapi d infusi on of thi s aci di c bank bl ood l eads to metaboli c aci dosi s is
debated. In the past, some cl i ni cians have admini stered sodium bi carbonate empiri cal ly to
pati ents on a fi xed schedul e (e.g., sodi um bi carbonate 44.6 mEq after each 5 uni ts of bank blood
infused). Others contend that the ci trate from the CPD soluti on i s metabol i zed by the pati ent to
P.214
endogenous bi carbonate and that acid-base disturbance is therefore self-correcti ng. Cli nicall y, in
the i njured pati ent who i s hypotensi ve and poorl y perfused and has i nadequate ti ssue
oxygenati on, i t wi ll be di fficul t to di fferenti ate what porti on of the metabol i c aci dosi s is because of
rapi d transfusi on and what porti on i s because of the producti on of lacti c aci d.
46
The appropri ate
course is to base bi carbonate therapy on bl ood gas analysis.
Hyperkalemia. Duri ng storage, potassium moves out of the RBCs, in part to maintain
el ectrochemical neutral i ty as hydrogen i ons generated duri ng storage redistri bute. The potassi um
concentration in pl asma may reach l evel s vari ously reported to be between 17 and 24 mEq/L at 21
to 35 days or 19 to 35 mEq/L i n blood stored for 21 days. Hazard exists if large volumes of stored
bl ood are admi ni stered rapidl y. Rates in excess of 90 to 120 mL/mi n have been associated wi th
hyperkalemia. Furthermore, whi le there are only 20 to 60 mL of pl asma i n a uni t of packed RBCs,
contemporary i nfusi on devi ces all ow bl ood to be transfused at rates of 500 to 1,000 mL/mi n. At
these infusi on rates, cri ti cal hyperkal emi a can occur and i ntraoperative arrests have been
documented.
50
ECG changes associated wi th hyperkalemia i ncl ude peaked T waves, a prol onged PR
i nterval , and a wi dened QRS compl ex. If ECG changes are observed, the transfusi on shoul d be
stopped and i ntravenous cal ci um shoul d be admi ni stered. Bi carbonate, dextrose, and i nsul i n may
al so be appropri ate accordi ng to the severi ty of the epi sode.
Citrate Intoxication. Commonl y used addi tive sol utions contai n ci trate, whi ch anti coagul ates by
chelati on of i oni zed cal ci um. When l arge vol umes of stored bl ood (> one bl ood vol ume) are
administered rapi dl y, the ci trate can cause a temporary reduction in i onized cal ci um l evel s. Ci trate
is normall y metaboli zed effi ci entl y by the l iver and decreased i oni zed cal cium l evel s shoul d not
occur unless the rate of transfusi on exceeds 1 mL/kg per mi nute or about 1 uni t of bl ood per 5
mi nutes i n an average-si zed adul t. Note that the now common Additi ve Sol ution (AS) preservative
bl ood has a much smal l er ci trate content than citrate-phosphate-dextrose-adeni ne (CPDA) bl ood.
However, most of the ci trate admini stered duri ng massi ve transfusion is i n the FFP rather than the
PRBCs. Impai red li ver function or perfusion wi ll l ower the rate threshold for developi ng ci trate
intoxi cation. Note that criti cal cardiac consequences occur before hypocalcemi a has significant
impli cati ons for coagul ati on. Si gns of ci trate intoxi cati on (hypocal cemia) i nclude: hypotension,
narrow pul se pressure, and el evated i ntraventri cular end-di astoli c pressure and central venous
pressure, prol onged Q-T i nterval , wi dened QRS compl exes, and fl attened T waves.
Microaggregate Delivery. Stored blood contains mi croaggregates. Platelet aggregates form
duri ng the second to fi fth day of storage and after approximately 10 days, l arger aggregates
composed of fi bri n, degenerated whi te cel l s, and pl atel ets appear. Macroaggregates of RBCs al so
develop. Standard fluid administrati on sets contai n 170 mi cron fil ters, whi ch wi ll remove these
larger cl ots. Mi cropore fi l ters, typicall y wi th a 40-mi cron pore si ze, have been advocated but
both thei r effi ci ency at removi ng the mi croaggregates and the si gni fi cance to pati ent wel l -bei ng is
uncertain. Microaggregates have been i mpl i cated in the pathogenesi s of pul monary insuffici ency
and the devel opment of ARDS, whi ch often fol lows l arge vol ume transfusi ons (defi ned as >10 to
12 uni ts in 24 hrs).
21, 51
However, the avail abl e data do not confi rm thi s suspi cion and suggest that
pul monary injury and the occurrence of ARDS are more often rel ated to the type of i njury and the
magni tude or severi ty of the injury than to the vol ume of blood transfused. Hypotensi on and
sepsi s may pl ay a much greater rol e i n the development of ARDS than mi croaggregates and some
of what has been attributed to mi croaggregates may i n fact be TRALI. A practi cal consi derati on
nonetheless frequentl y prompts cli nici ans to i ntroduce a mi cropore fi l ter between the blood unit
and the admi ni strati on set. Unfi l tered bl ood may cl og the 170-mi cron fi l ter of the standard set and
it i s less ti me-consuming to change the 40-mi cron fi l ter peri odi cal l y, for exampl e, after every
fourth RBC uni t, than to exchange the entire admi ni strati on set.
RBCs are frequentl y di l uted wi th crystall oid sol utions to increase the rate at whi ch the bl ood can
be transfused. Normal sal i ne i s commonl y recommended i n preference to l actated Ringer' s sol ution
(LR). In fact, the amount of ci trate present i n stored bl ood i s more than sufficient to bind the
smal l amounts of cal cium i n the 100 to 300 cc of LR typi cal ly used for dil uti on.
52
There i s no
evidence that any cl i ni cal l y si gni fi cant sequel ae have resulted from the use of LR as an RBC
di l uent.
51

BLOOD PRODUCTS AND TRANSFUSION THRESHOLDS
Red Bl ood Cel l s
The question level of what hemogl obi n/hematocrit l evel justi fies the risks associ ated with the
administrati on of bl ood has been wi dely di scussed (Tabl e 10-4). The once al l but i nvi ol abl e 10 to
30 rule has been abandoned. Experi ence wi th several pati ent subpopul ati ons (renal fail ure,
mi li tary casual ties, Jehovah' s Witnesses) and systemati c study has reveal ed that considerabl e
greater degrees of anemi a can be wel l tol erated

and that, i n many situations, morbidi ty and mortali ty rates did not i ncrease until hemoglobi n
level s fel l bel ow 7 g/dL.
53, 54
The contemporary transfusi on trigger for general medi cal -surgi cal
patients i s now 21%/7.0 g/dL (Hgb/Hct). However, there is evidence that the threshol d for
patients with cardi ac disease shoul d be hi gher.
53
That evi dence incl udes a wel l -conducted study
supporti ng a threshol d of 30%/10 g/dL (Hgb/Hct) i n pati ents who have suffered a recent acute
myocardial i nfarction
55
and an observati onal study suggesting better outcomes i n patients with
several cardi ac diagnoses (cardi ac and vascul ar surgery, i schemic heart disease, dysrhythmi as)
above a threshol d of 9.5 g/dL.
56
The Practi ce Gui deli nes for Bl ood Component Therapy devel oped
by the Ameri can Soci ety of Anesthesi ol ogi sts (ASA) state that red bl ood cel l transfusi on i s rarel y
i ndi cated when the hemogl obi n concentrati on i s greater than 10 g/dL and is al most always
indicated when it i s l ess than 6 g/dL. The i ndi cati ons for autol ogous transfusi on my be more
li beral than for al l ogenei c (homologous) transfusi on.
57

The cli nici an's responsi bil i ty i s to antici pate, on a pati ent-by-patient basi s, the mi ni mum
hemoglobi n l evel (probabl y in the range of 7 to 10 g/dL) that wi l l avoi d organ damage as a
resul t of oxygen deprivati on. Determi ni ng this i ndi vi dual transfusi on tri gger requi res reference to
the many elements of pati ent condi tion that determine demand for the del i very of oxygen and the
physi ol ogi c reserve (Tabl e 10-5). Ulti matel y the deci sion to transfuse red bl ood cell s shoul d be
made based on the cl i ni cal judgment that the oxygen-carryi ng capaci ty of the bl ood must be
increased to prevent oxygen consumpti on from outstri ppi ng oxygen del i very.
P.215
TABLE 10-4 Hazards Associated with Massive Transfusion
Hypothermia
Vol ume overl oad
Dil uti onal coagul opathy
Reduced O
2
carryi ng capaci ty (decreased 2,3-DPG)
Metabol ic acidosis
Hyperkalemia
Citrate intoxi cati on
Mi croaggregate del i very
TABLE 10-5 Conditions That May Decrease Tolerance for Anemia and Influence the RBC
Transfusion Threshold
Increased oxygen demand
Compensatory Mechanisms during Anemia
When anemi a devel ops, but bl ood volume i s mai ntained (i sovol emi c hemodi lution), four
compensatory mechanisms serve to mai ntain oxygen deli very: (1) an increase i n cardi ac output,
(2) a redi stributi on of bl ood flow to organs wi th greater oxygen requi rements, (3) i ncreases i n the
extraction rati os of some vascular beds, and (4) al terati on of oxygenhemogl obi n bi ndi ng to al l ow
the hemogl obi n to del iver oxygen at lower oxygen tensi ons.
1. Increased cardi ac output.
Wi th i sovol emi c hemodi luti on, cardi ac output increases pri maril y because of an increase i n
stroke vol ume brought about by reducti ons in systemi c vascular resi stance (SVR). There are
two pri nci pal determi nants of SVR: vascul ar tone and the vi scosi ty of bl ood.
58
As hematocri t
decreases, reduction of blood vi scosi ty decreases SVR. Thi s decrease i n SVR increases stroke
vol ume and consequentl y cardi ac output and bl ood fl ow to the ti ssues. Over a wi de range of
hematocri ts, isovol emi c hemodi l ution is sel f-correcti ng. Li near decreases in the oxygen
carryi ng capaci ty of the bl ood are matched by i mprovements in oxygen transport. Because
oxygen transport i s opti mal at hematocri ts of 30%, oxygen del i very may remain constant
between the hematocrits of 45 and 30%.
58
Further reducti ons i n hematocri t are accompanied
by i ncreases i n cardiac output, which reach 180% of control as the hematocrit approaches
20%. The exact hemogl obi n val ue at which cardiac output ri ses vari es among indi viduals and
is i nfluenced by age and whether the anemi a is acute or devel ops sl owly.
59

2. Redi stri buti on of cardi ac output.
Hyperthermi a
Hyperthyroidi sm
Sepsi s
Pregnancy
Limited abi l ity to i ncrease cardiac output
Coronary artery di sease
Myocardi al dysfunction (i nfarcti on, cardi omyopathy)
Beta adrenergi c bl ockade
Inabi l i ty to redi stri bute CO
Low SVR states
Sepsi s
Postcardiopul monary bypass
Occl usi ve vascul ar di sease (cerebral, coronary)
Left shift of the O
2
Hb curve
Al kal osi s
Hypothermi a
Abnormal hemogl obi ns
Presence of recently transfused Hb (decreased 2,3-DPG)
HbS (si ckle cel l disease)
Acute anemia (li mited 2,3-DPG compensation)
Impai red oxygenati on
Pul monary di sease
High altitude
Ongoi ng or i mmi nent bl ood l oss
Traumati c/surgi cal bleedi ng
Pl acenta previ a or accreta, abrupti on, uteri ne atony
Cli ni cal coagul opathy
Wi th i sovol emi c hemodi luti on, bl ood fl ow to the ti ssues i ncreases but thi s i ncreased bl ood
fl ow i s not di stri buted equal l y to al l tissue beds. Organs wi th higher extraction rati os (brai n
and heart) recei ve di sproporti onately more of the i ncrease in bl ood fl ow than organs with
low extracti on ratios (muscle, skin, vi scera).
The redi stri buti on of blood fl ow to the coronary circul ati on i s the pri nci pal means by whi ch
the healthy heart compensates for anemi a.
58
Coronary bl ood fl ow may increase by 400 to
600%. Because the heart under basal condi ti ons already has a hi gh extracti on ratio
(between 50 and 70% vs. 30% i n most tissues) and the pri mary compensati on for anemi a
invol ves cardi ac work (i ncreasi ng CO), the heart must rel y on redi stributing blood flow to
increase oxygen supply.
60
These factors make the heart the organ at greatest ri sk under
condi ti ons of i sovol emi c hemodi luti on. When the heart can no l onger i ncrease ei ther cardi ac
output or coronary bl ood flow, the li mi ts of isovolemic hemodi l uti on are reached. Further
decreases in oxygen deli very wi l l resul t i n myocardi al injury.
3. Increased oxygen extracti on.
Increasi ng oxygen extracti on rati o (ER) i s thought to play an important adapti ve role when
the normovol emi c hematocri t drops bel ow 25%. Increased oxygen extracti on i n multi ple
ti ssue beds leads to an i ncrease i n the whole body ER and consequentl y to a decrease i n
mi xed venous oxygen saturati on. One i nvestigation demonstrated that as hematocri t
decreases to 15%, whol e body oxygen ER i ncreases from 38 to 60%, and the SvO2 decreases
from 70 to 50% or l ess.
46
Some organs (brai n and heart) already have hi gh extracti on rati os
under basal conditi ons and have a li mi ted capaci ty to increase oxygen del ivery by thi s
mechani sm. The heart, under basal conditi ons, extracts between 55 and 70% of the oxygen
del i vered.
61, 62
In contrast, i n ki dney and skin, the ER i s 7 to 10%. In cl inical practi ce, we
cannot measure the extracti on rati os of the vari ous organs. Because the heart has the
hi ghest ER, i t is the organ at greatest ri sk under conditi ons of normovol emi c anemi a.
46

4. Changes i n oxygenhemoglobi n affinity.
The affinity of hemoglobin for oxygen is descri bed by the si gmoi d shaped oxygen
hemoglobi n di ssociation curve. Thi s curve rel ates the parti al pressure of oxygen i n the bl ood
to the percentage saturati on of the hemoglobi n molecule with oxygen. The parti al pressure
of oxygen at which the hemogl obi n molecul e i s 50% saturated wi th oxygen and 50%
unsaturated is termed the P50. P50 for normal adul t hemogl obi n at 37 degrees C and a pH of
7.4 is 27 mmHg. Changes i n aci d-base status or temperature can shi ft the oxyhemoglobin
di ssociation curve to the l eft or ri ght, l oweri ng or rai si ng the P50 value respectively. When
the curve is shifted to the l eft as wi th hypothermia or al kal osi s, the P50 i s l owered. Wi th a
lower P50, the hemogl obin mol ecule i s more stingy and requires lower oxygen parti al
pressures to rel ease oxygen to the tissues, that is, the hemoglobi n mol ecul e does not
rel ease 50% of i ts oxygen unti l an ambi ent PO
2
less than 27 mmHg is reached. Thi s may
impai r ti ssue oxygenation. By contrast, ri ght shi fti ng of the oxygen-hemoglobi n di ssociation
curve, as occurs wi th i ncreases in temperature or aci dosi s, results in an increase of P50,
decreased hemogl obi n affi ni ty for the oxygen molecul e, and rel ease of oxygen to ti ssues at
hi gher parti al pressures of oxygen.
When anemi a devel ops sl owl y, the affi nity of hemoglobi n for oxygen may be decreased, that
is, the curve is right shifted, as a result of the accumul ati on i n red bl ood cel l s of 2,3-
phosphogl ycerate (2,3-DPG). Synthesi s of supranormal level s of 2,3-DPG begins at a Hb of 9
g/dL. At Hb level s of 6.5 the curve is shi fted more promi nentl y. Stored red bl ood cel l s
become depl eted of 2,3-DPG. Temperature reducti on and storage-rel ated pH decreases al so
reduce the P50 of stored bl ood. These changes, however, are reversed in vivo but the
resynthesi s of 2,3-DPG by red bl ood cel l s may requi re from 12 to 36 hours.
60

Isovolemic Anemia versus Acute Blood Loss
P.216
Although the same compensatory mechani sms are operati ve i n acute and chronic anemias, they
have di fferent degrees of i mportance and occur at different level s of hemogl obi n. Wi th acute bl ood
loss, hypovolemia i nduces sti mulation of the adrenergic nervous system, l eadi ng to
vasoconstri cti on and tachycardi a. Increased cardi ac output does not contribute. In chronicall y
anemi c pati ents, cardi ac output increases as the hemogl obi n decreases to approxi matel y 78
g/dL.
59
In these pati ents, the accumul ati on of 2,3-DPG in the red bl ood cell s, thereby i ncreasi ng
the P50 of Hb, i s the important first mechani sm for compensation.
63

P l at el et s
Whi l e publ i shed gui del i nes for platel et admini stration are avai l abl e, there is once agai n a
substantial requirement for cli nici an judgment. The i ndi cati ons for pl atel et administrati on
presented i n Tabl e 10-6 are an amal gam of recommendati ons presented by the ASA i n 1996 and
the Briti sh Committee for Standards i n Haematol ogy i n 2003.
57, 64

Tabl e 10-6 makes i t apparent that the platel et admi ni stration threshol ds that wi l l most often
be rel evant to anesthesi ol ogi sts wil l l ie between 50,000 and 100,000/uL. The threshol d withi n
that range at whi ch pl atel ets are admi ni stered shoul d be based on the l ikeli hood of the i ntended
procedure to cause bl eeding, the hazard of bl eedi ng shoul d i t occur. For exampl e, i ntracrani al
neurosurgery > peri pheral orthopaedi cs and the presence or possi bi li ty of addi ti onal causes of
coagulation disturbance, for exampl e, recent admi ni strati on of anti pl atel et agents,
cardi opul monary bypass, DIC, di lution as a resul t of l arge vol ume administration. Bl eedi ng
mani festati ons can vary substanti al l y from patient to pati ent i n the face of si mil ar pl atel et counts.
Thi s occurs because some platel ets are more effecti ve than others. When thrombocytopenia
resul ts from peripheral destructi on of platelets, the bone marrow continues to produce normal ,
young, large platel ets that are hemostati cal l y very effecti ve. A pati ent wi th these pl atelets may
have more effecti ve pri mary hemostasi s than a pati ent with the same platelet count but whose
TABLE 10-6 Indications for the Administration of Platelets
Nonbl eeding pati ents wi thout other abnormal i ti es of hemostasis
65
<10,000/uL
Lumbar puncture, epi dural anesthesi a, central l ine placement,
endoscopy wi th bi opsy, l i ver bi opsy, or l aparotomy i n pati ents
without other abnormal iti es of hemostasi s
<50,000/uL
Intended procedures i n whi ch closed cavi ty bl eedi ng mi ght be
especial ly hazardous, for exampl e, neurosurgery
<100,000/uL
To mai ntai n pl atel ets duri ng ongoi ng bl eedi ng and transfusi on not
less than
50,000/uL
To mai ntain pl atel ets during DIC with ongoing bl eedi ng not l ess than 50,000/uL
Mi crovascular bleedi ng attri buted to pl atel et dysfuncti on, for
example, uremi a,
a
postcardi opul monary bypass, or i n associ ati on with
massi ve transfusi on
Cli nici an
judgment
a
After a tri al of DDAVP i f permi tted by the cli ni cal si tuati on.
66
pl atel ets were produced by a l ess acti ve, l ess heal thy bone marrow.
One platel et uni t wil l typi cal ly increase pl atel et count by 5 to 10,000/uL. However, the i ncrease
must be verified by pl atel et count, especi all y in patients who may have been al l oi mmuni zed by
frequent platelet admini stration.
Fr esh Fr ozen P l asma
In spite of the fact that over 2,000,000 uni ts of FFP are administered annual ly i n the Uni ted
States there i s remarkabl y li ttl e systemati cal l y deri ved evi dence of effi cacy.
67
Nonethel ess,
the use of FFP to restore coagul ati on factor l evels i s i nevi tabl y vali d i n many cl i ni cal
ci rcumstances. The i ndicati ons for fresh frozen plasma admini stration presented in Tabl e 10-7 are
an amal gam of recommendations presented by the ASA in 1996 and the Bri tish Commi ttee for
Standards i n Haematology i n 2004.
57, 68

Cr yopr eci pi t at e
Cryopreci pi tate contains factor VIII, the von Wi l lebrand factor (vWF), fibrinogen, fi bronectin, and
factor XIII. Virall y i nactivated Factor VIII coagul ati on factor concentrates, some of whi ch contai n
cl i ni cal ly effecti ve concentrati ons of vWF (Anti hemophi li c Factor, e.g., Humate P, Alphanate)
are now avai lable. As a resul t, hemophil i a A and von Wi l l ebrand' s disease (vWD) are usual ly
treated (in consultati on with a hematol ogi st) wi th those concentrates rather than cryopreci pi tate.

The remai ning i ndi cations for cryopreci pitate are presented in Tabl e 10-8.
5

TABLE 10-7 Indications for the Administration of Fresh Frozen Plasma
Correction of si ngl e coagulati on factor defi ci enci es for whi ch speci fi c concentrates are
not avai labl e (pri ncipal ly Factor V)
Correction of mul tipl e coagulation factor defi ci enci es, for example, DIC, wi th evi dence of
mi crovascul ar bl eedi ng and PT and/or aPTT >1.5 ti mes normal
Urgent reversal of warfari n therapy
a

Correction of mi crovascul ar bl eedi ng duri ng massi ve transfusi on (>1 bl ood volume) when
PT/aPTT cannot be obtai ned in a timely manner
a
Prothrombi n compl ex concentrate (II, VII, IX, X) i s an alternati ve that has been
reported to be more effecti ve than FFP.
69
P.217
TABLE 10-8 Indications for the Administration of Cryoprecipitate
Prophyl axi s before surgery or treatment of bl eedi ng i n pati ents wi th congeni tal
dysfibri nogenemi as
Mi crovascular bleedi ng when there i s a di sproporti onate decrease in fibrinogen, e.g., DIC
and very massi ve transfusi on,
a
wi th fi brinogen <80100 mg/dL (or assay resul t not
avai labl e)
Prophyl axi s before surgery or treatment of bl eedi ng i n hemophil i a A or vWD if
concentrates are unavai l abl e or i neffecti ve
Bl eedi ng because of uremi a that is unresponsi ve to DDAVP
BLOOD CONSERVATION STRATEGIES
Because of the many hazards of bl ood product admi ni strati on, numerous techniques and
al ternatives have been expl ored (Tabl e 10-9).
Aut ol ogous Donat i on
Preoperati ve donati on and peri operati ve sal vage of autol ogous blood have been used extensively
as part of programs to reduce homol ogous bl ood admini stration. Autol ogous bl ood may be
col l ected days to weeks pri or to surgery (predonati on); i t may be donated i mmedi atel y pri or to
surgery (isovolemic hemodilution); or it may be salvaged from the surgi cal fi el d or wound drai ns
and rei nfused (bl ood salvage). Deci ding whether any of these opti ons is appropri ate for i ndi vi dual
patients presents another chal l enge i n transfusi on medi ci ne.
Preoperative Autologous Donation
Preoperati ve autol ogous donati on (PAD) of bl ood has been appl i ed pri nci pal l y i n pati ents
undergoi ng major orthopaedi c procedures (total hi p and knee replacement, scol i osi s procedures)
and prostati c and cardi ac surgery.
70, 71
However, the systemati c experi ence has frequentl y fai l ed to
confi rm a reducti on in al l ogeni c bl ood exposure
72, 73, 74
and uti li zati on i s decli ni ng.
75
Effecti veness
has probabl y been l i mi ted because the pati ents' erythropoi eti c response is often not vi gorous, i n
whi ch case the process may si mpl y resul t in an anemia at the time of surgery. PAD has other
a
FFP i s the fi rst-li ne component for the factor depl etion associated wi th massi ve
transfusion.
TABLE 10-9 Blood Conservation Techniques
Preoperati ve autol ogous donati on
Acute normovol emi c hemodi lution
Intraoperati ve bl ood sal vage
Postoperative blood sal vage
Pharmacol ogic agents
Erythropoi eti n
Blood substi tutes (hemogl obin and nonhemogl obi n based)
DDAVP (Section VII)
Anti fi bri nol yti cs (Secti on VII)
di sadvantages. The PAD procedure i s more expensi ve than the coll ecti on of homol ogous bl ood. In
addi ti on, i f autol ogous blood i s unused, most insti tuti ons di scard i t and do not permit crossover
to other pati ents. Practi ces with respect to infecti ous agent testi ng al so vary. Some insti tutions
wi l l store and permi t return to the donor of HIV-, hepati ti s-, or CMV-i nfected bl ood whi l e others
di scard i t. Note al so that the transfusion of autol ogous bl ood does not el i mi nate the chance of
ei ther human error during blood col lection, processing, and reinfusi on or the ri sk of bacterial
contami nati on. Some i nsti tuti ons perform a crossmatch pri or to return of bl ood to the donor and
others do not. This underscores the caveat that no transfusi on is without ri sk.
The medi cal condi ti on of the patient must be consi dered pri or to recommendi ng PAD.
71
Severe
aorti c stenosi s, si gnifi cant coronary di sease or myocardi al dysfuncti on, and l ow i ni tial hematocrit
and blood volume (body wei ght l ess than 110 pounds) are rel ati ve contrai ndi cati ons to PAD.
76
If
the pati ent's hemogl obi n level , cardi ac status, and general condi ti on permi t, bl ood can be donated
at weekl y intervals prior to surgery. Four uni ts is typi cal l y the maxi mum donation because of the
shelf life of the fi rst unit coll ected.
Patients making PAD should recei ve supplemental i ron, for example, 2 mg/kg/day for 3 weeks. In
addi ti on, PAD can be suppl emented wi th admini stration of recombinant erythropoi eti n (Epo).
Erythropoietin
The effectiveness of Epo in hastening recovery of hematocri t i n conjunction wi th PAD and in
i mprovi ng hematocri t i n pati ents not submi tted to PAD has been demonstrated.
77, 78, 79, 80
However,
the practi ce has not become wi despread i n part because of the expense of the agent (not l ess than
500 to 1,600 USD/pati ent dependi ng on the regi men used) and i n part because of the necessi ty for
frequent (e.g., weekl y ti mes 3 weeks and 2 addi tional injecti ons in the final week) parenteral
(subcutaneous or iv) administration of Epo. Selective admi ni stration of Epo to anemic patients has
resul ted i n more obvi ous reducti on i n al logeni c bl ood admi ni strati on
81, 82
than has admi ni strati on to
all comers.
83, 84
Epo, a recombi nant product, i s usual ly accepted by Jehovah' s Witnesses and its
effi cacy i n that popul ati on has been demonstrated.
85
The recent demonstrati on of the reducti on of
transfusion requirements i n criti cal ly i ll pati ents by Epo
86
may i ncrease awareness and encourage
its systematic

use in anemic el ecti ve surgical patients. An al ternative erythropoi etic agent, darbopoi eti n al pha,
has recentl y been devel oped. Its l onger hal f-li fe results i n a more sustai ned erythropoieti c effect
than occurs wi th Epo.
87

Acute Normovolemic Hemodilution
Acute normovol emi c hemodil uti on (ANH) entai l s wi thdrawal of the pati ent's bl ood earl y i n the
intraoperative peri od wi th concurrent admini stration crystal loi ds or col l oi ds to mai ntain
normovol emi a. The rati onal e is that duri ng the ensui ng surgery, the pati ent wil l l ose bl ood of l ow
hematocri t and the wi thdrawn bl ood wi l l be avai l abl e for rei nfusi on at the end of the operati on.
The end poi nt for the i ni ti al wi thdrawal is a hematocri t of 27 to 33%, dependi ng on the patient' s
cardi ovascul ar and respiratory reserve. Selection for thi s techni que shoul d rely on careful
eval uation of the pati ent for coronary or cerebral vascul ar di sease. Thi s procedure evol ved i n the
anti ci pati on that i t woul d reduce total red cel l loss and homol ogous bl ood admini stration.
However, both mathemati cal model ing and empi ri c experi ence have reveal ed only a modest benefit
with respect to reduci ng the necessi ty for homologous RBCs.
80, 88, 89, 90, 91
By way of exampl e,
Goodnough
92
calcul ated that, in a 100-kg patient from whom three units of bl ood i s wi thdrawn and
repl aced by asanguinous fl ui d, i f the subsequent blood loss is 2,800 mL, 215 mL of RBCs (about
one unit) wi ll be saved. For patients of l i mi ted body si ze, l ow starti ng hematocrit, or blood loss
less than 70% of one bl ood vol ume,
93
avoi dance of al l ogeni c bl ood or pati ent benefi t mi ght be
di fficul t to achi eve. A recent meta-anal ysi s, whi l e confirmi ng that reducti on of all ogenic bl ood on
the order of one unit per pati ent was common among the reported i nvesti gati ons, on the basis of
the modest savings and the sci entific meri t of the i nvestigations, concluded that the li terature
supports onl y modest benefi ts from preoperati ve ANH. Wi despread adopti on of ANH cannot be
encouraged.
94
Nonethel ess, there are reports of favorable experi ences in l iver resection,
P.218
prostatectomy, total hip arthropl asty, and abdomi nal aorti c surgery.
80, 95, 96, 97
It is possi bl e that i n
the future the efficacy of ANH will be enhanced by admini stration of preoperati ve erythropoi eti cs
and/or by the use of either hemogl obi n-based oxygen-carryi ng compounds or perflourocarbon
emul sions to permit wi thdrawal of l arger volumes of bl ood.
ANH has al so been empl oyed for the purpose of making fresh autol ogous bl ood at the end of
procedures i n whi ch ei ther a di l utional or cardiopul monary bypass-rel ated coagul opathy may
occur. The efficacy i n thi s context has not been confi rmed by systematic study. Bl ood col l ected
and rei nfused for thi s purpose shoul d not be passed through a 40-mi cron fi l ter to avoi d pl atel et
el i mi nation.
P er i oper at i ve Bl ood Sal vage
Peri operative bl ood sal vage refers to the recovery of shed bl ood from the surgical fi el d or wound
drains and readmi nistrati on to the pati ent. In most i nstances, the process i nvol ves washing of
the sal vaged material wi th return of only the RBC component of blood. In some i nstances, usual l y
those involving wound drai nage, bl ood i s returned fi l tered but otherwi se unprocessed.
Intraoperative Blood Salvage
Intraoperati ve bl ood sal vage (IBS) i s empl oyed wi th many surgi cal procedures that have the
potential to requi re homologous transfusi on. Contemporary cel l saver devices anticoagul ate the
salvaged bl ood as i t leaves the surgical fiel d, separate the RBCs from other l i qui d and cel lular
el ements by centri fugation, and then wash the sal vaged RBCs extensi vel y with sal ine. The RBCs
are typicall y returned to the pati ent suspended i n sal ine i n aliquots of 125 or 225 mL wi th a
hematocri t of 45 to 65%
98
. Hi gher hematocrits can be achieved at the expense of the additi onal
time required for slower filling of the centrifuge chamber.
IBS has been used commonly duri ng cardi ovascul ar surgical procedures, aortic reconstructi on,
spi nal i nstrumentati on, joint arthropl asty, li ver transpl antation, resecti on of arteri ovenous
malformations,
99
and occasi onall y i n the management of trauma pati ents.
100
There have been
numerous demonstrati ons that IBS can reduce the use of homol ogous RBCs.
101, 102
The presence of
infecti on, mal i gnant cel l s, uri ne, bowel contents, and amni otic fl ui d i n the operati ve fi el d have
been vi ewed as contrai ndi cati ons. However, though mal i gnant cel l s are known to be retai ned with
RBCs after the washi ng process, IBS has been appl i ed i n the management of hepati c and urol ogi c
mali gnanci es wi thout evidence of metastasis.
103, 104
At least one IBS washi ng devi ce has also been
shown to remove the cri ti cal procoagul ant factors present i n amni oti c fl ui d
105
and IBS has been
employed successful ly in Cesarean section.
106
However, the safety of IBS use i n that context i s
unconfi rmed and shoul d not be routi ne.
107

The potenti al compl icati ons of IBS are largel y a functi on of the rei nfusion of material s that might
remai n after the washing process. These include fat, mi croaggregates such as platel ets and
leukocytes, ai r, red cel l stroma, free hemoglobi n, hepari n, bacteri a, and debri s from the surgi cal
fiel d. Most of these are i n fact removed qui te effi ci entl y by contemporary cell salvage equi pment.
Bacteri a are the exception and contami nation of cel l saver return wi th ski n organisms i s rel ati vel y
common.
101
Leukocyte reducti on fi lters have been shown to remove most bacteri a
108
and may be
rel evant to the use of IBS i n trauma. Massive ai r emboli sm has occurred as a resul t of user error.
Direct return from the cell saver apparatus has now been largel y abandoned i n favor of return vi a
an i ntermedi ary bag under the control of the anesthesi ol ogist. Care should sti ll be taken i n the
event that pressure i nfuser devices are appl i ed to these bags.
A dil uti onal coagulopathy i n associ ation wi th l arge vol ume IBS i s to be expected because
essential ly all cl otti ng factors and most platelets are removed by the washi ng process.
Management is the same as for a di l utional coagul opathy occurri ng with administration of
homol ogous or PAD bl ood. A DIC-l i ke coagulopathy, the salvaged bl ood syndrome,
109
has al so
been associ ated wi th IBS. However, i t seems li kel y that thi s syndrome was the resul t of
i nadequate preparati on of bl ood by ol der cell salvage devices. Unwashed, sal vaged blood has been
shown to contain numerous constituents that i nfl uence the coagul ati on process: thrombopl asti c
material , interleukins, complement, fibrin degradation products, and factors released from
acti vated leukocytes and pl atel ets.
99
The majority of these, however, are qui te effi cientl y removed
by contemporary processi ng devi ces and thei r presence i s used as an argument agai nst the return
of unprocessed blood (see l ater).
110

An addi ti onal coagulopathy risk arises wi th the use of thrombi n and mi crofi bri ll ar col lagen or
cel lul ose products in the surgi cal fi eld.
111
These agents are not rel iabl y removed by the washi ng
process and sucti on of bl ood to the IBS device shoul d be di sconti nued during the use of these
agents and resumed after the fi el d has been i rri gated.
The cli nici an shoul d appreciate that the recovery of shed RBCs by the IBS process is on the order
of 50%. Al l ogeni c bl ood wi l l therefore frequentl y be necessary i n spi te of the IBS and bl ood and
flui d repl acement cal cul ations should take thi s i nto account.
112, 113

Postoperative Blood Salvage
Postoperative recovery of blood from medi astinal chest tubes and wound drai ns after hip and knee
repl acement with immedi ate reinfusi on of unwashed bl ood has been empl oyed qui te commonl y.
The many substances present in the unprocessed bl ood (previ ous secti on) suggest that
coagulation dysfuncti on mi ght result and many are skepti cal regardi ng the wisdom of thi s
practi ce.
98, 110
However, there have been onl y occasional reports of apparent adverse
consequences.
114
Thi s may refl ect the fact that the recovered and rei nfused volumes are usuall y
smal l .
Hemoglobin-Based Oxygen Carrying Solutions
It seems possibl e that hemogl obi n-based oxygen carryi ng sol utions (HBOCs) wil l become avai l abl e
in the near future. Hemopure (Bi opure, Inc) has been approved for cli ni cal use in South Afri ca.
However, al though numerous pol ymeri zed hemogl obi n products have been studied onl y one,
Pol yHeme, Northfiel d Laboratori es, i s currently i n phase III tri al in the Uni ted States. The many
products studi ed use bovi ne, outdated human, or recombi nant hemoglobi n that has been entirel y
separated from red cel l membranes (stroma) and pol ymeri zed to increase hal f-li fe. The i ni ti al
di ffi cul ti es with renal fai l ure caused by stroma and excessi ve free hemogl obi n have been
overcome. However, there are several residual di ffi cul ties wi th whi ch cl inici ans wi ll probabl y have
to contend i ncluding methemogl obinemi a, interference wi th some cal ori metri cal ly based l aboratory
assays (i ncludi ng creatinine, total bi l i rubi n and LDH), some degree of vasoconstri cti on caused by
ni tri c oxi de bi ndi ng by free Hb, and a rel ati vel y short hal f-li fe. Pol ymerizati on i ncreases hal f-li fe to
18 to 36 hours but that peri od is suffici ently short that O
2
-carryi ng capaci ty wi l l usual ly become
inadequate before nati ve reti cul ocytosi s can compensate.
115, 116
Perfl ourocarbon emul si ons
116

appear to be further from potenti al cl inical appl i cati on than HBOCs and wil l not be di scussed here.
The J ehovah' s Wi t ness
In general , Jehovah' s Witnesses wi ll accept nei ther administration of homol ogous bl ood products
nor the readmi ni strati on of autol ogous products that have l eft the ci rculation. However, their fai th
al lows si gni fi cant personal discreti on and the wishes of each pati ent must be cl ari fi ed. Few wil l
permi t the admini stration of the common whole bl ood components and the majority wi ll decl i ne
PAD. However, many will accept procedures that mai ntain extracorporeal blood in continui ty wi th
the ci rculation. The acceptabi l ity of cardi opul monary bypass, acute normovol emi c hemodi lution,
and peri operati ve cell salvage must be cl ari fi ed wi th each pati ent i ndi vi dual l y. Most wil l permit
administrati on of Epo.
COLLECTION AND PREPARATION OF BLOOD PRODUCTS FOR
TRANSFUSION
Red Bl ood Cel l s
In the preparati on of red bl ood cel l s for transfusi on, whole bl ood is fi rst col l ected i n bags
P.219
contai ning citrate-phosphate-dextrose-adeni ne (CPDA) or CPD sol uti on. The ci trate chel ates the
calci um present i n blood and prevents coagul ati on. PRBCs are prepared by centri fugation. The two
common preparations ul timately del ivered to the cl i ni cian have ei ther CPDA or so-call ed Addi tive
Sol uti on as the preservative. CPDA bl ood has a hematocri t of about 70 to 75%, contains 50 to 70
mL of resi dual pl asma i n a total volume of 250 to 275 mL, and has a shelf l ife of 35 days. Wi th the
Addi ti ve Sol uti on preparati on, the ori ginal preservati ve and most of the pl asma (10 to 15 mL
residual ) i s removed and repl aced wi th 100 mL of Additi ve Soluti on. Thi s resul ts i n a lower
hematocri t, 60%, i n a total volume of 250 to 350 mL; l ess citrate per unit, 75 to 80% fewer
mi croaggregates; and a l onger shelf li fe, 42 days. Additi ve Sol uti on RBCs are thought to
regenerate 2,3-DPG more rapi dl y. The pH and K+ content of the two preparati ons are simil ar. The
smal l er pl asma vol ume i n Additi ve Sol ution blood resul ts i n smal l er amounts of coagul ati on factors
in PRBCs but al so a potenti all y l esser risk of al l ergi c reacti ons and TRALI.
Sequenti al centri fugati on at various spi n speeds and durati ons i s used to separate whole blood
into components; i ncl udi ng packed RBCs, platel et concentrates, cryopreci pitate, l eukocyte-poor
RBCs, and cel l -free pl asma. For preparation of platel et concentrates, centri fugation is fi rst
performed at room temperature. Thi s separates the platel et-ri ch pl asma fracti on from the red
bl ood cel l s. To separate al l other bl ood components, centri fugation is carried out between 1
degree and 6 degrees C.
There are al ternative RBC preparati ons that el i mi nate the vari ous passengers. Sal i ne-washed
RBCs may be used for patients who experi ence reacti ons to forei gn protei ns. Whi te cel ls can be
removed by washi ng, irradi ati on, or l eukofil trati on. The admi ni strati on of one uni t of packed RBCs
wil l i ncrease the Hb and Hct of a 70-kg adul t by approxi matel y 1 g/dL and 3%, respecti vel y.
RBCs can be frozen and stored i ndefi ni tel y. However, preservati ves to prevent freeze-thaw
associ ated damage must be added and subsequentl y removed before admi ni strati on, which must
occur wi thin 24 hours of thawi ng. The process is expensive and therefore not wi dely used.
Compatibility Testing
Compati bil i ty testing i nvol ves three separate procedures i nvol vi ng both donor and reci pi ent bl ood:
ABO, Rh bl ood type i denti fi cation, anti body screeni ng of donor plasma, and the donor/reci pi ent
crossmatch.
ABO, Rhesus Typing
The fi rst step is to determi ne the ABO blood group type and the Rh status of both donor and
recipi ent bl ood. This i s a cri ti cal step because most of the fatal hemol yti c transfusi on reacti ons
resul t from the transfusi on of ABO-incompatibl e bl ood. Bl ood types are defi ned accordi ng to the
anti gens present on the surface of the RBCs. Pati ents with type A bl ood have type A anti gens on
the surface of thei r red cell s. Type B bl ood has B anti gens. When both anti gens are present the
patient is said to have type AB bl ood and when both are l acki ng, the pati ent i s sai d to have type O
bl ood. The serum constituti vel y contai ns anti bodi es to the AB antigens that are l acking on the
RBC. Pati ents wi th type A bl ood have anti bodi es agai nst the B anti gen and vi ce versa. Pati ents
with no antigens on thei r cel ls, type O bl ood, wil l have both anti -A and anti -B antibodi es in the
pl asma. The approxi mate frequenci es of ABO blood types in the U.S. are presented i n Tabl e 10-10.
TABLE 10-10 Major RBC Surface Antigen Incidence (%) in the U.S. Population
117

GROUP WHITES BLACKS
O 45 49
Patients with the Rhesus (D) antigen are sai d to be Rh-posi ti ve and those who lack the D antigen
are termed Rh-negati ve. Approximatel y 85% of the population is Rh-positi ve. In contrast to the A
and B bl ood groups, anti -D anti bodies are not consti tutively present i n the serum of an Rh-
negati ve pati ent. However, 60 to 70% of Rh-negati ve pati ents exposed to donor Rh-positi ve RBCs
wi l l devel op anti -D anti bodi es. There i s a latency before these anti bodi es are synthesi zed. As a
consequence, the reacti on between the Rh-positi ve donor cel l s and

the anti -D evolves sl owly and may not be cl i ni cal l y apparent on first exposure. Thi s process,
whereby a forei gn anti gen sti mulates the synthesis of the correspondi ng anti body, i s termed
al loi mmuni zation. Subsequent exposure of these Rh-negati ve i ndivi dual s to Rh-positi ve cell s may
resul t in an acute hemol ytic reaction.
In determi ni ng what donor bl ood group types may be compati bl e for transfusi on to a parti cul ar
reci pi ent, i t i s useful to focus on whi ch anti bodi es wi l l be present in the reci pi ent pl asma. It i s the
reacti on of these anti bodies wi th donor RBC antigens that can acti vate compl ement and lead to
intravascul ar hemol ysis of the red cel l. Type O+ reci pi ents [type O, Rh(D)-positi ve] wi ll have both
anti -A and anti -B antibodi es, but not the anti -D antibody i n their pl asma. These pati ents must not
recei ve ei ther type A, type B, or type AB bl ood. They must recei ve type O bl ood but i t may be Rh-
positi ve or Rh-negati ve. In contrast, pati ents wi th bl ood type AB- (Type AB, Rh-negati ve), wi l l
lack both the A and B antibodi es i n thei r pl asma and may or may not have the anti -D antibody i n
thei r plasma. They can recei ve A-, B-, AB-, or O- blood. Indi vi dual s wi th the greatest number of
anti gens on thei r RBCs have the fewest constituti ve anti bodi es in their pl asma and can receive al l
bl ood types (Types A+, A-, B+, B-, AB+, AB-, O+, and O-), and are referred to as universal
reci pi ents. Indi vi duals with the fewest anti gens on thei r cel l s (type O-negati ve) have the greatest
number of anti bodies i n their pl asma. Type O-negati ve RBCs can be administered to al l ABO, Rh
types and these i ndi vi dual s are referred to as universal donors.
The Antibody Screen
The anti body screen, an i ndi rect Coombs test, i s performed to i denti fy reci pient anti bodi es agai nst
RBC antigens. Commercially supplied RBCs, sel ected for the panel of antigens they possess, are
mi xed wi th both donor and reci pient serum to screen for the presence of unexpected anti bodi es.
Only about 4 i n 1,000 bl ood donati ons demonstrate unexpected antibodi es. The l ikeli hood that the
anti body screen wi l l mi ss a potenti al l y dangerous anti body has been esti mated to be no more than
1 in 10,000. If the reci pi ent pl asma screen is posi ti ve, the anti body must be identi fi ed and
appropri ate anti gen negati ve donor units sel ected. The antibody screeni ng of reci pi ent pl asma
should be repeated i f the pati ent has been transfused since the last anti body screeni ng test.
The Crossmatch
Donor RBCs are mi xed wi th recipi ent serum. Thi s test requi res about 45 mi nutes and is carried out
A 40 27
B 11 20
AB 4 4
Rh (D) 85 92
P.220
in three phases: (1) the i mmediate phase, (2) i ncubati on phase, and (3) anti gl obul i n phase.
The i mmedi ate phase serves pri mari l y to ensure that there have been no errors i n ABO-Rh typi ng.
The test entail s exami nation of a mi xture of donor RBCs and pati ent serum for macroscopi c
aggl uti nati on. This i mmediate phase crossmatch requires onl y 1 to 5 mi nutes and detects ABO
incompatibi l iti es and those caused by antibodi es i n the MN, P, and Lewi s systems.
The second phase, the incubation phase, requi res 30 to 45 minutes and detects antibodies
pri mari l y i n the Rh system.
The thi rd phase, the anti gl obul i n phase, al so cal led the anti gl obuli n crossmatch or the indirect
anti gl obuli n test, entai l s the addi tion of antigl obul in sera at the end of the incubati on phase. Thi s
phase i s performed only on bl ood yi el di ng a posi ti ve anti body screen and requires 60 to 90
mi nutes. The test i denti fi es the presence of antibodi es attached to anti gens on the surface of the
donor red bl ood cel ls. Thi s phase i s an attempt to identi fy the most i ncompl ete anti bodi es (i .e.,
those that do not cause aggl uti nati on) from al l bl ood group systems, i ncl udi ng Rh, Kell , Ki dd, and
Duffy systems.
In pati ents who have been transfused previ ously or who may have been exposed to forei gn red
bl ood cel l anti gens duri ng pregnancy, onl y 1 i n 100 wi ll have an anti body other than the anti -A,
anti -B, and/or anti -Rh antibodi es and many of these are not reactive at physi ol ogi c temperatures.
Determi ni ng the ABO bl ood group type and Rh status al one yi elds the probabi l i ty that the
transfusion wi ll be compati bl e i n 99.8% of i nstances. The addi tion of the 30- to 45-mi nute
anti body screen i mproves the l ikel i hood of a compati bl e transfusi on to 99.94%; the addi ti on of a
compl ete crossmatch increases thi s to 99.95%.
63
In patients who have not previousl y been
transfused or pregnant, the odds that an incompatibl e transfusi on wil l occur when uncrossmatched
bl ood is admi ni stered i s onl y 1 i n 1,000. For those who have previ ousl y been exposed to foreign
red bl ood cell anti gens, the l i kel ihood that they wil l have devel oped an antibody is about 1 in 100.
Nonethel ess, al l blood banks perform the crossmatch. However, these data reveal that the
administrati on, i n emergency situations, of uncrossmatched blood to pati ents wi th no history of
pregnancy or transfusi on shoul d entai l rel ati vely l ow ri sk.
Type and Screen Orders
When bl ood i s ordered preoperati vel y for surgical cases i n whi ch i t is unl i kel y that the bl ood wi l l
actual l y be transfused, the orders shoul d be for type and screen only. The ABO, Rh status of the
patient is determined and the anti body screen (see earl ier) is performed to determi ne the
presence of anti bodi es other than ABO i n the potenti al reci pi ent's pl asma. If the anti body screen i s
negati ve, type specifi c uncrossmatched bl ood wi l l resul t in a hemol ytic reaction in l ess than
1/50,000 units
5
. If the screen is posi ti ve, the bl ood bank proceeds to i denti fy a pool of potenti al l y
compati bl e units.
Emergency Transfusions
The exsangui nating pati ent may require RBCs before compl ete compatibi l ity testi ng can be
performed. If testi ng i s to be abbrevi ated, there i s a preferred order for sel ecti ng parti al l y
tested bl ood. The first choi ce is to transfuse type-specific, parti al l y crossmatched bl ood. In urgent
si tuati ons in whi ch a pati ent needs bl ood before compati bi li ty testi ng can be completed, the use of
uncrossmatched bl ood i s i ndi cated. If the pati ent' s ABO and Rh type i s unknown or has not been
tested on a current sample, group O RBCs shoul d be admi ni stered until there is ti me to compl ete
ABO and Rh testi ng. Rh-negati ve blood i s preferabl e i f the pati ent's Rh type i s unknown or i f the
patient is a woman of chi ld-bearing age. If Rh-negati ve bl ood i s not avai l abl e for a cri ticall y il l ,
bl eedi ng Rh-negati ve pati ent, Rh-posi ti ve bl ood shoul d not be wi thhel d. If the bl ood bank has ti me
to test a current sampl e, then ABO and Rh type-specific uncrossmatched RBCs can be
administered. In either case, the blood bank wil l begi n compati bil i ty tests as soon as possi bl e

if a current pretransfusion sampl e i s avai l abl e. If a non group O patient receives a l arge vol ume of
group O red cel l s, the combi ned amount of anti -A and/or anti -B present i n the small amounts in
the resi dual pl asma each PRBC uni t may react wi th the patient' s own A, B, or AB red cell s and
P.221
cause some hemol ysis. For this reason, non group O pati ents who have recei ved group O red cel l s
approxi mati ng one pati ent bl ood vol ume (10 to 12 units) during the peri od of acute blood loss
should not be switched back to their own ABO group
118
unless testing has been performed to
confi rm that significant titers of anti -A or anti -B antibodi es are not present. The deci si on as to
whether or not to switch to type-speci fi c bl ood shoul d be made, i n conjunction wi th the bl ood
bank, on the basi s of that result and admi ni strati on of type O bl ood shoul d conti nue i n the
interim.
P l at el et s
Pl atel ets are separated from plasma by centrifugati on. They are commonl y suppl i ed as si ngl e-
donor units wi th the pl atel ets suspended in a small quanti ty of resi dual plasma. One uni t of
pl atel ets wil l i ncrease the pl atelet count of a 70-kg reci pient by 5 to 10,000/mm
3
. A common
practi ce i s to admi ni ster one uni t/10 kg of body wei ght. Accordi ngl y, pl atelet transfusi on wi ll often
entai l exposure to multi ple donors. Donor exposure can be mi ni mi zed by the use of single-donor
pl atel et pheresi s packs that contain the pl atel et equi valent of approximatel y six single units in a
vol ume of 200 to 400 mL. These are obtai ned by serial bl ood wi thdrawal s from a si ngl e donor
fol l owed by centri fugation and return of the RBCs to the donor.
Pl atel et vi abi l ity is opti mal at 22C but storage i s l imi ted to 4 to 5 days. The short shel f time
means that pl atel ets are usuall y admini stered before the resul ts of the newl y i ntroduced nucl ei c
acid anti gen (NAT) testing for viral agents are avail able.
Pl atel ets bear both ABO and human leukocyte anti gens (HLA). ABO compatibi l ity is i deal because
incompatibi l ity shortens the li fe span of the platelet. However, i t is not requi red. ABO/HLA-
matched pl atel ets are indicated for pati ents who become refractory to random donor platelets.
Pl atel ets do not carry the Rh anti gen. However, admi nistrati on of pl atel ets from an Rh-positi ve
donor to an Rh-negati ve femal e of chi l d-bearing age should be avoi ded i n order to prevent
sensi ti zation as a result of passenger RBCs in the pl atel et preparation. If it occurs, Rh-immune
gl obul i n shoul d be admi nistered.
Pl atel ets should be administered through a fil ter. The standard 170-mi cron fi l ter i s suffi cient and
there i s no advantage or necessi ty to use the 40-mi cron fi l ters typically used for RBC
administrati on.
5

Fr esh Fr ozen P l asma
Pl asma is separated from the RBC component of whol e bl ood by centri fugati on. One uni t has a
vol ume of 200 to 250 mL. It wi ll contai n the preservative added at the ti me of coll ecti on, usual l y
CPD-adeni ne. To preserve the two labi le cl otting factors (V and VIII), it i s frozen promptl y and
thawed only i mmedi atel y pri or to admi nistrati on. FFP must be ABO compati ble. Rh-positi ve pl asma
can be gi ven to an Rh-negati ve reci pi ent but i deal l y thi s shoul d be avoi ded i n young females
because of the possi bil i ty of al l oi mmunizati on to the Rh anti gen on passenger RBCs in the FFP.
Sol vent Det er gent P l asma
One of the pri nci pal hazards of FFP admini stration has been vi rus transmi ssi on. Three procedures,
pasteuri zation, photochemi cal treatment, and sol vent detergent (SD) treatment, have been used
to i nacti vate viruses. The SD techni que i s hi ghl y effecti ve i n inactivati ng al l of the li pi d
encapsul ated vi ruses, for exampl e, HIV, HCV, HBV, and HTLV. The di sadvantage of the SD
technique i s that the process i nvol ves pool i ng of large numbers of si ngl e FFP units (>1,000) and is
not effecti ve agai nst nonl i pi d envel oped vi ruses (HAV, parvovi rus) or the agent of Creutzfel dt-
Jakob di sease. The concern wi th SD pl asma i s that the pool i ng process mi ght resul t i n wi de
dissemi nation of an infectious agent. The inci dence of parvovi rus vi remia among donors is
esti mated to be between 0.03 and 0.6%.
119
Parvovirus infection has been reported as a
consequence of transfusion. Whi le the disease is usuall y sel f-li mi ted, si gnificant morbi di ty, for
example, red cel l apl asi a, meningiti s, especial ly i n i mmunocompromised patents, can occur.
119
The
future of SD pl asma is not cl ear to the authors of thi s revi ew.
Cr yopr eci pi t at e
Cryopreci pi tate is the precipi tate that remai ns when FFP is thawed slowly at 4C. It is a
concentrated source of factor VIII, factor XIII, vWF, and fi bri nogen. One unit of cryopreci pi tate
(the yiel d from one uni t of FFP) contains sufficient fibrinogen to i ncrease fibri nogen l evel 5 to 7
mg/dL.
120
Accordi ngl y, it i s usual ly provi ded i n bags that contain 10 or 20 uni ts. ABO compati bil i ty
is not essenti al because of the li mited antibody content of the associ ated plasma vehi cle (10 to 20
mL). Vi ruses can be transmi tted with cryoprecipi tate. It is stored at -20C and thawed
i mmedi atel y pri or to use.
Fact or VI I I and I X
Recombi nant and viral l y i nacti vated FVII concentrates are avai l abl e.
Ant i t hr ombi n I I I
Virus-treated antithrombi n III (ATIII) concentrates are avail able. They have been empl oyed i n the
treatment of congenital and acqui red ATIII defi ci enci es.
121
The l atter incl ude DIC and ful minant
hepati c fail ure.
THE HEMOSTATIC MECHANISM
Normal hemostasi s invol ves a seri es of physi ol ogic checks and bal ances that assure that blood
remai ns i n an invari ably l iquid state as it ci rculates throughout the body but, once the vascul ar
network i s vi olated, transforms rapidl y to a sol id state. That transformati on to a soli d state, that
is, coagul ati on, must i nevi tabl y be compl emented by processes for el iminati ng cl ot that i s no
longer needed for hemostasis. The l atter i s accompl i shed by fi bri nol ysi s
The Nomencl at ur e of Coagul at i on
Understandi ng the coagul ati on process has been made more di ffi cul t by the compl exi ty of the
nomencl ature. An earl y attempt was made to standardi ze it by assi gni ng Roman numerals to each
of the 12 known clotti ng factors. Unfortunately, the factors were numbered i n the order i n whi ch
they were discovered and not i n the sequence i n whi ch they interact. To compli cate matters, the
first 4 of the ori ginal 12 factors are usual l y referred to by their common names, fibrinogen,

prothrombi n, ti ssue thrombopl astin (ti ssue factor), and calci um, and not by their Roman numerals.
Factor VI no longer exi sts; i t proved to be acti vated factor V. The more recently di scovered
cl otting factors, for exampl e, prekal l ikrei n and hi ghmol ecul ar-weight ki ni nogen, have not been
assi gned Roman numeral s. They too are i dentified by common names, and to further compl icate
matters, some have more than one name (Table 10-11).
P.222
TABLE 10-11 Factor Nomenclature and Half-Lives
FACTOR SYNONYMS IN VIVO HALF-LIFE
(HOURS)
I Fi bri nogen 100150
II Prothrombi n 5080
III Ti ssue thrombopl astin, ti ssue factor (TF)
The Coagul at i on Mechani sm
The classi cal , dual -cascade (intrinsic and extri nsi c pathway) model of coagul ati on (Fi gs. 10-1
and 10-2) i s now recognized to be an inadequate representation of i n vivo coagulation. It
fai l ed to expl ain several cli ni cal phenomena. Fi rst, persons lacki ng factor XII, prekal l ikrei n, or
hi ghmol ecul ar-weight ki ni nogen do not bleed abnormall y, suggesting that contact acti vati on i s
not criti cal for normal hemostasi s. Second, pati ents wi th onl y trace quanti ti es of factor XI
withstand major trauma without unusual bl eeding and those compl etel y lacki ng factor XI have onl y
a mil d hemorrhagi c di sorder. Factor XI therefore appears to have a more mi nor role in coagul ati on
than ascri bed to it by cl assi cal theory. Next, defici encies of factor VIII (an extrinsi c pathway
factor) and factor IX (an intri nsi c pathway factor) lead to Hemophi l ia A and B, respectively. The
cl assi cal

descri ption of two pathways of coagul ati on leaves i t uncl ear cl ear why ei ther type of hemophi l iac
coul d not simply clot vi a the unaffected pathway. Most importantl y i t i s now appreci ated that whi l e
the cl assi cal theori es may provide a reasonable model of i n vi tro coagul ation tests, that i s, the
aPTT and PT, they fai l to i ncorporate the central role of cel l -based phospholi pi d surfaces i n the i n
vivo coagul ation process. The three stages of that process, whi ch has been thoroughl y defi ned and
IV Cal cium ion
V Proaccel erin, l abi l e factor 24
VII Serum prothrombin conversi on accel erator
(SPCA), stable factor
6
VIII Antihemophi li c factor (AHF) 12
vWF von Willebrand factor 24
IX Christmas factor 24
X Stuart-Power factor, Stuart factor,
autoprothrombi n
2560
XI Pl asma thrombopl asti n antecedent (PTA) 4080
XII Hageman factor 5070
XIII Fi bri n stabil i zi ng factor (FSF) 150
Prekall i krein Fl etcher factor 35
HMW
kini nogen
Fi tzgeral d, Flaujeac, or Wi l li ams factor;
contact-acti vation cofactor
150
P.223
descri bed by Hoffman, are summari zed i n the next secti ons and i n Fi gure 10-3.
122

FIGURE 10-1. The cl assical intri nsi c pathway of coagul ati on. A cascade initi ated by contact
with a forei gn surface leads to the formation of the fi bri n (Ia) necessary for the generati on of
a fibri n cl ot. The dotted arrows indi cate the occurrence of an enzymati cal l y mediated
conversion of an i nacti ve factor to i ts acti ve form. The open-headed arrows indi cate the
transl ocation of an activated factor to partici pate i n a subsequent reacti on. The shaded
spheroids represent the phosphol i pi d surfaces (usuall y provi ded by acti vated platelets).
FIGURE 10-2. The cl assical extri nsi c pathway of coagul ati on. Thi s pathway i s depicted as i t
was ori ginal l y thought to occur, that i s, largel y extravascul arl y and independent of the
cl assi cal intri nsi c pathway (compare Fi g. 10-1). The dotted arrows indi cate the occurrence of
an enzymati cal l y mediated conversion of an inactive factor to i ts acti ve form. The open-
headed arrows indi cate the translocati on of an acti vated factor to a phosphol i pid surface to
parti cipate in a reacti on compl ex. The shaded spheroi d represents the phosphol ipi d surface
(usual l y provided by acti vated pl atel ets).
FIGURE 10-3. The coagulation mechani sm. See text. TF, membrane-bound tissue factor on a
extravascul ar cel l surface; vWF-VIII:C, ci rculating factor VIII bound to i ts carrier protei n, the
von Willebrand factor.
Activation
Acti vati on of the coagulation process begins when a breach i n the vascular endothel i um exposes
bl ood to the membrane-bound protein, ti ssue factor (TF) (Fi g. 10-3A). TF acti vates ci rcul ati ng FVII
to yi el d a compl ex of TF and activated (a) FVII (FVIIa) (Fi g. 10-3B). The TF-VIIa compl ex in turn
acti vates factors IX and X (Fi g. 10-3C). Xa then acti vates FV (Fi g. 10-3D), resul ti ng i n the
formation of the prothrombi nase compl ex, composed of Xa and Va, on the phosphol i pid surface
provi ded by membrane bound TF. The prothrombi nase compl ex catal yzes the conversi on of
prothrombi n (FII) to thrombi n (FIIa) (Fi g. 10-3E). It i s thi s ini ti al formati on of thrombi n i n smal l
amounts that advances the coagul ati on process to the more effi cient ampli fi cation phase that
fol l ows. (For those in need of a mnemonic, it i s the ni ckel -di me, Va-Xa prothrombi nase complex
that i s responsi bl e for the i ni ti al, modest thrombin generati on.)
Amplification
Whil e i t was the phospholi pi d surface provided by membrane-bound TF that i ni tiated the
coagulation process, i t is now the phosphol i pi d surface provi ded by pl atel ets that serves to
perpetuate i t. The breach i n the vascul ar tree that began the acti vati on process al so exposed
pl atel ets to col lagen to whi ch they become bound by vWF vi a the GPIb receptor on the pl atel et
surface (Fi g 10-4). The thrombin just generated by the TF-bound prothrombi nase complex
supports the ampl i fi cation of the coagul ati on process i n four ways. First, it further acti vates the
adjacent platelets (Fi g. 10-3F). That acti vati on results i n pl atel et surface changes, most notably
the appearance of the GPIIIb/IIa receptor, and i n the rel ease of the contents of platelet granul es
(Fi g. 10-5). Among those contents are ADP, a powerful platel et acti vator and proaggregant that
rapi dl y recrui ts other pl atel ets to the growi ng pl atel et mass, and Factor V. Thrombin' s second
effect i s to promote the acti vation FV to FVa (Fi g. 10-3F). Third, thrombin releases ci rcul ati ng
FVIII from its carri er mol ecul e (vWF) and activates it (Fi g. 10-3G); and fourth, thrombin acti vates
FXI (Fi g. 10-3H). FXIa i n turn activates FIX (Fi g. 10-3H), further addi ng to the pool of IXa that
first formed during the activation phase above (Fi g. 10-3C). The net resul t of this ampl i fi cation
stage is the avai labi li ty of activated pl atelets and acti vated factors V, VIII, and IX.
FIGURE 10-4. Platelet rel ease reacti on. Pl atel ets undergo a rel ease reaction coi ncident wi th
shape change or i n response to physiologi c agoni sts i ncl udi ng epi nephri ne, ADP, and
thrombin. The numerous substances rel eased from the al pha and dense granul es of pl atel ets
Propagation
The pl atel et then provi des the phospholi pi d surface on which two coagul ation factor
compl exes form and act to produce the expl osi ve generation of thrombi n. First, VIIIa and IXa
form the tenase complex, whi ch activates FX (Fi g. 10-3I). The resul tant Xa forms addi tional
prothrombi nase compl ex (XaVa) and l arge amounts of thrombi n are elaborated (Fi g. 10-3J). (For
mnemonic purposes i t i s ei ght-ni ne and ni ckel -di me that together are responsi ble for the
thrombi n burst.) Thrombi n (IIa) catal yzes the formation of fi bri n from

fi bri nogen and fi bri n acts to crossli nk the platelets to reinforce the fri abl e pl atelet pl ug (see Fi g.
10-4). Thrombi n al so activates thrombi n acti vatabl e fi brinol ysi s inhi bi tor (TAFI) and FXIII (nei ther
shown), both of which serve to stabil i ze the fi bri n cl ot. Fi bri n monomers initi al l y aggregate
rel ati vely l oosel y to form a cl ot composed of fi bri n S (solubl e), whi ch i s hel d together onl y by
hydrogen bonds. FXIII (fi bri n stabi l izing factor) mediates the formation of coval ent pepti de bonds
between the fi bri n monomers to yi eld a stable (i nsol uble) fi bri n cl ot.
Additional Principles of Coagulation
A few addi ti onal facts wi ll ai d i n achi evi ng a broader understandi ng of coagul ati on:
contri bute to pl atel et aggregati on (fi bri nogen), to the acti vati on and adhesi on of additi onal
pl atel ets (ADP, epi nephri ne, thrombi n, vWF) and to cl ot formati on (vWF, fi bri nogen,
thrombi n, cal ci um, Factors V and XI, fi bronecti n).
P.224
FIGURE 10-5. Platelet adhesion and aggregati on. When the endothel i um i s denuded, von
Wi l lebrand factor (vWF) binds to col l agen i n the subendotheli al layer. Pl atelets patrol li ng the
bl ood vessel l ining adhere vi a thei r gl ycoprotein (GP) 1b receptors to vWF. The bi ndi ng of
vWF to the GP1b receptors i ni ti ates pl atel et activati on. Pl atelets change thei r shape from
di scoi d to spheroid and extrude multi ple pseudopods. Pl atel ets aggregate to one another by
crossli nking vi a fi bri nogen (or vWF, not shown) between gl ycoprotei n IIb/IIIa receptors
expressed on the pl atel et surface during the process of platelet acti vati on.
1. Most cl otting factors ci rcul ate i n an i nacti ve form.
Most of the clotti ng factors ci rculate as i nacti ve proenzymes. Duri ng the process of
coagulation, a porti on of the molecul e i s cl eaved off, resul ting i n acti ve enzymes (designated
by the addition of a lower case a after the Roman numeral, e.g., Xa), most of which are
serine proteases.
2. Most cl otting factors are synthesized by the li ver.
Accordi ngl y, thei r normal structure and functi on are dependent on normal hepati c acti vi ty.
One possibl e excepti on i s factor VIII, which probabl y al so has some extrahepati c synthesis.
3. Factor VIII is actual l y a l arge, two-mol ecul e complex (vWF and coagul ant factor VIII).
Factor VIII ci rcul ates as a very l arge compl ex of two distinct protei n components. The hi gh
mol ecul ar-weight porti on (VIIIR:Ag) encompasses both the factor VIII anti gen (used to
identi fy factor VIII in the l aboratory assay) and the vWF. The vWF portion serves as a
carri er protei n for the second and small er component of this macromol ecular compl ex, VIIIC,
whi ch contai ns the factor VIII coagul ant activity. The vWF has a second functi on i n addi ti on
to i ts rol e as carri er protei n. During the process of pri mary hemostasis when the endotheli al
li ni ng has been denuded, vWF medi ates adhesi on of pl atelets to col lagen. Absence of the
smal l er porti on of the factor VIII complex (VIII:C) resul ts in hemophil i a A. Absence of vWF
causes two hemostati c abnormal iti es: (1) a defect in primary hemostasi s because of a fai lure
of platel et adhesi on to the si tes of vascul ar i njury and (2) cl i ni cal hemophi li a A because of
an absence of ci rcul ati ng factor VIII:C. Restoration of vWF l evels restores normal
hemostasi s. Synthesis of the vWF occurs i n endotheli al cel ls and megakaryocytes. The site of
synthesis of the coagulant porti on of factor VIII is unknown but may be located i n the
hepati c si nusoi dal endothel i al cel l s.
4. Four clotti ng factors are vi tamin K dependent.
Four of the cl otting factors, II, VII, IX, and X, require vi tamin K for completi on of thei r
synthesis i n the li ver. Each undergoes a fi nal enzymati c additi on of a carboxyl group that
requi res the presence of vi tamin K. The carboxyl group enables these factors to bind (wi th
calci um as a cofactor) to phosphol i pid surfaces. Without vi tami n K, factors II, VII, IX, and X
are produced i n normal amounts but are nonfunctional .
The anticoagulant acti on of vitami n K antagoni sts i s the result to thei r abi l ity to i nhibi t thi s
final carboxyl ati on step. The warfari n-li ke drugs compete wi th vitami n K for binding sites on
the hepatocyte. Wi th suffi cient warfari n admi ni stration, vi tamin K is di splaced and the
vitami n Kdependent factors are not carboxyl ated. Of the four vi tami n Kdependent factors,
factor VII has the shortest hal f-li fe. It i s the fi rst cl otti ng factor to di sappear from the
ci rculati on when a patient is pl aced on warfarin or begi ns to devel op vi tami n K defi ci ency.
5. Factors V and VIII have short storage hal f-li ves.
Factors V and VIII are al so referred to as the labil e factors because thei r coagulant acti vi ty
i s not durabl e i n stored bl ood. Whi l e packed RBCs contai ns resi dual pl asma wi th cl otting
factors, massi ve transfusion wi th stored blood wil l nonethel ess l ead to a di lutional
coagulopathy because of dimi ni shed acti vity of factors V and VII.

Fi br i nol ysi s
The process of fibri nolysi s leads to the dissol uti on of fi bri n cl ots. Fi bri nol ysis serves to remodel
fibri n cl ots and recanal i ze vessel s that have been occluded by thrombosi s.
The Formation of Plasmin
Fi bri nol ysis i nvol ves primari ly the producti on of pl asmi n, an active fi bri nol ytic enzyme. Plasmi n is
P.225
formed by the conversi on of pl asminogen to pl asmin (Fi g. 10-6). Pl asmi n does not ci rculate freel y
because i t i s rapi dl y degraded by ci rculating antipl asmi ns. Instead, pl asmi nogen, the precursor to
pl asmi n, ci rcul ates and when it comes into contact wi th fi bri n bi nds to i t. In fact, when a fi bri n
clot is forming, plasminogen i s incorporated i nto the growi ng fi bri n cl ot together wi th ti ssue
pl asmi nogen activator (t-PA). Once bound to the fi bri n surface, pl asmi nogen is converted to
pl asmi n by t-PA. The bound pl asmi n i s protected from attack by ci rcul ating anti pl asmins because
the binding si te by which the pl asmi n binds to the fibrin is the same si te to which the antipl asmins
bi nd.
123
When plasmi n i s rel eased i nto the bl oodstream (with its bi ndi ng si te exposed), i t i s
immedi ately neutral i zed by al pha-2 anti pl asmin. Thus, l ike the coagul ati on cascade, the
fibri nolyti c system rel i es on surface-mediated reacti ons both for the producti on of pl asmin and for
the local i zati on of fibrinol ysi s to the si te of vascul ar i njury.
Tissue Plasminogen Activator
Ti ssue pl asmi nogen activator, whi ch converts pl asmi nogen to pl asmi n, i s produced by vascul ar
endothel i al cel ls. This si te of synthesi s i s important to the mai ntenance of the nonthrombogeni c
endothel i al surface. If a cl ot begi ns to form on the normal endothel ial surface, several
mechani sms, including the el aboration of t-PA from endotheli al cel l s, wi ll rapi dl y i nhibi t cl ot
formation or l ead to its di ssoluti on. t-PA rel ease from endothel ial cell s can be sti mulated by
several factors. If suffi cient thrombi n has been synthesized, thrombin wi l l form a compl ex with
thrombomodul in and acti vate protei n C. Activated protei n C (APC) then sti mul ates the rel ease of t-
PA from endothelial cells. t-PA is al so released from the endotheli um i n response to venous
occl usi on, physical acti vi ty, stress, or vasoacti ve drugs (such as epinephrine, vasopressi n, and
DDAVP).
124
t-PA, once rel eased from endothel ial cel l s, sel ecti vel y bi nds to fi bri n, much l ike
pl asmi nogen, whi ch also sel ecti vel y bi nds to fi bri n. Bound to fi bri n, the t-PA converts plasmi nogen
to pl asmi n.
t-PA does not acti vate ci rcul ati ng pl asmi nogen. Thi s has i mportant impl icati ons. Because t-PA
acti vates onl y pl asmi nogen bound to fi bri n, the process of fi bri nol ysi s by pl asmi n i s l ocal ized to
the fi bri n cl ot. Therefore, under normal circumstances, wi despread, uncontrol l ed fi bri nol ysis i s
prevented. The vascul ar endothel ium and platelets al so synthesi ze an i nhibi tor of t-PA,
FIGURE 10-6. Control of fi bri nol ysis. Normal endothel ial cel l s rel ease tissue pl asminogen
acti vator (t-PA), whi ch acti vates pl asminogen, l eadi ng to the breakdown of fi bri n to i ts
vari ous degradation products (FDPs) in areas remote from si tes of vascul ar i njury. The acti on
of t-PA can be i nhi bi ted by pl asminogen acti vator i nhi bi tor (see text).
pl asmi nogen acti vator inhi bi tor (PAI-1), whi ch reduces the amount of pl asmin formed and serves
to slow the fi bri nolyti c process (Fi g. 10-6). Some pati ents with thrombotic di sorders have been
found to have increased l evel s of thi s inhi bitor.
124
A si mil ar i nhi bitor i s found i n pl acental ti ssue.
It may be that the progressi ve hypercoagul abl e state associated wi th pregnancy i s rel ated to
increased l evel s of thi s t-PA inhi bi tor.
124

Plasminogen Activators
There are plasmi nogen acti vators in additi on to t-PA. Urokinase i s present i n the urine but unl ike
t-PA, it has no affinity for fibrin and i s not present i n ci rcul ati ng bl ood.
123
Physi ol ogic activators of
the fi bri nol yti c system i nclude vi gorous exerci se, anoxia, and stress, i n addi ti on to factor XIIa and
thrombi n. Exogenous pl asmi nogen activators i nclude streptoki nase, urokinase, and recombinant t-
PA. These fi bri nol ytic agents al l di ffer wi th respect to thei r acti on, cl ot speci fi city, systemi c
fi bri nol yti c effect, anti genic effect, and efficacy. Proteins deri ved from streptococci and
staphyl ococci have al so been found to be acti vators of the fi bri nol yti c system. The therapeutic
fibri nolyti c agents, streptokinase and urokinase, differ from t-PA in that they wil l activate
ci rcul ati ng pl asmi nogen. These l ead to more widespread fi bri nol ysi s. Fibrinolytic therapy has been
used in the treatment of unstabl e angi na, acute peri pheral arteri al occl usi ons, deep vei n
thrombosi s, and pul monary embol i sm, and i n occl uded i ndwel l ing catheters and arteri ovenous
shunts.
Fibrin Degradation Products
The primary acti on of pl asmin i s to degrade fi bri n cl ots. The degradati on products produced are
cal l ed fi bri n degradati on products (FDPs) or fi bri n spl i t products (FSPs). Their structure vari es
according to whether plasmi n cl eaves fibri nogen, fibrin that is crossl i nked, or fi bri n that i s not
crossli nked.
125
Under normal ci rcumstances, FDPs are removed from the bl ood by the l i ver,
ki dney, and reti cul oendotheli al system. They normal ly have half-li ves of about 9 hours. However,
if the FDPs are produced at a rate that exceeds thei r normal cl earance, they wil l accumul ate. Thi s
happens when the fibrinol yti c system is excessi vel y acti ve. In hi gh concentrati ons, FDPs i mpai r
pl atel et functi on, i nhi bi t thrombi n, and prevent the crossl inki ng of fibri n strands.
126
The defecti ve
pol ymeri zati on of the fibri n monomers results in a clot that i s more readil y degraded by
pl asmi n.
124
In such hi gh concentrati ons, FDPs l ead to bl eedi ng because FDPs are inhi bitors of
both platelets and coagul ati on.
Excess Circulating Plasmin
Under normal ci rcumstances, once plasmi n has degraded fi bri n cl ot and escapes from the fi bri n
surface, i t i s rapi dl y i nacti vated by anti pl asmi ns. Defi ci ency of al pha-2 anti pl asmi n

l eads to a bl eedi ng tendency because, wi th reduced l evel s of antipl asmin i n the ci rculation,
pl asmi n can ci rcul ate. In addi tion, in pathol ogic condi ti ons in whi ch the fi brinol yti c system
produces large quanti ti es of plasmi n (primary fibri nolysi s), the antipl asmin capacity may be
exceeded and pl asmi n may circul ate. Thi s can al so happen when fi bri nol ysis i s sti mulated in
response to di ssemi nated intravascul ar coagulation (secondary fi bri nol ysis). Excess plasmi n can
lead to a coagulopathy. Thi s i s because plasmi n pri mari l y degrades fi bri n; but because i t i s a
serine protease, i t can al so degrade other coagul ati on factors, for exampl e, fi brinogen, factor V,
factor VIII, factor XIII, and al so vWF.
124
Pl asmi n can al so di gest the platel et receptor, GPIb.
Accordi ngl y, ci rcul ati ng pl asmi n inhi bits pl atel et function and di srupts coagul ati on.
Summary of the Control of Fibrinolysis
Under normal condi ti ons, pl asmin i s generated only at the si te of cl ot formation, is protected from
degradation whi l e attached to fi bri n, and i s destroyed rapi dl y once released into the ci rculati on.
Cont r ol of Coagul at i onThe Checks and Bal ances
Coagul ati on must be preci sel y regul ated to prevent rampant, uncontrol led cl otting, such as that
P.226
whi ch occurs wi th DIC. Several mechani sms regulate and control coagulation.
Endothelial Inhibition
The fi rst l ine of defense i s the vascul ar endothelium. The i ntact endotheli al has properties that
serve to l i mi t both platelet aggregati on and coagulati on and to i nduce fi brinol ysi s should a cl ot
begi n to form on normal endotheli um. They are summari zed in Tabl e 10-12.
The ThromboxaneProstacyclin Balance. Pri mary hemostasi s is, i n part, control l ed by the
bal ance between the acti ons of two prostagl andi ns, thromboxane A
2
and prostacycl i n.
Thromboxane A
2
(TxA
2
) i s synthesi zed at the site of vascular damage by acti vated pl atel ets. TxA
2

has two hemostati c effects: (1) i t i s a potent vasoconstri ctor that causes bl ood vessel s to constri ct
locally and shunt blood flow away from the site of i njury, and (2) i t sti mul ates addi ti onal ADP
rel ease from pl atelets and thereby causes recrui tment of addi ti onal platelets.
127

Remote from the si te of vascul ar damage, normal endothel i al cel ls synthesize prostacycli n (PGI2).
PGI2, whi ch i s al so synthesi zed from arachidoni c aci d, has acti ons opposi te those of TxA
2
. PGI2
inhi bits pl atelet activati on, secreti on, and aggregati on and i s a potent vasodi lator. It therefore
serves to prevent pl atel et aggregation and cl ot formation on the endothel ial surface beyond the
si te of injury.
Nitric Oxide and ADPase. The effects of prostacycl i n are potenti ated by ni tric oxi de (formerl y
call ed endotheli um-dependent rel axi ng factor, EDRF), which is consti tutively synthesized by
normal endothel ium and whi ch al so has vasodi l atory and pl atel et anti aggregant effects.
128
As an
addi ti onal means of preventing cl ot formati on on the surface of normal endothel i um, ADPases are
expressed on the outer membrane of endotheli al cel l s and serve to degrade surpl us ADP that
mi ght otherwi se ini ti ate pl atel et aggregation on normal surfaces.
Inhibition of Coagulation
Many factors serve to l i mi t and l ocal i ze cl ot formati on. Fi rst, the cl otti ng factors themsel ves
ci rculate in an i nacti ve form. Once they do become activated, normal bl ood fl ow di l utes thei r
concentration and washes them away from si tes of injury, li mi ting clot formation. Activated
cl otting factors are preferential ly removed from the circul ati on by the li ver and the
reticul oendothel i al system. And fi nal ly, the fact that some i nteracti ons of the coagul ati on pathway
requi re the presence of a phospholi pi d surface l ocal izes cl ot formation to these phosphol i pid
surfaces. Several speci fi c coagul ation inhi bi ti ng systems exi st. Three of them are depicted in
Fi gure 10-7 and descri bed l ater.
TABLE 10-12 Endothelial Control of Platelet Aggregation, Coagulation, and Fibrinolysis
Endothel ial control of pl atel et aggregati on
Synthesis of prostacycl i n
Synthesis of ADPases and ni tri c oxide
Endothel ial inhi bi ti on of coagul ati on
Synthesis of thrombomodul i n
Synthesis of heparan sul fate
Endothel ial control of fi bri nol ysis
Synthesis of t-PA
Thrombin, Thrombomodulin, and Protein C and Protein S. Thrombi n, i n a negati ve feedback
manner, can decrease its own synthesis by i nhibi tion of factors V and VIII. That inhi bi ti on i s
accompl i shed vi a protei n C, a vi tamin Kdependent anticoagulant protein. Protei n C ci rculates in
pl asma as an inactive precursor unti l i t is acti vated by thrombin. Thrombomoduli n is a protein
located on the vascul ar endothel ial cel l surface. The bi ndi ng of thrombi n to thrombomodul in alters
the thrombi n molecul e such that it can no longer di rectl y acti vate clotti ng factors V and VIII or
catal yze the conversi on of fi bri nogen to fibrin (Fig. 10-3). Instead, the thrombinthrombomodul i n
compl ex rapi dl y converts protei n C to acti ve protei n C (APC). APC, wi th protei n S as a cofactor,
cl eaves and inactivates factors Va and VIIIa. Li ke protei n C, protei n S i s vi tami n K dependent. The
location of thrombomodul i n on the endotheli al surface i s strategic. Where the endothel i um is
intact, the thrombomodul i n-thrombi n-protei n C i nteracti on wi l l inhi bi t coagul ati on and

maintai n the nonthrombogeni c property of the endotheli al li ning. Where the endothel ium has
been stri pped away or damaged, thi s anti coagul ant mechani sm wil l be absent and cl otti ng can
conti nue unopposed.
Thrombin and Antithrombin III. ATIII i s a ci rculating seri ne protease i nhi bitor that bi nds to
thrombi n and thereby inactivates i t. ATIII can bind and i nacti vate each of the acti vated cl otti ng
factors of the classi cal intrinsic coagulation cascadefactors XIIa, XIa, IXa, and Xa
129
(see Fi g.
10-7). By virtue of i ts broad i nhi bitory action, ATIII pl ays a central rol e in the regul ati on of
hemostasi s i n vivo. The ATIII mol ecul e has two cri ti cal bi ndi ng si tes, one of which reacts wi th
thrombi n (and the other activated clotti ng factors), and a second to whi ch hepari n can bi nd. In
the absence of heparin, ATIII has a relatively low affinity for thrombi n. However, when heparin i s
bound to ATIII, the effici ency of bi ndi ng of ATIII to thrombi n and the other factors increases
dramati cal l y. Congeni tal ATIII defi ci ency (l evels 40 to 50% of normal ) can l ead to dangerous
thromboti c events. Acqui red defi ci enci es of ATIII may occur in a number of condi tions, incl udi ng
l i ver di sease, prol onged hepari n admi ni strati on, nephrotic syndrome, DIC, sepsi s, preecl ampsi a,
fatty l i ver of pregnancy, and fol lowi ng surgery.
130
Plasma ATIII l evel s are someti mes depressed by
oral contraceptive use. ATIII concentrates have been used in ATIII defi ciency states, i ncl udi ng
FIGURE 10-7. Inhi bi ti on of coagul ati on at three l evels. Three i mportant mechanisms that
serve to prevent unrestrai ned coagul ati on are depi cted. (1) A compl ex of thrombomodul i n
(TM) and thrombi n (IIa) activates protei n C, whi ch, wi th protei n S as a cofactor, i nhi bits
acti vated factors V and VIII. (2) Anti thrombi n III (AT III) binds, and thereby i nhi bi ts, several
acti vated cl otti ng factors (XIIa, XIa, IXa, Xa, IIa). (3) Ti ssue factor pathway inhi bi tor (TFPI)
inhi bits both of the pathways that lead to the activation of Factor X (see text).
P.227
hepari n resi stance.
131, 132

Tissue Factor Pathway Inhibitor (TFPI). Superfi ci all y, the descripti on of the cell -based
coagulation mechani sm sti l l leaves i n pl ace one of the i nadequaci es of the classi cal cascade
theories of coagul ati on, that is, i f acti vated factor Xa can be formed via the direct acti on of the
VIIa/TF complex, why i s i t that hemophil i acs bl eed? Why do they appear to be dependent on both
factors VIII and IX to produce acti vated factor X (Xa)? The answer l i es in the exi stence of a
feedback i nhi bitor of the extri nsic pathway known as ti ssue factor pathway i nhi bitor (TFPI) (see
Fi g. 10-7). TFPI, whi ch i s generated i n a factor Xa-dependent fashi on, i s a potent i nhibi tor of the
formati on of factor Xa by both VIIa/TF-initi ated sequences.
133
In the presence of TFPI, further
acti vation of factor X becomes enti rel y dependent on the reaction sequences of the classi cal
intrinsic pathway. The TF pathway can i ni ti ate the fi rst fl urry of thrombi n generationenough to
acti vate platelets and sti mul ate cofactors V and VIII. Thereafter, conti nued thrombi n producti on
appears to requi re the acti on of factors VIIIa and IXa.
122

Heparan Sulfate. There i s a fourth nati ve anti coagul ant mechanism. The endothel ial surface i s
coated wi th a mucopol ysaccharide referred to as the gl ycocal yx. One of the consti tuents of thi s
gl ycocal yx i s a natural l y occurri ng hepari n-l i ke component, heparan sul fate. Much l ike hepari n,
heparan has the abi li ty to accelerate the bi ndi ng of ATIII to thrombi n and the other acti vated
cl otting factors of the cl assi cal intri nsi c pathway. Thi s heparan sulfate i s well positi oned because i t
is at this blood-endothel i al i nterface that activated factors of the coagulation cascade are bei ng
generated. The presence of heparan sul fate on the endothel ial surface further hel ps to promote
the anti thrombotic property of the normal endothel ial li ning.
The Compl exi t i es of t he Hemost at i c Mechani sm
The precedi ng secti ons reveal that many mechani sms interact to maintai n the li quid state of the
bl ood under normal ci rcumstances and to transform blood into a sol i d clot when i njury occurs.
These mechani sms include numerous feedback processes. The compl exi ty i s reveal ed by the
existence of doubl e agents, whi ch act at some ti mes as procoagul ants and at other ti mes as
anti coagul ants. Chi ef among them i s thrombi n. Thrombi n i s pri maril y a procoagul ant. Under
normal circumstances, i t promotes pri mary hemostasis by activati ng pl atel ets and promotes
coagul ati on by di rect activati on of factors V, VIII, and XIII. Thrombi n, i n the fi nal step of the
coagulation cascade, cleaves fi bri nogen to fi bri n. However, i t al so has anti coagul ant effects. As
descri bed in the coagulation secti on earl i er, when thrombi n is first synthesized, it sti mulates
producti on of TFPI, which sl ows coagul ati on vi a the ti ssue factor pathway and makes continued
coagulation dependent on the reacti on compl ex formed by factors VIII and IXa. Thrombi n al so
inhi bits coagul ati on through i ts interacti on wi th thrombomoduli n and protein C. Acti vated protei n
C sti mul ates the rel ease of t-PA from endotheli al cel l s and by thi s mechani sm it has a fi bri nol ytic
effect. Recal l , however, that the thrombin generated as part of the thrombi n burst at the end of
the propagation phase of coagulation al so causes the rel ease of the fi bri nol ysi s i nhibi tor TAFI.
Accordi ngl y, thrombi n acts at different loci as a procoagul ant, an anti coagul ant, a profi bri nolyti c,
and an anti fi brinol yti c.
The Hemost at i c Mechani sm: Summar y
Under normal ci rcumstances, the hemostati c mechani sm i s qui escent wi th many of the potential
parti cipants circul ati ng i n an i nacti ve form. Onl y when the endothel ial l ini ng i s breached i s the
hemostati c mechani sm set i n moti on. Wi th col l agen and ti ssue factor exposed, the i ntertwi ned
processes of platelet-mediated pri mary hemostasi s and factor-medi ated coagul ati on begi n and
rapi dl y the vascul ar injury i s seal ed by a pl atel et mass i nto which are incorporated fi brinogen,
thrombi n, pl asmi nogen, and t-PA. The compl eti on of the coagul ati on process converts fi brinogen
i nto fi bri n and the pl atel et plug i s transformed into a fi bri n clot. Si mul taneousl y, several
properties of adjacent intact endotheli um (elaborati on of ADPases, prostacycl i n, thrombomodul in,
heparans, and t-PA) serve to prevent extensi on of the cl ot beyond the si te of injury. Withi n the
cl ot, pl asmi n, generated from the trapped pl asmi nogen and t-PA, begi ns the process of
fibri nolysi s. Over ti me, the entire fi brin clot dissol ves, new endothel ial cel l s li ne the vessel , and
flow is restored.
LABORATORY EVALUATION OF THE HEMOSTATIC MECHANISM
Labor at or y Eval uat i on of P r i mar y Hemost asi s
Platelet Count
A platelet count shoul d be the first test ordered i n the evaluati on of pri mary hemostasi s. The
pl atel et count is qui ck, accurate, and reproduci ble. However, it reveals onl y pl atel et numbers and
gi ves no information regardi ng their function. Normal pl atel et counts range between 50,000 and
440,000/mm
3
. Counts bel ow 150,000/mm
3
are defi ned as thrombocytopenia. Spontaneous
bl eedi ng i s unli kel y in pati ents wi th pl atel et counts >10 to 20,000/mm
3
.
65
With counts from 40 to
70,000/mm
3
, bl eedi ng i nduced by surgery may be severe.

Bleeding Time
The Ivy bleedi ng ti me i s the most wi del y accepted cl inical test of platelet functi on. Both poor
pl atel et functi on and thrombocytopeni a can prolong the bl eedi ng ti me. A bl ood pressure cuff i s
pl aced around the upper arm and infl ated to 40 mmHg. A cut is made on the volar surface of the
forearm and the wound bl otted at 30-second i nterval s unti l bl eedi ng stops. The

Simplate Bl eeding Ti me (BT) devi ce, whi ch uti li zes a spri ng-l oaded l ancet, standardi zes the si ze
and depth of the cut. The normal range for the Ivy BT i s 2 to 9 minutes. Vari ati ons in venous
pressure, blotti ng technique, and patient cooperati on resul t i n a l ack of preci si on and
reproduci bil i ty that make thi s test somewhat less rel i abl e than other coagul ati on tests. The BT i s
purported to evaluate the ti me necessary for a platel et pl ug to form fol l owi ng vascul ar i njury. Thi s
requi res a normal number of circul ating pl atel ets, pl atel ets wi th normal functi on (which can
adhere and aggregate) and an appropri ate pl atel et i nteracti on wi th the bl ood vessel wall . A
prolongation of the BT may be a resul t of (1) thrombocytopeni a, (2) pl atel et dysfuncti on
(adhesion, aggregati on), and (3) vascul ar abnormal i ti es such as scurvy or the Ehl ers-Danlos
syndrome. BTs are prol onged i n patients with many condi tions that cause pl atel et dysfuncti on, for
example, use of aspi ri n or uremi a. However, prolonged BTs have been observed wi th numerous
di sorders that are not associ ated wi th pl atel et dysfuncti on, for exampl e, vi tamin K defi ci ency of
the newborn, amyloidosis, congeni tal heart disease, the presence of factor VIII i nhibi tors.
134

Whether or not the BT test represents a speci fi c measure of in vi vo pl atel et function i s debated.
The test is unpl easant for the pati ent and l eaves a smal l scar. In spite of the correl ati on of BT
with condi tions known to i nfluence platelet function, and i n spi te of BT qui te rel iably becoming
progressi vel y prolonged as pl atelet count fall s below 80,000/uL, there are no convincing data to
confi rm that bl eedi ng ti me is a reli able predictor of the bl eeding that wi ll occur i n associ ati on wi th
surgi cal procedures.
Platelet Function Analyser
The PFA-100 i s a poi nt-of-care device. The test i s based on vari ati on i n the resistance to passage
of platel ets through a standard aperture in the presence of platel et acti vators, for exampl e,
col l agen and ADP. Its predi cti ve val ue has not been wel l confi rmed and it i s not yet used
widely.
135

Platelet Aggregometry
The abil i ty of pl atelets to aggregate can be assessed quanti tati vel y by observi ng the response to
stimul ati on with ADP, epi nephri ne, col lagen, or ristoceti n. The platel et aggregometer measures
pl atel et aggregati on spectrophotometri cal l y. Clot retracti on i s another function of platel ets that
can be assessed grossl y. When maintai ned at 37C, a clot shoul d begin to retract wi thin 2 to 4
hours. Thi s test is di ffi cul t to quanti fy and onl y qual i tative resul ts (retraction vs. no retraction)
are usual ly reported.
P.228
Labor at or y Eval uat i on of Coagul at i on
Evolution of the Prothrombin Time (PT) and the Partial
Thromboplastin Time (PTT)
When bl ood i s pl aced i n a gl ass test tube, cl ot formati on occurs i n response to contact wi th the
foreign surface. No exogenous reagents are requi red because al l of the factors necessary for
contact to i niti ate coagul ati on are intrinsic to bl ood. The ti me to formati on of a clot vi a this
pathway can be prol onged by defi cienci es of any factors in the cl assical intri nsic pathway.
However, the observati on that, even i n hemophi l iacs, the additi on of thrombopl asti n (now more
commonly cal led ti ssue factor) to the test tube could shorten the ti me to cl ot formation suggested
the presence of an alternative pathway of fibrin formation. That pathway requi red the addi ti on of
somethi ng extri nsic to blood and di d not requi re the presence of factors VIII or IX. In 1936,
when Qui ck introduced the PT to cl i ni cal medi cine, suffici ent thromboplasti n was used to yi el d a
cl otting time of approxi matel y 12 seconds. Under these circumstances, even pati ents l acki ng
factors VIII or IX showed normal cl otti ng ti mes.
136
However, when di l ute thromboplasti n (or a
parti al thromboplasti n) was used i n li eu of the 12-second reagent, hemophi l iacs showed much
longer clotti ng ti mes than di d healthy control s. The two di fferent pathways could be tested
i ndi vi dual l y si mpl y by varyi ng the amount and type of thrombopl asti n added to bl ood. Wi th
compl ete thrombopl asti n, coagulation coul d proceed vi a reacti ons that were i ndependent of
factors VIIIa and IXa. With a lesser thrombopl asti n stimul us, coagulati on woul d proceed vi a a
sequence of reacti ons that requi red the presence of factors VIIIa and IXa.
Basic Elements of the PT and PTT
The PT and the PTT di ffer pri mari l y by the type of thrombopl asti n that i s used. Cal cium must al so
be added because of the chel ati ng agent i n the blood speci men container. The time to fibri n strand
formati on i s then measured.
Prothrombin Time
The PT eval uates the coagulation sequence ini ti ated by TF and l eadi ng to the formati on of fi bri n
without the parti cipation of factors VIII or IX, that is, the cl assi cal extri nsi c pathway (see Fi g. 10-
2). The PT measures the ti me to fi brin strand formati on vi a a short sequence of reacti ons
invol vi ng onl y TF, and factors VII, X, V, II (prothrombi n), and I (fi brinogen). Ti ssue factor forms a
compl ex with VIIa and together this compl ex acti vates factor X. From that point, coagul ati on
proceeds vi a the common pathway of coagulation. The test does not eval uate the coagul ati on
process that i s i ni ti ated by the cl assical i ntrinsic pathway or that sequence of reacti ons i ni ti ated
by tissue factor that generate Xa vi a the reacti on complex formed by factors IXa and VIIIa.
The normal PT is 10 to 12 seconds. The PT wi l l be prol onged i f defi ci enci es, abnormali ties, or
i nhi bi tors of factors VII, X, V, II, or I are present. The PT test has l imitati ons. First, it i s not very
sensi ti ve to defi ci enci es of any of these factors. In fact, the coagulant acti vi ty of these factors
must drop to 30% of normal before the PT i s prol onged. The PT i s most sensi tive to a decrease in
factor VII and l east sensi tive to changes i n prothrombi n (factor II). When prothrombi n l evel s are
only 10% of normal , the increase i n the PT may be onl y 2 seconds. Also, PT wi l l not be prol onged
unti l the fi bri nogen level i s bel ow 100 mg/dL. A prol onged PT does not define the exact hemostati c
defect. However, i f the aPTT (see later) i s normal , then a prol onged PT i s most l ikely to represent
a defi ci ency or abnormal i ty of factor VII. Because factor VII has the shortest hal f-li fe of the
cl otting factors synthesized i n the l i ver, factor VII i s the cl otti ng factor that fi rst becomes
defici ent wi th l i ver disease, vitami n K defi ci ency, or warfari n therapy. Prol ongation of the PT may
al so occur because of defi ci enci es of multi ple factors. However, when mul tipl e factor defici encies
coexi st, the PTT or activated PTT (see later) wi ll usuall y be prol onged as wel l .
International Normalized Ratio. Another diffi culty wi th the PT test i s that many different
thromboplasti n reagents are used. Thi s results i n wide vari ation in normal values, whi ch makes
compari son of PT resul ts between l aboratories di ffi cul t. The Internati onal Normal i zed Rati o was
introduced to circumvent thi s diffi culty.
137
Each thrombopl asti n i s compared wi th an international ly
accepted standard thrombopl astin and assi gned an International Sensi ti vi ty Index (ISI). If the test
thromboplasti n is equival ent to the international standard, it wil l have an ISI i ndex of 1. Once the
ISI number has been determined, PT test times obtai ned wi th that reagent are normali zed and
reported as an Internati onal Normali zed Rati o.
138

Partial Thromboplastin Time
The PTT assesses the functi on of the classi cal i ntrinsi c and final common pathways (see Fi g. 10-
1). It entail s the additi on of a parti al thromboplasti n (usuall y a phosphol i pi d extracted from
rabbi t brai n or human pl acenta) and cal cium to citrated plasma. The PTT reflects the ti me to fi brin
strand formation vi a the cl assi cal intrinsic pathway of coagul ati on. The PTT wi ll reveal
defici encies, abnormal i ti es, or i nhi bitors to one or more coagul ati on factorshi ghmol ecul ar-
weight ki ni nogen (HMWK), prekal li krei n, XII, XI, IX, VIII, X, V, II, and I. The normal val ues for
PTT vary wi del y. However, the PTT has been made more reproduci bl e and the range of normal
val ues narrower by the addi tion of contact acti vator in additi on to the partial thrombopl asti n;
hence the name acti vated parti al thromboplasti n ti me (aPTT).
139
Surface acti vation in the
laboratory parall els the contact-acti vation phase i nvol vi ng factors XII and XI, prekal li krei n, and
hi ghmol ecul ar-weight ki ni nogen that are thought to i ni tiate the i ntri nsi c pathway i n vivo.
Diatomaceous earth, kaoli n, cel i te, and ell agic aci d are used as surface acti vators. The aPTT i s
much faster than the PTT, whi ch may be as l ong as 120 seconds, because i t eli mi nates the lengthy
natural contact-acti vation phase. Normal aPTT val ues are between 25 and 35 seconds.
140
The
aPTT i s prol onged when there i s a defi ciency, abnormal ity, or i nhibi tor of factors XII, XI, IX, VIII,
X, V, II, and I (i .e., al l factors except VII and XIII). The aPTT i s most sensi ti ve to defi cienci es of
factors VIII and IX, but, as is the case with the PT, l evel s of these factors must be reduced to
approxi mately 30% of normal val ues before the test i s prol onged. Hepari n prol ongs the aPTT but
with hi gh level s wi l l al so prol ong PT. As wi th the PT, the l evel of fi bri nogen must al so be reduced
to 100 mg/dL before the aPTT is prol onged. FXII defi ci ency, whi ch is a rel ati vel y common cause of
aPTT prol ongati on, does not cause a cli ni cal coagulopathy. aPTT results (l i ke those of the PT) vary
from laboratory to l aboratory because of nonstandardizati on of the phosphol i pi ds and acti vators.
Activated Clotting Time
The acti vated cl otti ng ti me (ACT) is si mi lar to the aPTT i n that i t tests the abi l ity of blood to clot
in a test tube and i s dependent on factors that are al l intrinsic to bl ood (the classi cal i ntri nsi c
pathway of coagul ati on). Fresh whol e bl ood i s added to a test tube that contains a particul ate
surface activator of factors XII and XI. The ti me to clot formation is measured. Parti al
thromboplasti n or a pl atelet phospholi pi d substi tute i s not added. Coagul ati on i s therefore
dependent on adequate amounts of pl atel et phosphol i pi d bei ng present i n the blood sample. The
automated ACT i s wi dely used to monitor heparin therapy i n the operating room. Normal val ues
are in the range of 90 to 120 seconds.
139
The ACT i s far l ess sensi tive than the aPTT to factor
defici encies i n the cl assi cal i ntri nsi c coagul ati on pathway. In fact, the ACT may not be prol onged
unti l the coagul ant activity of some of the factors i s reduced to 1% of normal .
Thrombin Time
Thrombi n ti me (TT), al so cal l ed the thrombi n cl otting time, is a measure of the abi l ity of
thrombi n to convert fi brinogen to fibri n. This test, whi ch is performed by addi ng exogenous
thrombi n to citrated plasma, bypasses all the precedi ng reactions. The thrombi n ti me may be
prolonged because of condi tions that effect either the substrate, fi bri nogen, or the acti on of the
enzyme thrombin. The TT is prol onged when there i s an i nadequate amount of fi bri nogen (<100
mg/dL) or when the fibrinogen mol ecules that are present are abnormal (dysfibri nogenemi a), for
example, advanced l i ver disease. Thrombi n' s enzymati c functi on can be inhi bi ted by i nhi bi tors
such as hepari n (complexed to ATIII), FDPs, or by i nhi bi tors that may be seen i n pati ents wi th
pl asma cel l myel oma and other immunoproli ferati ve conditi ons.
141
The normal TT i s <30 seconds.

P.229
Reptilase Time
When the thrombi n ti me i s prol onged, the repti l ase ti me can be used to di fferenti ate between the
effects of hepari n and FDPs. Repti l ase, whi ch i s deri ved from a snake venom, converts fibrinogen
to fi bri n. The acti on of repti l ase is unaffected by heparin but i s i nhi bi ted by FDPs. A prol onged TT
and a normal repti l ase ti me suggest the presence of hepari n. Prol ongati on of both TT and repti l ase
ti me wil l occur i n the presence of FDPs, or when fibri nogen l evel is l ow. The normal repti l ase time
is 14 to 21 seconds.
Ecarin Clotting Time
Direct thrombi n i nhi bi tors (DTI) (hi rudi n, argatroban, bi vali rudi n, lepi rudi n) are frequentl y used i n
pati ents wi th hepari n-i nduced thrombocytopeni a. At l ow DTI concentrati ons, TT and ACT provi de
reasonable correl ati ons with DTI concentrati ons, but wi th the concentrations requi red for
cardi opul monary bypass the correlati on becomes poor and the ri sk of overdose wi th these agents,
for whi ch there are no antagoni sts, becomes si gnifi cant. The ecari n clotti ng ti me (ECT) provides a
better correl ati on and can be used for moni toring i n thi s context.
142
The test employs the venom
of the Saw-Scal ed (a.k.a. Sawtooth) Vi per (Echis cari natus). A metal l oprotease i n the venom
converts normal prothrombin to a form that i s inhi bi ted by the DTIs i n a dose-dependent manner.
Fibrinogen Level
Normal val ues are between 160 and 350 mg/dL. Bel ow 100 mg/dL, fi bri nogen may be i nadequate
to produce a cl ot. Fi bri nogen i s rapi dl y depl eted duri ng DIC. A marked increase i n fi bri nogen may
occur in response to stress including surgery and trauma. Levels i n excess of 700 mg/dL may
occur. Because of thi s increase, i n spi te of rapid fi bri nogen consumpti on duri ng a hypercoagul abl e
state such as DIC, the fi bri nogen level may sti ll appear to be normal .
Labor at or y Eval uat i on of Fi br i nol ysi s
Fibrin Degradation Products and D-Dimer
The fi bri n degradati on products (FDP) test i denti fies the breakdown products of fi bri n (crossl i nked
or uncrossl inked) and fi brinogen itself. The D-dimer assay i s speci fi c for breakdown products of
crossl i nked fi bri n. FDPs wi l l be i ncreased i n any state of accelerated fi brinol ysi s, including
advanced l i ver di sease, fi bri nol ysis associ ated with cardiopul monary bypass, admini stration of
exogenous thrombolyti cs, for exampl e, streptokinase, and DIC. D-di mer i s speci fi c to conditi ons in
whi ch extensi ve l ysi s of the crossl inked fi bri n of mature thrombus i s occurring, i n parti cul ar DIC
but al so DVT and PE.
The Thr omboel ast ogr am
Thromboel astography provides a measure of the mechani cal properti es of evolving clot as a
functi on of time. A principal advantage of thi s test i s that the processes i t measures requi re the
integrated acti on of all the el ements of the hemostati c process: pl atel et aggregati on, coagul ati on,
and fi bri nol ysi s. The thromboel astogram (TEG) i s obtai ned by placi ng a speci men of bl ood i n a
rotati ng cuvette into whi ch a pi ston is l owered. As cl ot formati on begi ns, the piston rotates as
functi on of the adherence of the evol vi ng fi bri n cl ot to the pi ston. The pi ston

is connected to a recorder and the rotati on of the pi ston resul ts i n a to and fro excursi on of the
styl us, the ampl i tude of whi ch is proporti onal to the speed of piston rotati on.
Fi gure 10-8 depi cts a normal thromboelastogram. Several parameters are derived from the TEG.
The most commonl y used ones and thei r i nterpretati on are as fol lows.
144

P.230
R, the reacti on time, i s the i nterval until i ni tial clot formation. It requi res thrombi n
formati on, and prol ongation i s usuall y indi cati ve of an i ntri nsi c pathway factor defi ci ency.
K, the cl ot formati on ti me, i s the i nterval requi red after R for the thromboel astogram to
achi eve a wi dth of 20 mm. Prolongation occurs with defi ci enci es of thrombi n formation or
generati on of fibri n from fi bri nogen.
The alpha angle, li ke K, i s a measure of the speed of clot formation. A decrease of the al pha
angle has si mi l ar significance to a prol ongation of K.
MA, the maxi mum ampli tude, i s a measure of the strength of the ful l y formed cl ot. It refl ects
pri mari l y pl atel et number and functi on, al though i t al so requi res proper fi bri n formation to
achi eve normal values. MA typicall y occurs between 30 and 60 mi nutes.
The (MA + x)/ MA, the ratio of the ampl i tude at a specific ti me interval (x) after MA di vi ded
by MA, is used as a measure of the rate of fi bri nol ysis. The (MA +60)/MA rati o has been
used most widel y.
145
A rati o of l ess than 0.85 i s evi dence of abnormal fi bri nol ysi s.
146
In
cl i ni cal practi ce, particul arl y i n l iver transpl antation, a nonquanti tative appreci ati on of the
typi cal tear drop shape (Fi g. 10-9) is used more often to support a diagnosis of i ncreased
fibri nolysi s than are speci fi c numeri cal val ues. F, the i nterval from MA to return to a zero
ampli tude, i s a measure of the rate of fi bri nolysi s. F i s suffi cientl y long in normal subjects
that often the test i s usual l y terminated before this time elapses.
FIGURE 10-8. The normal thromboelastogram and the variabl es commonly deri ved from i t.
See text for expl anati on. (From Kang et al , Epsi l on-aminocaproic acid for treatment of
fibri nolysi s duri ng l i ver transplantati on. Anesthesi ol ogy 66:766, 1987, wi th permi ssi on.)
The thromboel astogram has been employed i n cardiac surgery, major trauma, and hepati c
transpl antati on. It is i n the l atter that it i s used most frequentl y. Commonl y, i n that context, an
increased R prompts the admi nistrati on of FFP, a decreased MA l eads to platel et admi ni strati on,
and the tear drop configuration of fi bri nolysi s to the admini stration of anti fi brinol yti cs. The use of
the thromboelastogram in l iver transpl antati on has been shown to decrease both the amount of
RBCs and FFP transfused as compared wi th transfusi on guided by routi ne coagul ati on tests.
148

I nt er pr et at i on of Test s of t he Hemost at i c Mechani sm
An effecti ve approach to the i nterpretation of coagul ati on tests is to appreci ate i n advance the
constel l ati on of test results (the coagul ati on profile) that i s li kel y to occur wi th each of the
common bl eedi ng disorders (Tabl e 10-13). The most commonly ordered coagul ation tests are the
pl atel et count, PT, aPTT, and occasi onall y BT. When a greater di srupti on of the hemostati c
mechani sm i s suspected, further tests incl udi ng fibri nogen, TT, and assays for fi bri n degradati on
products and the D-di mer may be ordered.
FIGURE 10-9. Thromboel astogram patterns seen in normal subjects and i n subjects wi th four
abnormali ties of hemostasis. (From Kang YG: Moni tori ng and treatment of coagul ati on.
Wi nter KM, Kang YG: Hepati c Transpl antation: Anestheti c and Peri perative management, p.
151. New York, Praeqer, 1986, wi th permission.)
TABLE 10-13 Interpretation of Coagulation Tests
PLATELET
COUNT
BLEEDING
TIME
aPTT PT TT FIBRINOGEN FDPs POSSIBLE
CAUSE
EXA
N or N N N N N Producti on
sequestrati on
Consumpti on
Immune
destructi on
Radi a
chemo
Splen
Exten
ti ssue
dama
HIT
N N N N N N Pl atel et Drugs
dysfuncti on NSAID
Clopi d
IIb/II
inhi bi
uremi
vWD
N N N N N Severe vWF
defici ency
vWD
N N N N N N Factor
defici ency
Factor inhi bi ti on
Anti phosphol i pi d
anti body
Hemo
or B
Low-d
hepar
LMWH
Poor
coll ec
techn
Lupus
anti co
N N N N N N Factor VII
defici ency
Earl y
di seas
Earl y
K defi
Earl y
Coum
thera
N N N N Mul ti pl e factor
defici encies
Late v
K defi
Late
Coum
thera
Hepar
thera
N Di l uti on of
factors and
pl atel ets
Massi
transf
Hypercoagul abl e
state
producti on of
factors
DIC
c

Advan
li ver d
, i ncreased; , decreased; N, normal ; aPTT, acti vated parti al thromboplasti n ti me; PT, prothrombin
Because the coagulation defects that appear most often are reveal ed as abnormal val ues of PT
and/or aPTT, Fi gure 10-10 provi des an algori thm for the eval uation of those abnormal i ti es.
Common Coagulation Profiles
Platelet Count Decreased (Normal aPTT and PT). Di fferenti al diagnosis: causes (see l ater) of
decreased pl atelet production, excess consumption, pl atelet destruction, or sequestrati on i n the
spl een (see bleedi ng di sorders, thrombocytopeni a).
Prolonged BT (Normal Platelet Count, aPTT, PT). Di fferenti al diagnosis: antipl atel et drug
i ngesti on (NSAIDs, ASA, cl opi dogrel , etc.), uremi a, vWD (al though the factor VIII:C l evel s may be
decreased wi th vWD [type 1], onl y 25 to 30% of VIII:C coagul ant acti vi ty i s necessary to produce
a normal aPTT).
Prolonged aPTT (Normal Platelet Count and PT). Di fferenti al diagnosis: hepari n, the l upus
anti coagul ant or other anti phospholi pi d antibodi es, for exampl e, anti cardi oli pi n and anti -B2-GPI
TT, thrombi n ti me; FDPs, fi brin degradati on products; HIT, hepari n-i nduced thrombocytopeni a; vWF, v
Wi l lebrand factor; vWD, von Wi l lebrand's di sease; LMWH, l owmol ecul ar-weight hepari n; NSAIDs,
nonsteroi dal anti -infl ammatory drugs; DIC, dissemi nated intravascul ar coagulation.
a
aPTT prol ongati on i s more l i kel y to occur wi th LMWHs wi th l ower Xa/IIa effect rati os, for exampl e, ti n
than wi th greater rati os, for exampl e, enoxapari n.
b
Bleeding time may also be prol onged i n associ ati on with a marked aPTT i ncrease.
c
DIC may be di sti ngui shed by the presence of D-di mers.
FIGURE 10-10. An approach to the evaluati on of prol onged PT and/or aPTT. APA,
anti phosphol i pi d anti body (e.g., l upus anti coagul ant, anti cardi ol ipi n and anti -B2-GPI
anti bodi es); DD, D-di mers; DIC, di ssemi nated intravascul ar coagulation. (Reproduced [with
modification] from Bombeli T, Spahn DR: Updates i n peri operati ve coagul ati on: Physi ol ogy
and management of thromboembol i sm and haemorrhage. Br J Anaesth 93:275, 2004, wi th
permi ssi on.)
anti bodi es, defi ci ency of factor XII, HMWK, or prekal l i krei n, Hemophil i a A or B, vWD, acqui red
factor i nhibi tors, poor col lecti on techni que.
Disorders that produce thi s combinati on affect factors of the intri nsi c pathway (prekall i krei n,
HMWK, factors XII, XI, IX, VIII) and/or the common pathway (X, V, II, and I). Wi th hepari n
therapy, i ni tial ly onl y the aPTT is prol onged. At hi gher doses both the aPTT and PT are prol onged.
The l upus anti coagul ant and other anti phosphol i pi d anti bodi es are common causes of a
prol onged aPTT. That prol ongati on i s the resul t of the bi ndi ng of the phosphol i pid used to i niti ate
coagulation in vi tro. The pati ents do not have a bl eedi ng di athesi s. In fact, they have a
prothromboti c tendency. Thi s laboratory abnormal ity i s not corrected when the pati ent' s plasma i s
mi xed wi th normal pl asma because of the presence of i nhibi tors. Defi ci enci es of factor XII, HMWK,
or prekal l ikrei n, i n particul ar FXII, are al so common causes of aPTT prol ongation. However, they
are not usual ly associ ated wi th a si gni fi cant cl i ni cal hemostati c defect. Col l ection technique can
prolong the aPTT ei ther by hepari n contami nati on or because factors V and VIII, the l abil e factors,
may be consumed i f the bl ood becomes partial ly clotted prior to del ivery to the laboratory.
149
The
aPTT i s very sensi ti ve to factor VIII defici ency.

When a PTT i s prol onged i n i sol ati on, i s it l ess l i kel y to be because of a bl eedi ng di sorder that
invol ves mul ti pl e factor defici encies (such as l i ver disease, vitami n K defi ciency, the
administrati on of warfari n, or the coagul opathy associated wi th massi ve transfusi on or DIC).
Heparin therapy or congenital disorders of hemostasi s are more probable.
Prolonged PT (Normal Platelet Count and aPTT). Di fferenti al diagnosis: vi tamin K defici ency,
warfari n admini stration, early l iver dysfunction, FVII defi ciency, acquired coagul ati on factor
inhi bitors.
Because of the vi tami n Kdependent factors, factor VII has the shortest hal f-li fe, depl eti on of the
vitami n Kdependent factors wi l l fi rst prol ong the PT and l ater the aPTT as well . Simil arl y, the
development of l i ver disease wil l l ead to defi ci enci es of factor VII fi rst and i ni tial ly prol ong onl y
the PT. Wi th further deterioration of l iver function, both the PT and the aPTT

wi l l be prol onged. Li ver di sease can al so lead to thrombocytopeni a and pl atel et dysfunction.
Acquired coagul ati on factor inhi bi tors are rare but can occur i n patients wi th l ymphoma or
coll agen vascul ar disease.
Prolonged PT and aPTT (Normal Platelet Count). Di fferenti al diagnosis: vi tamin K defici ency,
warfari n, hepari n.
Al though l i ver di sease can produce mul tipl e factor defici encies and thi s pattern, the platelet count
is usual l y decreased. FDPs wil l also be elevated (see l ater).
Prolonged PT, aPTT, and TT (Normal Platelet Count). Di fferenti al di agnosi s: hepari n, DTIs or
FDPs, hypofi bri nogenemi a, dysfi bri nogenemi a.
Simul taneous prol ongati on of the TT makes the di agnosi s of si mple vi tami n K defici ency or
warfari n therapy unl i kely. TT i s sensiti ve to mi nute level s of heparin. Addi ti on of protami ne or
reptil ase ti me wi l l identi fy hepari n. FDPs may be el evated with fibri nolyti c therapy, DIC, or l i ver
di sease. DIC and l i ver disease usuall y resul t in thrombocytopenia as wel l. A normal platelet count
makes hepari n or extensive fi bri nol ysis more l ikel y.
Prolonged PT, aPTT, TT (Decreased Platelet Count). Di fferenti al di agnosi s: DIC, di l uti on by
massi ve transfusi on, li ver di sease, hepari n therapy.
FDPs and D-di mer are el evated in DIC and al l ow differenti ati on from dil uti onal effects and excess
hepari n. Heparin causes thrombocytopeni a onl y when prol onged exposure resul ts i n HIT. FDPs, but
not D-di mer, are elevated in severe li ver di sease.
The i nterpretati on of coagulation tests may be made more di ffi cul t by the fact that patients who
devel op a bl eedi ng di athesi s i n the peri operati ve period may have more than one bl eedi ng di sorder
(e.g., DIC and coagul opathy as a resul t of massi ve transfusion) and may al so have a surgi cal
P.231
P.232
cause for bleedi ng.
DISORDERS OF HEMOSTASIS: DIAGNOSIS AND TREATMENT
The hemostati c mechani sm i nvol ves an i ntri cate balance that serves to l i mi t blood loss i n the
event of vascular injury whi l e mai ntai ni ng the l iquid character of blood at other ti mes. Under
normal circumstances, an equi li brium between clotti ng and bl eedi ng is mai ntained wi th the help of
mul tipl e activators, i nhibi tors, cofactors, and feedback l oops, both posi ti ve and negati ve. Under
pathologi c ci rcumstances, that equi li bri um may be l ost, l eadi ng to ei ther hemorrhagi c or
thromboti c compli cati ons. Accordi ngl y, di sorders of hemostasis can be broadl y cl assified i nto those
that l ead to abnormal bl eedi ng and those that l ead to abnormal clotti ng. The di sorders may be
further categorized accordi ng to whether they involve platel ets, cl otti ng factors, and/or the
presence or absence of inhi bitors (such as FDPs). Fi nall y, disorders may be heredi tary or acqui red.
These organizati onal frameworks wi ll be helpful in reachi ng a diagnosi s on the basi s of the resul ts
of coagul ation tests. The treatment that fol lows from di agnosi s may requi re administration of
hemostati c agents (pl atelets and/or clotti ng factors) or the use of pharmacol ogi c agents. The
latter may be chosen for effects on platelets (desmopressin, antipl atel et drugs), on cl otti ng
factors (vitami n K, warfari n, hepari n), or on natural ly occurri ng inhi bi tors (anti fi brinol yti c agents,
protami ne, fi bri nolyti cs).
The preoperative hi story i s i nvaluabl e i n the identi fi cati on of disorders of hemostasis.
Abnormal i ti es of pri mary hemostasi s, usual ly caused by reduced pl atel et number or functi on, wil l
be reveal ed by evi dence of superfi cial (skin and mucosal ) bl eedi ng i ncl udi ng easy brui si ng,
petechi ae, prol onged bl eedi ng from mi nor ski n lacerati ons, recurrent epistaxis, and menorrhagi a.
Coagul ati on abnormal i ti es are associ ated with deep bl eedi ng events i ncluding hemarthroses or
hematomas after bl unt trauma.
Her edi t ar y Di sor der s of Hemost asi s
Von Willebrand's Disease
Von Wi l l ebrand' s di sease i s the most common heredi tary bl eedi ng di sorder. Some form of the
di sease i s present i n approxi mately 1% of the general population, though i t i s overtly symptomati c
in onl y about 10% of those affl icted.
151
vWD i s the resul t of abnormal synthesi s of the von
Willebrand factor (vWF). The vWF, a protein synthesi zed by endothel i al cel ls, megakaryoctyes, and
pl atel ets, is i mportant for both pri mary hemostasis, that i s, the bi ndi ng of pl atel ets to si tes of
vascul ar i njury, and coagul ati on, the l atter through its rol e as a carrier protein/stabi l izer for FVIII.
The vWF has several di sti nct binding domains responsibl e for its several hemostatic functions.
Those domai ns i nclude sites that are speci fic for col l agen (for adherence to the subendothel i um),
the platelet GPIb receptor (for pl atelet adhesi on to col lagen), the pl atel et GPIIb/IIIa receptor (for
pl atel et aggregati on), and factor VIII:C (for i ts carrier protein functi on). There are at least 50
geneti c vari ati ons of vWD, whi ch accounts for i ts phenotypi c heterogenei ty. There are three
pri nci pal subtypes. Type 1, whi ch comprises 70 to 80% of vWD, i s a quanti tative defect. vWF i s
present but i s secreted i n reduced amount. Pati ents wi th Type 1 vWD present wi th a pattern of
bl eedi ng that i s characteri sti c of abnormal i ti es of pri mary hemostasi s. Type 2 vWD, which
comprises 20 to 30% of patients wi th vWD, i ncl udes a host of qualitative defects of vWF. Some
mutati ons affect the platel et i nteracti ons of vWF and others the factor VIII interaction. Type 2 i s
subdi vi ded i nto four subtypes. 2B i s characteri zed by a vari ant of the vWF that causes abnormal
aggregati on of pl atel ets and thrombocytopenia. The abnormal vWF has a hi gh affi ni ty for the
pl atel et GPIb receptor. The bl eedi ng diathesis i s probably the result of formation and clearance of
vWF-pl atel et compl exes and the resul tant thrombocytopeni a. In the subtype 2N (Normandy) vWD,
the vWF has a markedly reduced affinity for factor VIII. These pati ents demonstrate normal
pl atel et functi on, but bleed because of decreased factor VIII coagul ant activity. These pati ents are
readil y mi sdi agnosed as havi ng mi ld hemophi l ia A. Type 3, whi ch i s very rare, entail s a compl ete
absence of vWF, resulti ng i n a severe abnormal i ty of both pri mary hemostasi s and coagul ati on.
The Role of vWF in Hemostasis. vWF i s essenti al for platelet pl ug formati on. It medi ates
pl atel et adhesi on to the subendotheli al surface of bl ood vessel s. After bindi ng to the
subendothel i um, the vWF undergoes a conformati onal change that al lows pl atel ets to adhere vi a
thei r gl ycoprotein GPIb receptors (Fi g. 10-4). Thi s bindi ng can onl y occur after the conformational
change and i n soluti on, platelets wi ll not spontaneousl y bi nd to vWF. The antibi oti c ri stoceti n can
induce the pl atel et GPIb-vWF interaction and, accordi ngl y, i s the basi s for one laboratory test of
pl atel et functi on. vWF al so parti ci pates i n pl atel et to platelet aggregati on. Pl atel et aggregation
occurs by bi ndi ng of vWF molecul es to the GPIIb/IIIa receptors on the surface of several pl atelets.
The vWF also acts as a carrier protei n for the coagul ant activity of factor VIII, referred to as
VIII:C, wi th whi ch i t ci rcul ates i n a compl exed form that prolongs VIII:C' s ci rculation ti me.
Diagnosis and Treatment of vWD. History will commonl y reveal abnormal bl eedi ng from
mucosal surfaces. Si xty percent of the pati ents wi ll report epistaxis, 50% report menorrhagi a, and
35% wi l l acknowl edge gi ngi val bl eedi ng, easy brui si ng, and hematomas.
152
vWD shoul d be
consi dered i n patients who give a hi story of unexpl ai ned postoperative bleedi ng,

parti cul arl y fol lowi ng tonsi ll ectomy or dental extraction. Although thi s is a heredi tary di sease, a
cl ear fami l y hi story is not al ways evi dent because di sease severi ty vari es substanti al l y.
Speci al i zed l aboratory tests, i deall y di rected by a hematol ogist, may be requi red to confi rm
the diagnosis and type of vWD. One or more vWF markers including vWF factor anti gen
(vWF:Ag), vWF ri stoceti n cofactor activity (vWF:RCo), or vWF col lagen binding acti vi ty (vWF:CB)
wil l be di mi ni shed or absent. Because vWD i s a carri er protein/stabi l i zer of FVIII, FVIII half-li fe is
di minished and FVIII l evels are characteri sti cal l y also decreased.
151
What is i mportant for the
anesthesiol ogi st to appreci ate i s that the resul ts of the most commonly ordered coagulation tests,
the platelet count, the aPTT, and the PT, may be normal i n the pati ent wi th vWD. Whi le the hal f-
l i fe of VIII:C i s di mi ni shed i n vWD there i s usuall y suffi cient VIII:C to yiel d a normal aPTT i n basal
condi ti ons.
The two establi shed treatments for vWD are DDAVP and factor concentrates.
153
DDAVP (1-
deami no-8-D-arginine vasopressin), whi ch promotes rel ease of vWF, is effecti ve fi rst-li ne therapy
for the l arge majori ty (approximatel y 80%) of pati ents wi th vWD, i ncl udi ng those wi th type 1 and
type 2A di sease. However the recogniti on of subtype 2B (see earli er) i s i mportant because DDAVP
wil l cause thrombocytopeni a i n these pati ents.
154
DDAVP, gi ven i ntravenousl y i n a dose of 0.3
ug/kg, i ncreases factor VIII:C and vWF two- to fivefold in most pati ents. Its effect is maximal
after 30 mi nutes and el evated level s persi st for 6 to 8 hours
152
(see Pharmacol ogic Therapy:
Desmopressi n secti on). For the 20% of pati ents who do not respond adequatel y to DDAVP, factor
concentrates, for exampl e, Haemate-P, wi l l be appropri ate. Thei r effi cacy i s well confirmed.
155, 156

Antifibrinol yti c agents, epsi lon-aminocaproic acid, and tranexami c aci d are someti mes used i n
combi nation with DDAVP to manage these pati ents during the peri operati ve period.
154
They may be
given intravenously or orally. They have also been admi ni stered topicall y, as mouthwashes, i n
patients with vWD undergoi ng dental extracti ons. Oral contracepti ves (estrogens) have been used
to treat patients with vWD and menorrhagia or who are undergoing el ecti ve surgery.
154
The
mechani sm of acti on of the estrogens is not wel l understood, al though a connecti on wi th vWF
synthesis i s suspected. Anti platel et drugs shoul d be avoi ded i n patients with vWD.
The Hemophilias
Hemophi li a A resul ts from mutati ons that l ead to ei ther defi ci ent or functional l y defecti ve factor
VIII:C. Hemophi l ia B (Christmas disease) and hemophil i a C are caused by defi ciency or
abnormali ty of factors IX and XI, respecti vel y.
157
The relative frequenci es of the three hemophi l ias
are factor VIII:C, 85%; factor IX, 14%; and factor XI, 1%. Rare inheri ted defi ci enci es of factors
II, VII, V, and XI al so occur.
157
Both hemophil i a A and B are sex-li nked recessi ve disorders, whi ch
therefore occur al most excl usi vel y i n males. Hemophil i a C i s an autosomal recessive disorder that
occurs al most excl usi vely i n Ashkenazi Jews.
157
About 50% of operati ons in hemophil i acs are
orthopaedic procedures required for treatment of the arthriti c consequences of hemarthroses.
Hemophilia A. Factor VIII i s a very l arge macromolecul e wi th two components, the coagul ant
factor VIII (VIII:C) and the von Wi l lebrand factor. The VIII:C mol ecul e ci rculates bound to and
protected by vWF. In hemophi l i a A, patients have normal l evel s of vWF, but have reduced or
P.233
defective factor VIII:C. Hemophi l ia A occurs i n approximatel y 1 i n 10,000 males.
Hemophi l i acs experi ence deep ti ssue bl eedi ng, hemarthroses, and hematuria most commonl y.
Cli nicall y, hemophi l ia A can be cl assi fi ed as mil d, moderate, and severe. Patients wi th mi ld disease
have factor levels of 5 to 30% of normal and usual ly bleed abnormall y only foll owi ng trauma.
Patients with moderate disease have factor l evel s of 1 to 5% and occasi onal l y bl eed spontaneously
as wel l as fol l owi ng trauma. The great majori ty of hemophi l i acs have the severe form of the
di sease. Factor VIII:C l evel s are l ess than 1% of normal and they frequentl y experi ence
spontaneous bleedi ng epi sodes. The severi ty of cli ni cal symptoms usual l y correlates with the l evel
of cl otting factor acti vi ty. Li ke the patient wi th vWD, hemophi l iacs should avoi d aspi ri n and other
pl atel et inhi bi ti ng agents.
Di agnosis and treatment of hemophi l ia A. Pati ents wi th hemophil i a A wi l l commonly report a
hi story that reveal s the X-li nked recessi ve pattern of di sease i nheri tance. Di agnosi s of hemophil i a
A i s made on the basi s of a prol onged aPTT and speci fi c factor assays demonstrating a defi ci ency
of factor VIII coagulant acti vi ty wi th normal l evel s of vWF, factor IX, and factor XI. The pati ent
wil l have a normal PT and BT. Hemophil i a A i s treated wi th pl asma-deri ved concentrates that have
been treated by vi ral attenuation procedures or, now more commonly, with recombinant factor
VIII.
157

If a hemophi l iac presents for el ecti ve surgery, the pati ent' s hematol ogist shoul d be consulted. The
requi red factor replacement wi l l be dependent on (1) the pati ent' s plasma volume and (2) the
desi red procoagul ant acti vi ty. The pati ent' s pl asma vol ume can be assumed to be equal to 40 mL
of pl asma per ki l ogram of body wei ght. A 60-kg person woul d have a pl asma vol ume of 2,400 mL.
One unit of procoagulant acti vi ty per mi ll i l iter of plasma i s defined as a pl asma procoagulant l evel
of 100%. A procoagul ant l evel of 25% is a common target for achieving control of a bl eeding
epi sode. Thi s would mean that a total of 600 units (25% 2,400 mL) of factor VIII:C woul d be
requi red. For elective surgery, the level of factor VIII:C acti vi ty i s usuall y rai sed to 50 to 100% of
normal . Many hemophi l iacs develop i nhibi tors to factor VIII:C. The presence of the i nhibi tor
increases the amount of factor VIII:C that must be admi nistered to manage a gi ven hemostati c
chal l enge. Recombi nant acti vated FVIIa (see l ater) may be required for the pati ent wi th i nhi bitors.
DDAVP wi l l al so i ncrease pl asma factor VIII:C and vWF concentrati ons and may be effecti ve i n
mi ld hemophi l ia A. DDAVP i s thought to cause the release of factor VIII:C from li ver endothel ial
cel ls. There i s a large vari ati on i n patient response to DDAVP and i t i s most effecti ve i n pati ents
with factor VIII:C level s greater than 5%.
66, 158
It is given iv in a dose of 0.3 ug/kg in 50 mL of
sali ne over 15 to 30 mi nutes. It causes a prompt i ncrease i n factor VIII:C. However, tachyphylaxi s
does devel op, whi ch l i mi ts i ts useful ness.
The antifibri nolyti cs epsi lon aminocaproic acid and tranexami c aci d have been used to treat
hemophi l i ac pati ents pri or to dental procedures. The agents are contrai ndi cated i n bl eedi ng
epi sodes i nvol vi ng joi nts or the uri nary tract because the cl ots that do form may not be l ysed for a
l ong peri od of ti me.
Hemophilia B. Factor IX defi ci ency is al so an X-li nked recessi ve di sorder, occurring i n ca.
1/25,000 mal es,
157
that produces a bl eeding di athesi s that i s cl i ni cal l y i ndi sti ngui shabl e from
hemophi l ia A. A recombi nant FIX factor concentrate i s now avail able. Typicall y, mi nor hemorrhage
i s managed by achi evi ng FIX l evel s of 20 to 30% of normal . Level s of 50 to 100% are sought for
more severe hemorrhage and i n antici pation of surgery. Factor IX compl ex concentrates, al so
known as prothrombi n compl ex concentrates (II, VII, IX, X), have been used i n the face of
resistance to FIX concentrates. However, they convey an infectious hazard and may entai l a ri sk of
thrombosi s and DIC because of the presence of acti vated factors.
Protein C and Protein S Deficiency
Heredi tary defi cienci es of protei n C and protei n S are associ ated wi th thromboembol ic events
origi nating on the venous

si de of the ci rcul ati on, for exampl e, DVT, PE, and stroke as a consequence of paradoxi cal
P.234
embol i zati on. The complete absence of protei n C is associated wi th death in i nfancy. Pati ents who
experi ence thromboembol ic events and have decreased l evel s of protei n C or protei n S shoul d
remai n on anti coagul ant therapy indefini tel y.
Acqui r ed Di sor der s of Hemost asi s
For mnemonic purposes, i t i s hel pful to cl assi fy bleedi ng di sorders according to whi ch of the three
hemostati c processes are i nvol ved: pri mary hemostasis (pl atelet di sorders), coagul ati on (cl otting
factor di sorders), fi bri nol ysis (production of inhi bi tors such as FDPs), or some combinati on of the
three. Si mi l arl y, i t i s useful to use the results of coagul ati on tests to determi ne whether the
cl i ni cal probl em i nvol ves primary hemostasi s (decreased platelet count, i ncreased bleedi ng ti me,
etc.), coagul ati on (prolonged PT and aPTT, decreased factor level s, etc.), fi brinol ysi s (i ncreased
FDPs, i ncreased D-di mer), or some combinati on of the three. Ul timatel y, therapeuti c decisi ons
(e.g., administrati on of pl atel ets, FFP, or an antifibrinolyti c agent) wi l l si mil arl y be oriented to
treatment of one or more of these processes.
Acquired Disorders of Platelets
The cli nical condi ti ons that cause an isol ated di sorder of pri mary hemostasis typi cal l y i nvol ve
abnormali ties of ei ther platel et number or functi on.
Thrombocytopenia. Platelets are deri ved from megakaryocytes in the bone marrow in response
to thrombopoieti n, whi ch i s synthesized by the li ver. The causes of thrombocytopenia may be
categori zed as fol l ows: (1) i nadequate producti on by the bone marrow, (2) increased peri pheral
consumpti on or destruction (nonimmune medi ated), (3) i ncreased peri pheral destructi on (i mmune
mediated), (4) di luti on of ci rcul ati ng platelets, and (5) sequestrati on (Fi g. 10-11).
1. Bone marrow producti on of pl atel ets can be i mpaired i n many ways. Physi cal and chemical
agents (radiation and chemotherapy), various drugs (thi azi de di ureti cs, sulfonamides,
FIGURE 10-11. Thrombocytopenia. The fi gure depi cts the fi ve processes that can lead to
thrombocytopeni a. They include platelet destruction, as occurs i mmunol ogi cal l y i n l upus
erythematosus; pl atel et consumpti on, as occurs wi th burns or other massi ve ti ssue i njury
condi ti ons; inadequate producti on, as can occur wi th marrow infi l trati on, chemotherapy, or
radiation; sequestrati on, as can occur i n the presence of spl enomegal y; and di l uti on,
occurri ng duri ng massi ve transfusi on.
di phenyl hydantoi n, al cohol ), infecti ous agents (hepati tis B, TB, overwhelming sepsi s), and
chroni c disease states (uremia, l i ver disease) can all cause bone marrow suppressi on.
Infiltration of the bone marrow by cancer cel l s or replacement by fi brosi s wi l l al so resul t i n
inadequate pl atelet producti on.
2. Accelerated nonimmunologi cal ly medi ated consumpti on can occur i n many condi tions that
cause extensi ve acti vati on of coagul ati on with or wi thout the occurrence of DIC. After
extensi ve ti ssue damage such as occurs with burns or massive crush injuri es, whi ch denude
vascul ar endothel ium, the normal process of hemostasi s activates platel ets, leading to their
consumpti on and to thrombocytopeni a. In a si mi lar fashi on, the i nteracti on of pl atel ets wi th
nonendotheli ali zed structures such as l arge vascular grafts can al so lead to a transient
thrombocytopeni a. Platelets are consumed i n pati ents with an extensive vascul i ti s such as
occurs with toxemi a of pregnancy. The many condi tions that cause DIC (see l ater) wil l also
cause pl atel ets to be consumed or destroyed faster than they can be produced.
3. Immunologically mediated consumption can be caused by vari ous drugs (heparin, quinidi ne,
cephal ospori ns) and autoi mmune di sorders (systemi c lupus erythematosi s, rheumatoi d
arthri tis, thromboti c thrombocytopeni c purpura). Al l oi mmunizati on resul ting from previ ous
bl ood transfusi ons or pregnancy can cause refractoriness to platelet transfusi ons.
4. Dil uti on of pl atel ets wi l l occur in the context of massi ve transfusi on (see l ater and Col lection
and Preparati on of Bl ood Products for Transfusi on secti on).
5. Under normal condi ti ons, approxi matel y one-third of pl atel ets are sequestered i n the spleen.
When the spl een enlarges, an increasi ng number are sequestered and thrombocytopenia may
resul t. Thi s may occur with the spl enomegal y associ ated with myel odyspl asti c syndromes
and ci rrhosi s of the li ver, though i n the latter condi tion decreased producti on al so
contri butes to thrombocytopeni a.
Disorders of Platelet Function
Uremia. Platelet dysfuncti on i s common i n uremi c pati ents.
The accumul ati on of guanidi no succi ni c aci d and hydroxy phenol ic aci d i s thought to contri bute to
this dysfunction through i nterference wi th the platelet' s abi li ty to expose the PF3 phosphol ipi d
surface. These compounds are dial ysabl e and, accordi ngl y, di al ysi s frequently i mproves the
hemostati c defect associ ated wi th uremia. An additi onal abnormal i ty i nvol vi ng the i nteraction of
vWF wi th pl atelet receptors is al so suspected. DDAVP (desmopressi n), which among other effects
induces immedi ate rel ease of vWF from endothel i al cel ls, rapidl y i mproves pl atel et
adhesi veness.
159
However, the mechani sm of thi s effect i s not understood. It i s not si mpl y a
matter of restoring vWF l evel s because circul ating vWF i s typi call y present i n normal level s i n
uremia. Admi ni stration of erythropoi eti n and conjugated estrogens have al so been observed to
cause gradual i mprovement of the hemostati c defect associ ated wi th uremia. The mechani sms of
these effects are simi larl y not known. Cryopreci pi tate wi l l al so i mprove the pl atel et dysfunction of
uremia but, given the effi cacy of DDAVP, the associated ri sks are not justi fi ed. When li fe-
threateni ng bl eedi ng occurs i n the uremi c pati ent, pl atel et concentrates shoul d be admi ni stered.
Anti pl atel et agents. Numerous medications are administered expressly for the purpose of pl atel et
inhi biti on i n order to reduce the ri sk of myocardi al i nfarcti on, stroke, and other thromboembol ic
compl i cati ons. They i nduce pl atel et dysfuncti on by several mechanisms, whi ch include i nhi bi ti on of
cycl ooxygenase, i nhi biti on of phosphodi esterase, ADP

receptor antagoni sm, and bl ockade of the gl ycoprotein IIb/IIIa receptor.
Cyclooxygenase i nhi bitors. Aspi ri n i s the prototype. Aspi ri n produces irreversibl e i nhibi tion of
pl atel et cycl o-oxygenase (cox), which prevents synthesi s of thromboxane A
2
, a potent pl atel et
proaggregant and vasoconstri ctor. In moderate doses, there is sel ecti ve sparing of the synthesi s
of prostacycl i n (antiaggregant, vasodi l ator), whi ch resul ts in ti l ti ng the bal ance substanti al l y i n
favor of pl atel et i nhi bi ti on. Indomethaci n, phenyl butazone, and al l the nonsteroi dal anti -
P.235
infl ammatory agents si mil arl y i nhi bit cyclooxygenase. However, thei r i nhi biti on i s promptly
reversi bl e wi th clearance of the drug. The recently introduced cox-2 inhi bi tors sel ecti vel y i nhi bit
the cox-2 isoform, the i soform responsibl e for generating the medi ators of pai n and infl ammati on,
whi l e sparing the cox-1 isoform, inhi bi ti on of whi ch causes both gastric damage, decreased renal
bl ood flow, and inhi bi ti on of pl atel et thromboxane A
2
. Accordi ngl y, pl atel et function should not be
impai red. However, there has been concern that cox-2 inhi bi tors, whi ch should reduce prostacycl in
generati on by vascular endotheli al cel ls, may thereby actuall y ti l t the natural balance toward
pl atel et aggregati on.
160
That concern has been rei nforced by the report i n 2004 of an i ncreased
rate of myocardial i schemic events i n pati ents taki ng cox-2 i nhi bi tors, and the wi thdrawal of
certai n cox-2 inhi bi tors from the market.
Phosphodi esterase i nhi bi tors. Cycl ic AMP is an inhi bi tor of platel et aggregati on and l evel s are
i ncreased by i nhi bi ti on of phosphodi esterase. Di pyri damol e, which i s used for stroke prophyl axis
al one or more commonl y i n combi nation with aspi ri n, and cil ostazol appear to act pri maril y by thi s
mechani sm. Caffei ne, aminophyl l ine, and theophyl l i ne wi l l al so si mil arl y produce mi ld, reversibl e
pl atel et inhi bi ti on.
ADP receptor antagoni sts. Ticl opi di ne and cl opidogrel , whi ch are admi nistered for stroke
prophyl axi s, block the ADP receptor, activati on of which leads to expressi on of the IIb/IIIa
receptor. They noncompeti tively and i rreversi bly i nhibi t ADP-i nduced pl atel et aggregati on.
Ti cl opi dine has been withdrawn from the market because of the occurrence of neutropenia and
thromboti c thrombocytopenic purpura.
Gl ycoprotei n IIb/IIIa receptor antagoni sts. These agents bl ock platelet aggregati on by blocki ng
the GPIIb/IIIa receptor. The IIb/IIIa si te, by whi ch fibrinogen crossl inks platelets, is the fi nal
common pathway for pl atelet aggregati on. The IIb/IIIa antagoni sts have been used princi pall y for
the management of acute coronary syndromes. They i ncl ude abciximab, a monocl onal anti body,
ti rofi ban, and epti fi bati de. These agents al l require i v admi ni strati on. Their effect i s reversibl e.
The hal f-li ves are approxi matel y 2.5 hours for ti rofi ban and epti fi bati de and 12 hours for
abciximab.
161
However, abci xi mab has a rel ati vel y high affi ni ty for the IIb/IIIa receptor and
pl atel et dysfuncti on may be l onger (ca. 48 hours) than i mpli ed by half-li fe. Al l of these agents
have also been associ ated with thrombocytopeni a, the i nci dence of which has been greater for
abciximab (2.5%) than ti rofi ban and epti fi bati de (0.5%).
162
Note that these agents cause
prolongation of the ACT.
161

Herbal Medication and Vitamins. Several herbal medi cati ons, including gi nkgo bi l oba, gi nseng,
garl i c, and gi nger, may cause i nhi biti on of pl atelet function. Because the actual ri sks are not wel l
defi ned, they shoul d be di sconti nued before surgery, and i n particul ar, before cardiac, neurologi c,
and cosmetic surgi cal procedures. Vi tamin E is al so a platelet i nhibi tor and shoul d si mi larly be
di sconti nued.
163

Other Conditions. Myel oprol i ferative and myel odysplasti c syndromes can produce intri nsi c
defects in pl atel ets. In these disorders, the platelets may be abnormal i n both morphol ogy and
functi on. Platelet dysfuncti on occurs i n conjunction wi th conditi ons that also cause other
hemostati c abnormal i ti es (l i ver disease, fibri nolyti c states i ncl udi ng DIC, storage defects) and i s
di scussed i n the fol lowi ng secti on.
Acqui r ed Di sor der s of Cl ot t i ng Fact or s ( I ncl udi ng
Ant i coagul ant Ther apy)
Vitamin K Deficiency
Hepati c synthesis of cl otti ng factors II, VII, IX, and X, as wel l as protei n C and protei n S requi res
the presence of vi tamin K. Vi tami n K i s necessary for the enzymati c carboxylation of the vi tamin
Kdependent clotti ng factors. The carboxyl group enabl es these factors to bi nd via a cal ci um
bri dge to phosphol i pi d surfaces duri ng the coagul ati on process. When vitamin K deficiency occurs,
these factors are depleted i n an order determined by thei r i ndi vi dual hal f-li ves. Factor VII has the
shortest hal f-li fe and is the first to be depl eted, then factors IX and X, and final l y factor II.
Vitami n K actual l y refers to a group of vi tami ns.
164
Vitamin K
1
(phyl loqui none) i s found i n
l eafy green vegetabl es. The greatest quanti ti es occur i n Brussel s sprouts. Vi tamin K
2

(menaqui none) i s synthesized by the normal intesti nal fl ora. It i s uncommon for pati ents to
devel op vi tami n K defi ci ency sol el y because of di etary defi ci ency but i t may occur i n pati ents who
are receiving parenteral nutri tion without vitami n K suppl ementati on and who are bei ng treated
concurrentl y wi th broad-spectrum antibi oti cs that destroy the gut fl ora. Because the body has no
appreci abl e stores of vi tami n K, defici encies can develop i n roughly 1 week. Newborns, who have a
steri l e gut at bi rth, have been noted to develop vitamin K deficiency.
Vitami n K i s a fat-solubl e vi tami n and therefore requi res bi l e sal ts for absorpti on from the
jejunum. Patients with biliary obstruction, pancreati c insuffici ency, mal absorpti on syndromes, GI
obstruction, or rapi d GI transit can devel op vi tami n K defici ency as a resul t of i nadequate
absorpti on.
Diagnosis and Treatment of Vitamin K Deficiency. Vi tami n K defi ciency wi l l cause prol ongati on
of the PT. Thi s occurs because factor VII i s depl eted fi rst. Wi th more prol onged defici ency, the
aPTT wi l l al so be i ncreased because of decl i ni ng level s of factors IX and X. Platelet count wi l l be
normal . Vi tamin K may be admi ni stered orall y, intramuscul arl y, or i ntravenousl y. Urgent treatment
of vi tami n K defi ci ency i s best accompl ished by the i ntramuscul ar or intravenous admi ni strati on of
vitami n K (Aquamephyton), usual ly i n doses 1 to 5 mg. Vi tami n K should be administered sl owl y to
avoi d the occurrence of hypotension. Improvement of the coagul ati on disturbance wi l l begi n to be
apparent withi n 6 to 8 hours.
Warfarin Therapy
Warfari n produces i ts anti coagul ant effect by competi tion wi th vi tami n K for the carboxyl ati on
bi nding sites. Admi ni strati on of warfari n leads to the depl eti on of factors II, VII, IX, X, protein C,
and protei n S. As wi th vi tami n K defici ency, FVII is the first factor to be depl eted. Subsequentl y,
FIX and FX are depl eted, and then FII. Accordingl y, i ni tial ly onl y the PT wi l l be prol onged. Wi th
hi gher doses, the aPTT wi l l be affected as wel l .
Warfari n i s admi ni stered for the preventi on of deep venous thrombosi s and pul monary embol i sm
and to pati ents wi th atri al fibri ll ati on, some prostheti c heart val ves, and ventri cular mural thrombi
in the setti ng of acute myocardi al . Pati ents wi th protei n S or protein C defici ency may al so be
treated wi th l ong-term anti coagul ati on wi th warfari n. Warfarin therapy i s adjusted according to
the international i nternal ized ratio (INR) (see tests of the hemostati c mechani sm). The primary
untoward effect of warfari n therapy i s bl eedi ng. Rapi d reversal (12 to

24 hours) of warfari n effect
69
can be accompli shed by admi ni strati on of vi tamin K, 5 mg i v.
Small er doses, 0.5 to 3 mg, shoul d be used in l ess-urgent si tuati ons when the objecti ve i s to
lower rather than normali ze INR. INR should be rechecked at 6-hour interval s. Vitami n K
administrati on may have to be repeated at 12-hour interval s. In situations of greater urgency, FFP
has been admini stered. However, as noted i n Disorders of Hemostasi s: Di agnosi s and Treatment
secti on, prothrombi n compl ex concentrate, whi ch contai ns FII, VII, IX, X, i s an al ternati ve that
has been reported to be more effecti ve than FFP
165, 166
because FFP admi ni stration frequently fails
to achieve adequate concentrati ons of FIX
165
and because some pati ents cannot tol erate the
requi site vol ume, that i s, ca. 15 mL/kg. If FFP or concentrates are admini stered for rapi d reversal
and sustai ned reversal i s desi red, vi tami n K shoul d be admi ni stered si mul taneously because of
FVII's short (6 hours) hal f-li fe. Recombinant FVIIa (see l ater) has al so been used to achi eve rapi d
normal izati on of INR.
167

Heparin Therapy
Heparin i s used wi del y for anti coagul ati on i n vascul ar surgery and in procedures requi ring
cardi opul monary bypass (CPB). It i nhibi ts coagul ation pri nci pal l y through its i nteracti on wi th one
of the body's natural anti coagulant protei ns, anti thrombi n III (ATIII). Hepari n bi nds to ATIII and
in so doi ng causes a conformational change that greatl y increases ATIII' s inhi bi tory activity. In
spi te of its name, anti -thrombi n III, ATIII also i nhi bi ts several activated factors i ncl udi ng, in
P.236
addi ti on to IIa (thrombi n), Xa, IXa, Xia, and XIIa. It i s most acti ve agai nst thrombin and Xa.
Heparin also i ncreases the activity of a second native anti thrombin, heparin cofactor II. Heparin
cofactor II i nhi bits thrombi n and not the other acti vated factors. Its contri buti on to the cli ni cal
effects of heparin i s not cl ear. Resistance to hepari n can occur i n pati ents who are defici ent in
ATIII on ei ther a heredi tary or an acqui red basi s. The l atter may occur i n pati ents on sustained
hepari n therapy or i n the presence of depl eti on by a consumpti ve coagul opathy. Hepari n
responsi veness can be restored by admi ni strati on of ATIII (ATIII concentrates
131, 132
or FFP).

LowMolecular-Weight Heparin (LMWH). Lowmol ecul ar-weight fracti ons of heparin have been
employed pri ncipal ly for deep vei n thrombosi s prophyl axi s and treatment and are supplanti ng
subcutaneous unfracti onated hepari n and coumadi n for these i ndi cations.
168
There are several
avai labl e agents: i ncludi ng certopari n, dal tepari n, danaparoi d, enoxapari n, revipari n, and
ti nzapari n. These agents do not appear to di ffer i n thei r effi cacy
150
and enoxapari n i s used most
widel y in the Uni ted States. LMWHs, whi ch al so act via ATIII, have greater acti vi ty agai nst factor
Xa than thrombin (IIa). However, the ratio of that activity vari es among the agents, for exampl e,
enoxapari n 3.8:1; tinzapari n 1.9:1.
169
Accordingly, the effect of these agents on standard
coagulation tests wil l vary (mi ni mal for enoxapari n
170
) as wi l l the effect of protami ne
neutral izati on, whi ch is very i ncompl ete for enoxapari n. Monitori ng i s usual ly not required or
performed. If i t is deemed necessary, the anti -Xa level i s the appropri ate test. The LMWHs cause
less platel et i nhi bi ti on and are associ ated with a l esser incidence of hepari n i nduced
thrombocytopeni a.
171
There has been considerabl e di scussi on of opti mal dose regi mens. European
practi ti oners have often started prophyl axi s 12 to 24 hours preoperati vel y. However, there i s li ttl e
evidence that that practi ce is superi or to postprocedure i niti ation.
150
Whi le twice-dai ly dosi ng wi th
enoxapari n has been common in North Ameri ca, once-dai ly regi mens are usual ly suffici ent.
Because of the rel ati vely l ong hal f-li fe of enoxaparin, twi ce-dai ly dosi ng poses a problem wi th
respect to removal of epidural catheters because there i s no anticoagulant nadi r (see Chapter 40).
Heparin-Induced Thrombocytopenia/Thrombosis.
172
As many as 5% of pati ents who
recei ve hepari n therapy for 5 days wi l l devel op thrombocytopeni a as a resul t of anti bodi es
(usual l y IgG) directed agai nst platelet factor 4-hepari n compl exes on the pl atel et surface. Onset
requi res several days i n the hepari n-na ve pati ent but can occur much more qui ckly (10 to 12
hours) i n those who have been exposed wi thi n the precedi ng 100 days.
173
Occurrence appears to
be dose rel ated and i s more common wi th bovi ne than porci ne hepari n. Hepari n-i nduced
thrombocytopeni a/thrombosi s (HITT) i s rel ati vely uncommon wi th LMWH and requi res longer
peri ods of exposure.
174
Whi le HITT is most often i denti fi ed because of thrombocytopeni a, not al l
patients become markedl y thrombocytopeni c. Thromboti c and thromboembol ic events, incl udi ng
DVT, PE, l i mb or acral i schemi a, MI, stroke, not i nfrequently reveal the occurrence of HITT.
172

Diagnosis i s compl i cated by the fact that not al l pati ents who devel op anti platel et anti bodi es have
cl i ni cal HITT. A hematologi st shoul d be consul ted. Treatment entail s wi thdrawal of hepari n after
insti tuti ng an alternate anti coagul ant, for exampl e, a DTI (hi rudi n, argatroban, l epi rudi n,
bi val i rudi n) or a hepari noi d, for exampl e, danaparoi d (but not a LMWH). Warfari n is
contrai ndi cated because the combi nati on of protei n C and S i nhibi tion by warfarin in the face of
ongoi ng pl atel et cl umpi ng may aggravate thrombosi s. Pl atelets si mil arl y shoul d not be
administered unl ess thrombocytopeni a i s extreme.
Heparin in Cardiopulmonary Bypass. A comprehensi ve di scussi on of the use and moni tori ng of
hepari n therapy i n CPB i s beyond the scope of this chapter. Extensive revi ews are avai labl e.
175, 176

In bri ef, the common practice i s to mai ntain ACT >480 to 500 seconds for the durati on of bypass.
There i s substanti al vari ation in the hepari nACT dose-response rel ationship, probabl y because of
vari abi l ity i n hepari n binding to many nati ve surfaces i ncl udi ng pl atel ets, WBCs, endotheli um, and
pl asma protei ns i ncl udi ng the vWF and ATIII.
175, 176
Whi le there i s controversy, i t appears that
there i s greater hazard i n al lowi ng ACT to be on the low si de than i n mai ntaini ng more complete
hepari ni zati on.
177
Evi dence of pl atel et activati on i s l ess apparent when l onger ACTs are
maintai ned. Whether thi s i s a functi on of di rect i nhi bi ti on of pl atel ets, whi ch are subject to contact
acti vation by the CPB ci rcui t, bi ndi ng of vWF, or the resul t of reduced formation of thrombi n and
i nhi bi ti on of pl atel ets by i ts breakdown products (FDPs) is not apparent to the authors of thi s
revi ew. Protami ne i s admi ni stered for reversal of heparin effect. Many cl inici ans empl oy an mL-
for-mL technique. However, a more careful ti trati on of protami ne against ACT i s ideal to avoid
excessive admini stration of protami ne, whi ch has inherent anti coagul ant effects including pl atel et
inhi biti on, sti mul ati on of t-PA rel ease from endothel ium, and inhi bi ti on of fi bri nogen cl eavage by
thrombi n.
178

Various al ternati ves have been consi dered for the patient wi th HIT who requi res CPB.
Pl asmapherei s pri or to surgery with subsequent use of hepari n has been empl oyed.
179
The
nonhepari n al ternatives for anti coagul ation include speci fi c inhi bi tors of thrombi n (see later) and
the defi bri nogenati ng agent Ancrod (from the venom of the Malaysi an pi t vi per). The contact
acti vation of platel ets is not i nhibi ted and i t may be appropri ate to admi nister pl atel et inhi bitors
si multaneously. Experi ence i s li mited and wel l -defi ned protocol s are not establ i shed.
Direct Thrombin Inhibitors
The agents most commonl y used CPB when there are contrai ndi cati ons to heparin are the DTIs.
Thi s group i ncl udes hi rudi n, argatroban, l epi rudi n, and bival i rudin. Hi rudi n i s a recombi nant
product and the others are synthetic. There are di sadvantages to their use i n CPB. The first i s that
there i s no anti dote. Termi nation of effect is l argel y dependent on renal

el i mi nation. The excepti on i s bi vali rudi n, whi ch is i n part cl eared by proteol ysi s by thrombi n. In
the pati ent wi th renal fail ure or i n urgent situations, el i mi nation can be accompli shed by dial ysis
or hemofi l trati on.
180

Ximelagatran i s a direct thrombi n i nhi bitor that can be taken oral l y. It has no relevance to CPB
but has undergone phase three tri al i n the preventi on of recurrent venous thromboembol ism wi th
favorabl e results.
181
It has a relativel y short half-li fe (ca. 4 hours) and i s largel y el i mi nated by the
kidneys. Because of predi ctabl e bioavail abi l i ty, coagul ati on moni tori ng i s usual ly not empl oyed.
Like other DTIs, i t wi l l prolong TT, aPTT, PT, and ACT, but not i n a well dose-rel ated manner. As
with the other DTIs, i f monitori ng is requi red, the ecari n cl otti ng ti me (see earl ier) is probabl y the
preferred method.
181

Inhibitors of Xa
These agents (fondaparinux, i drapari nux) act vi a anti thrombin to inhi bi t FXa. The prototype i s
fondapari nux. It i s an i ncreasingl y popul ar al ternative for DVT prophylaxi s,
168
i n part because i ts
very predi ctable uptake (after once-dai ly subcutaneous admini stration) and ki netics make
moni tori ng and dosage adjustment unnecessary.
181, 182
However, these agents have long half-li ves
(fondapari nux, 17 hours; i drapari nux, 80 hours
181
) and there i s no anti dote. Excreti on i s vi a the
kidneys. Therapeuti c doses do not cause changes i n PT, aPTT, or ACT.
181

Acquired Combined Disorders of Platelets and Clotting Factors
with Increased Fibrinolysis
Liver Disease. Chroni c li ver di sease is associ ated wi th abnormal i ti es of all three phases of
hemostasi s: pri mary hemostasis, coagulation, and fi bri nol ysis.
183
Tabl e 10-14 provi des an
overvi ew of these abnormal iti es.
P.237
TABLE 10-14 The Etiology of Hemostatic Abnormalities in Liver Disease
Thrombocytopeni a
Decreased production
Hyperspl eni sm
Increased consumption (DIC)
Impai red platel et functi on
Decreased FDP cl earance
Impai red pri mary hemostasi s. Impai red pri mary hemostasi s occurs as a resul t of both
thrombocytopeni a and i mpai red platelet functi on. The former is l argel y the resul t of decreased
producti on, whi ch in turn i s probably the result of decreased thrombopoi eti n secreti on by the l iver.
Hyperspl eni sm may al so contri bute but i ts rol e has been overemphasi zed. Pl atel et dysfuncti on can
occur when l iver di sease i s suffi cientl y advanced that clearance of FDPs i s impaired or when DIC
compl i cates the coagul ati on di sturbance. The FDPs coat the surface of pl atel ets and i mpai r
aggregation. Ethanol can al so directl y contri bute to pl atel et dysfuncti on by inhi bi ti on of the
synthesi s of ADP, ATP, and thromboxane A
2
. Accordi ngl y, when faced wi th a pati ent wi th l i ver
di sease who is bl eeding, a normal pl atel et count cannot be assurance of i ntact primary
hemostasis. DDAVP may be helpful, but transfusion of pl atelet concentrates may be necessary.
Di sturbances of coagulati on. With li ver disease, factor producti on decreases and consumpti on
increases. The l i ver synthesizes al l of the cl otti ng factors (wi th the probable excepti on of factor
VIII). As with vi tami n K defici ency, hepati c disease fi rst l eads to a defici ency of factor VII since it
has the shortest hal f-li fe. Thereafter, defi cienci es wi l l develop i n factors II, IX, and X. Di etary
defici ency of vitami n K, as may occur in alcoholi cs, and wi th di mi nished secretion of bi le salts
leading to malabsorpti on, wil l exaggerate these defici encies. If i mpai red coagulation is the result
of vi tami n K defi ci ency and not hepati c damage, then parenteral vi tami n K may be helpful i n
restori ng factor l evel s of II, VII, IX, and X. Further deteri orati on of hepatic functi on wi ll affect the
remai ni ng factors, I, V, XI, and XII. Impai red li ver function can al so cause a thromboti c tendency,
whi ch l eads to i ncreased consumpti on of cl otting factors. This occurs for two reasons. Fi rst,
synthesis of the natural anti coagul ants, anti thrombin III, protei n C, and protei n S, may be
di minished thereby al teri ng the bal ance of pro- and anti coagul ant forces, and second, clearance of
acti vated cl otti ng factors from the circul ati on may be impai red thereby al l owi ng persi stent
acti vation of the coagul ati on cascade.
Increased fi brinol ysis. Increased fi bri nol ysis occurs as a resul t of decreased clearance of t-PA from
the ci rculation by the i mpai red l i ver and decreased hepati c synthesis of al pha-2 anti pl asmin.
184

For uncertai n reasons, the production of the natural i nhibi tor of the pl asmin system, PAI-1, is
di minished.
185
The combi nati on of accel erated coagul ati on and i ncreased fi bri nol ysis i n pati ents
with advanced li ver di sease can lead to a persistent, l ow-grade DIC. The rel ease i nto the
ci rculati on of the breakdown products of necroti c hepatocytes may contribute to the devel opment
of DIC.
164

Di agnosis and treatment of coagulation abnormal iti es associated wi th l iver di sease. The i ni tial
laboratory evaluati on shoul d i nclude pl atelet count, PT, aPTT, fibri nogen l evel , and D-di mer. In the
event of thrombocytopenia and cl ini cal bl eedi ng or pendi ng surgery, pl atel et transfusi ons are
appropri ate. If the PT i s prol onged (>1.5 ti mes control), vitami n K shoul d be admi ni stered
specul ati vel y. In the absence of a response to vi tamin K (whi ch requi res a mi nimum of 8 hours),
factor defi ci enci es should be treated wi th FFP wi th attenti on to the possibi l ity of volume overload.
Cryopreci pi tate is appropri ate i n the event of hypofi brinogenemi a (fi bri nogen <100 to 125 g/dL).
Decreased factor synthesi s
Decreased hepatocyte functi on
Vi tamin K defi ci ency (di et, mal absorpti on)
Increased factor consumption
Decreased cl earance of acti vated factors
Decreased synthesis of inhi bitors (protei n C, protein S)
Increased fi bri nol ysi s
Decreased synthesis of al pha-2 anti pl asmin
Decreased cl earance of t-PA
Decreased synthesis of PAI-1
However, cryoprecipi tate does not contai n the vi tami n Kdependent factors. Whi l e antifibrinolyti cs
have been appli ed i n the context of l i ver transplantati on, they shoul d not otherwi se be used for
bl eedi ng associ ated with l iver di sease because of the catastrophi c consequences of admi ni steri ng
these agents in the face of an unrecogni zed DIC.
186

Diagnosis of DIC (see l ater) i s often diffi cult because the laboratory tests used to i denti fy DIC are
al ready abnormal i n pati ents wi th li ver dysfunction. Thrombocytopeni a, prol onged PT and aPTT,
decreased fi bri nogen level , and circul ating FDPs wi l l commonly occur i n the absence of DIC.
El evated D-di mer i s somewhat more specifi c for the occurrence of DIC.
Disseminated Intravascular Coagulation. Detai led revi ews of DIC are avai l abl e.
187, 188
DIC is
characteri zed by excessi ve deposi ti on of fi bri n throughout the vascul ar tree, wi th si multaneous
depressi on of the normal coagul ati on i nhibi tory mechani sms and i mpai red fibri n degradati on. It i s
tri ggered by the appearance of procoagul ant materi al (ti ssue factor or equi valent) i n the
ci rculati on i n amounts suffi cient to overwhel m the mechani sms that normal ly restrain and local i ze
cl ot

formation. That appearance may be the resul t of either extensi ve endothel ial i njury, whi ch
exposes ti ssue factor of fi broblasti c ori gin, or the rel ease of TF i nto the circul ati on as occurs with
amni oti c flui d embolus, extensive soft tissue damage, severe head injury, or any cause of a
systemi c infl ammatory response. Tabl e 10-15 li sts the numerous cl inical condi tions that have been
associated wi th DIC. For reasons not enti rel y cl ear, the nati ve pathways that inhi bi t coagul ation,
anti thrombi n III and the protei n C pathway are si multaneously i nhibi ted. The accel erated process
of cl ot formati on causes both ti ssue ischemia and, ul timately, cri tical depl eti on of pl atel ets and
factors. Si mul taneousl y, the fi bri nol ytic system i s acti vated and pl asmi n i s generated to l yse the
extensi ve fi bri n cl ots. Fibri n degradati on products appear i n the circul ati on. FDPs sti mulate rel ease
of plasmi nogen acti vator inhi bi tor, type 1 (PAI-1), from the endotheli um and thrombolysi s
becomes i mpaired. The FDPs al so i nhi bi t pl atel et aggregati on and prevent the normal crossl inki ng
of fi bri n monomers. Depl eted of platelets and clotti ng factors and i nhi bi ted by FDPs, the
coagulation system fail s and the patient bleeds. Si multaneously, the microvascular occlusion by
fibri n causes ti ssue i schemia, contri buti ng to multi organ fai lure.
P.238
TABLE 10-15 Clinical Conditions Associated with Disseminated Intravascular
Coagulopathy
Sepsi s (Gram + or -)
Viremias
Obstetri c condi tions
Amni oti c fl ui d embol us
Fetal death i n utero
Abrupti o pl acentae
Preecl ampsi a
Extensive tissue damage
Burns
Trauma
Li ver fai l ure
Extensive cerebral injury
Head injury
Stroke
Extensive vascular endotheli al damage
Vasculitis
Preecl ampsi a
Hemolyti c transfusi on reacti ons
Metastati c mali gnanci es
Tabl e 10-15 reveal s that several cli ni cal entiti es that are encountered frequentl y i n anestheti c and
criti cal care practi ce are associ ated with the devel opment of DIC. Sepsis i s the most common
cause. Endotoxi ns or l i popol ysacchari de break down products from Gram-negati ve and -positi ve
bacteri a, respectively, i ncite an i nfl ammatory response that includes the generation of cytoki nes
(tumor necrosis factor alpha, vari ous interl euki ns). These cytokines in turn stimul ate the rel ease
or expression of TF by endothel ial cell s, macrophages, and monocytes, and the DIC sequence i s
initi ated.
Several obstetric condi ti ons can cause DIC. Amniotic fl uid emboli sm, pl acental abrupti on, and fetal
death i n utero result i n the direct rel ease of TF-equival ent materi al into the ci rcul ati on.
Preecl ampsi a i s characteri zed by a systemi c vasculi tis. The associ ated endothel i al damage causes
an i ni ti all y l ow-grade DIC that accel erates as vascul iti s-rel ated damage leads to release of TF from
ischemi c tissues, i n parti cul ar pl acenta.
Large burns, extensi ve traumati c soft tissue i njuries, severe brain injury, and hemol yti c
transfusion reacti ons can al so l i berate TF-equival ent materi al i nto the circul ati on and i nci te DIC.
Certai n mal ignanci es, most notably promyel ocyti c l eukemia and adenocarci nomas, are associated
wi th DIC. However, wi th mal i gnancyassociated DIC, thromboti c manifestati ons are more l ikely to
appear first, whereas with the others menti oned earli er, the hemorrhagic diathesis i s often the
first cl i ni cal mani festation.
A few general condi tions such as acidosis, shock, and hypoxi a are associ ated wi th DIC. Shock
promotes coagul ati on because one of the control mechani sms (rapid blood fl ow) i s compromi sed.
Clearance of acti vated cl otti ng factors i s reduced when bl ood fl ow i s decreased. Aci dosi s and
hypoxia may contribute to both ti ssue and endothel i al damage.
The cl i ni cal mani festati ons of DIC are a consequence of both thrombosi s and bl eedi ng. Bl eedi ng i s
a more common cl ini cal presentati on i n pati ents wi th acute, ful mi nant DIC. Petechi ae,
ecchymoses, epi staxis, gingi val /mucosal bl eeding, hematuri a, and bl eedi ng from wounds and
puncture si tes may be evi dent. Wi th the chroni c forms of DIC, thrombotic mani festati ons are more
li kel y. Organs with the greatest bl ood fl ow, for exampl e, ki dney and brai n, typi cal l y sustai n the
greatest damage. Pul monary functi on may deteriorate as a consequence mi crothrombus
accumulation.
Di agnosis of DIC. There is no absol utel y consi stent constel l ation of l aboratory fi ndings among
routine tests.
187
Increased PT, aPTT, thrombocytopeni a, a decreased fi bri nogen l evel , and the
presence of FDPs and D-di mer may al l be noted. The peri pheral smear may reveal schi stocytes
(fragmented RBCs refl ecti ng the mi croangiopathy that occurs as a consequence of wi despread
fibri n deposi tion). Thrombocytopenia (<100,00/uL) is not al ways evident early i n the process, but
true DIC without sequenti al reduction in pl atel et count i s very unl i kely. PT and aPTT may remain
normal i n spi te of decreasi ng factor levels because of the presence of hi gh l evels of acti vated
factors including thrombin and Xa. Fi brinogen l evel may not be decreased, that i s, <100 mg/dL,
Leukemi a
Snake venoms
initi al l y. Fi brinogen i s an acute phase reactant, whi ch i ncreases in response to stress and the
early consumption of fi bri nogen may simply reduce its l evels to normal . FDPs are a sensi ti ve
measure of fibrinol yti c activity al though they not speci fi c for DIC. D-di mer (which i s a breakdown
product of the crossl inked fi bri n in a mature cl ot) i s somewhat more speci fi c for DIC, but not
enti rely so, and shoul d be measured when that diagnosis i s suspected.
Various other laboratory assays have been empl oyed to support a di agnosi s of DIC,
187
but shoul d
probabl y not be consi dered part of the anesthesi ol ogi st' s routi ne. They i ncl ude level s of
prothrombi n fragments F1+F2 (a marker of prothrombi n conversi on to thrombi n-increased),
thrombi n-ATIII (TAT) compl exes (i ncreased), ATIII (decreased), al pha-2 anti pl asmi n (decreased
by bi ndi ng to excess pl asmi n), protei n C (decreased), pl asmi nogen (decreased), and factor VIII
(decreased i n DIC but normal wi th hepatic fai l ure wi thout DIC).
Treatment of DIC. Treatment shoul d focus on management of the underl yi ng condi tion. Septi cemi a
wil l requi re anti biotic therapy. The obstetri c condi tions are frequently sel f-li mi ted, al though
evacuation of the uterus or hysterectomy may be warranted. Hypovol emi a, aci dosi s, and
hypoxemi a shoul d be corrected to prevent thei r contri buti on to the DIC process. When bl eeding i s
or may become life threatening, the consumpti ve coagul opathy must be treated. Pl atel ets wi l l be
requi red for thrombocytopeni a, for example, <50,000/mm
3
. FFP wi l l repl ace the clotti ng factor
defici encies. Fi bri nogen l evel shoul d be rai sed to >100 mg/dL. When hypofi brinogenemi a i s severe
(<50 mg/dL) cryoprecipi tate may be requi red. Si x units of cryopreci pitate wil l i ncrease fi bri nogen
l evel by approxi matel y 50 mg/dL i n a 70-kg pati ent.
189

Heparin has been advocated. However, the contemporary practi ce is to restri ct its use to only
those situations where thrombosi s i s cl i ni cal ly probl emati c, pri nci pal l y DIC associated wi th
mali gnanci es. There is no proven benefi t i n si tuati ons

in which bleedi ng i s the predominant mani festation. Antifibri nolyti cs have been consi dered.
However, thei r use i n the face of widespread thrombosi s is potenti all y disastrous and they shoul d
not be used. Anti thrombin III concentrates have been admi ni stered. The hope i s that its
administrati on wil l serve to slow the runaway coagul ati on process. However, a benefi cial effect on
outcome from DIC has not been confi rmed (see data revi ew by Levi
188
) and its use shoul d be
viewed as experi mental . An i nsuffici ency i n the protei n C endogenous coagulation inhi bi ti on
system i s thought to contribute to the prothromboti c state i n DIC. Acti vated protei n C has been
shown to decrease mortali ty and organ fai lure i n pati ents wi th sepsi s and that improvement is also
evi dent among pati ents wi th sepsis with overt DIC.
190
Its use shoul d be consi dered i n any
sustained episode of DIC.
190

Cardiopulmonary Bypass and Coagulation. The management of anticoagul ati on and post-CPB
bl eedi ng are addressed i n the chapter on Cardi ac Anesthesi a.
P har macol ogi c Ther apy
Recombinant Factor VIIa (rFVIIa, NovoSeven, Novo Nordisk,
Bagsvaerd, Denmark)
Recombi nant FVIIa was devel oped for, and i ts onl y current on-label use is, the treatment of
patients with hemophi l ia A or B and i nhi bi tors to exogenous FVIII or FIX preparati ons. However, it
is fast becomi ng the hemostati c agent of l ast (and someti mes earl i er) resort i n many cl i ni cal
si tuati ons. Its use has been reported i n trauma, hepatic fai lure, and i n cardiac, prostatic, hepatic,
spi nal , neurologi c, and hepatic transpl antation surgery. It has been used to reverse the
anti coagul ant effect of warfarin and sel ecti ve Xa i nhi bitors. It has been admi ni stered to pati ents
with thrombocytopeni a and both congeni tal (Bernard Soul i er syndrome, Gl anzmann' s
thrombasthenia) and acqui red (uremi a, aspi rin, ADP and IIb/IIIa antagoni sts) pl atel et
abnormali ties.
167

The mechanism of action is uncertai n. It i s clearl y more than an augmentati on of the nati ve
functi ons of FVII. Were that the case, i t woul d not be effecti ve in hemophil i a. However, FVIIa,
whose preferred l i gand i s TF, al so undergoes l ow affi ni ty bi ndi ng to acti vated pl atel ets. In the
P.239
concentrations achi eved with typical rVIIa dosing, the serum level s are several hundred times
those achieved physi ol ogicall y and are probably suffici ent to acti vate Xa on the platelet surface
and to achi eve the thrombi n burst necessary to support the propagation phase of coagul ation
(Fi g. 10-3).
122
Because rVIIa i s an acti ve procoagulant onl y when it i s i n contact wi th TF or
acti vated platelets, unwanted coagul ati on has been very i nfrequent. However, it shoul d be viewed
as rel ati vel y contrai ndi cated in cl i ni cal states in which TF may be ci rcul ati ng freel y, that i s, i n
most of the condi tions associated wi th DIC.
The appropri ate dosing of thi s expensi ve agent (1,020 USD for 1.2 mg at UCSD) is not wel l
defined. The dose used most often in hemophi li a has been 90 ug/kg. However, doses as l ow as 20
ug/kg have been effective in some reports.
191
The current, somewhat arbitrary, al gori thm in pl ace
at the Uni versi ty of Cal iforni a, San Di ego, provi des for the admini stration of 60 ug/kg for profuse
bl eedi ng unresponsi ve to conventi onal therapy specifies. That dose i s rounded to the nearest
1,200 ug i n recogniti on that the agent i s suppl ied in vi als of 1.2 mg. The half-li fe i s ca. 2.5 hours
and repeat dosi ng at 2-hour interval s may be requi red.
Desmopressin
Desmopressi n (DDAVP, 1-deami no-8-D-arginine vasopressi n) i s a synthetic anal ogue off the
natural hormone vasopressin. The actions of vasopressi n are thought to medi ated by two general
cl asses of receptors: V1 receptors, whi ch mediate smooth muscl e contracti on i n the peri pheral
vascul ature, and V2 receptors, whi ch regul ate water resorpti on i n the col lecting ducts of the
nephron. Desmopressin has no acti vi ty at the V1 receptors and accordingl y has vi rtual l y no
vasoconstri ctor effect. It does, however, act at V2 receptors. In fact, desmopressin i s a more
potent antidi ureti c than vasopressi n and has a more prolonged acti vi ty. Desmopressin was used
pri mari l y for cl i ni cal condi tions such as di abetes i nsipi dus unti l its hemostatic effects were
recognized. The hemostati c effects of desmopressin are thought to be medi ated by low-affinity,
extra-renal V2-li ke receptors.
159
Desmopressi n causes rel ease of coagulati on factor VIII:C, vWF,
and ti ssue pl asmi nogen activator. Desmopressin i s thought to rel ease VIII:C from the si nusoi dal
li ver endotheli al cel l s and the vWF from endotheli al cel ls. In mi l d hemophil i a A, desmopressi n can
increase the ci rculating factor VIII:C concentrati on two- to sixfol d. Desmopressi n al so increases
pl atel et adhesi veness and shortens the bleedi ng time, though the mechanism of these effects is
not ful ly understood. It appears to entai l more than a simple increase i n the pl asma vWF l evel .
Indications. Desmopressi n has proven effecti ve treatment for certai n types of vWD and mil d
hemophi l ia (see earli er). Desmopressi n has been shown to reduce the bl eedi ng ti me in a vari ety of
condi ti ons associ ated with platel et dysfuncti on. It produces rapi d and temporary correcti on of
prol onged bl eedi ng ti mes i n uremi c pati ents foll owi ng i ntravenous or i ntranasal admi ni strati on. In
ci rrhotics, desmopressi n increases the concentrati ons of larger vWF mul ti mers and shortens
prol onged bl eedi ng ti mes. Desmopressi n al so decreases the prol onged bleedi ng ti mes caused by
many drugs including aspi rin, nonsteroidal anti -infl ammatory drugs (NSAIDs), dextran,
cl opi dogrel , and hepari n.
159

The prophyl acti c use of desmopressin i n cardi ac surgi cal pati ents has been controversi al . Because
pl atel et dysfuncti on and thrombocytopeni a are common, numerous studies have been performed.
Those that have revealed decreased blood loss or bl ood product admi ni strati on have i nvol ved
pri nci pal ly pati ents who were predi sposed to bl ood l oss, for exampl e, redo procedures
192, 193, 194, 195

and pati ents recei vi ng aspi ri n.
196

Dosage Recommendations. Desmopressi n is commonl y admi ni stered intravenousl y i n a dose of
0.3 mg/kg. The effect of desmopressi n i s al most i mmedi ate. Peak l evel s of factor VIII:C and vWF
are achi eved within 30 to 60 mi nutes and the effect l asts for several hours.
159
Desmopressi n
administrati on may be repeated after 8 to 12 hours. When used in cardiac surgery, the drug
should be admini stered after termi nation of cardi opul monary bypass. Water bal ance shoul d be
moni tored. However, whil e congesti ve cardiac fai lure and hyponatremi a and sei zures in chi ldren
have been reported, cl i ni cal l y si gni fi cant water retenti on i s rel ati vel y uncommon. Desmopressi n
may be admi ni stered as a nasal spray and i s avai l abl e for home use for both mi l d hemophil i acs
and pati ents wi th vWD (type 1). Intravenous admi nistrati on causes a more rapi d ri se in VIII:C
level s and i s therefore preferabl e for acute hemostati c chal l enges.
Antifibrinolytics
Antifibrinol yti c agents have been used frequentl y in situations i n whi ch exaggerated fi brinol ysi s is
suspected of contributi ng to i ntraoperati ve bleedi ng. The si tuati ons i n which favorable effects on
bl ood l oss and repl acement have been reported i nclude cardi opul monary bypass procedures,
hepati c transplantati on, scol i osis surgery, total joi nt replacement, and prostate
surgery.
197, 198, 199, 200, 201
The use of anti fi bri nol ytic mouthwashes in the context of dental
procedures i n pati ents wi th hemophil i a has

been menti oned el sewhere in thi s chapter. There are three commonly avai l abl e anti fi bri nol yti cs.
They are the l ysi ne anal ogues, epsil on-aminocaproic acid and tranexami c aci d, and the serine
protease inhi bitor aprotini n.
Epsilon-Aminocaproic Acid (EACA) and Tranexamic Acid (TXA). EACA and TXA bind to and
produce a structural change i n both pl asmi nogen and pl asmi n. That structural change prevents the
conversion of plasmi nogen to pl asmi n and also prevents pl asmi n from degradi ng fi bri nogen and
fibrin. The dual action of these agents results i n two effects on the hemostati c mechani sm. Fi rst,
decreased synthesi s of plasmi n from pl asminogen results i n reduced fibri nolysi s. The second effect
of these drugs, the inactivation of plasmi n, decreases the formati on of degradati on products of
fibri nogen and fi bri n. These FDPs have anticoagulant effects, i ncludi ng the i nhi biti on of platelet
aggregati on and the i nhi bi tion of the crossl i nki ng of fi bri n strands, whi ch are thereby avoi ded.
Aprotinin. Aprotinin produces i ts anti fi brinolytic effect by a different mechani sm. It is an inhi bi tor
of numerous seri ne protease enzymes i ncl udi ng plasmi n and kall i krei n. The l atter partici pates in
the process of contact acti vation of Factor XII. As a consequence of its i nhi bi ti on of pl asmi n,
aproti ni n, l i ke EACA and TXA, prevents degradati on of fi bri nogen and fi bri n. As i s the case wi th
EACA and TXA, the reducti on i n FDPs shoul d i mprove both pl atel et and coagul ati on function.
However, aproti ni n i s bel ieved to have addi ti onal benefi ci al effects on the infl ammatory response
to CPB, i n general , and on pl atel ets, i n parti cul ar.
202, 203
The mechanism of these effects is not
known wi th certai nty. However, thrombi n i s a serine protease that can activate pl atelets vi a a
protease acti vated receptor (PAR) on the platelet surface.
202
Better preservati on of the GP1b
receptor (which i s necessary for i ni ti al platelet adhesion to vascular defects) has been reported
during CPB in patients who received aprotini n.
204
Aprotinin also appears to reduce neutrophi l
acti vation and transmi gration across capi ll ary endotheli um, perhaps vi a an effect on an endothel ial
PAR
205
and may therefore al so bl unt the neutrophi l medi ated component of the response to
endothel i al i njury.
Use of anti fi brinol ytics i n cardi ac surgery. Meta-anal yses of the many studies of these agents
performed in the context of CPB confi rm that, overall , bl ood l oss and the admi ni stration of
al l ogenei c bl ood i s di mi ni shed by the use of al l three agents.
197, 206, 207
Concern has been expressed
that antifibri nolysi s mi ght l ead to an increased rate of graft occl usi on, myocardi al i nfarcti on, and
renal fail ure. However, the meta-anal yses have not borne out those concerns.
197, 206, 207
There does
not appear to be a cl ear consensus as to whi ch of the three agents i s most appropriate in the
context of CPB. Vari ous authors have argued that EACA and TXA are preferable to aproti ni n
because they are less expensi ve and have apparentl y si mi l ar efficacy.
208, 209
However, the most
recent of those meta-anal yses reported a trend toward a reduced i nci dence of atri al fi bri l l ati on
and a reduced i nci dence of stroke i n pati ents receiving aproti ni n
207
and thi s resul t may well create
a stronger bi as i n favor of aproti nin.
The patterns of use of antifibri nolyti c agents i n cardiac surgery vary substanti al l y among
insti tuti ons. Few appear to use these agents routi nel y for al l CPB procedures. Some reserve thei r
use for si tuati ons more l i kel y to be associ ated wi th post-CPB bl eedi ng, for exampl e, redo
procedures, circul atory arrest procedures. Sti ll others appear to reserve anti fi brinol ytics for
refractory bl eedi ng postcardiopul monary bypass. The l atter seems l ess logical because much of the
acti vation of the hemostatic mechani sm occurs during CPB.
There i s a small but fi ni te rate of al lergi c responses to aproti ni n. Accordi ngl y, a test dose has
P.240
been recommended for patients who have had prior exposure to aproti ni n. The potenti al for
developing sensi ti vi ty has been used as a rational e for avoi ding admi ni strati on of aproti ni n in
ci rcumstances where i t is not cl early indi cated, for example, first ti me coronary artery bypass
graft (CABG), so that i t may be used safel y i n the event of a redo procedure. The ri sk of an
anaphyl acti c/toid response appears to decl i ne very substantial ly wi th reexposure i nterval s greater
than six months.
210

Use of anti fi brinol ytics i n l i ver transplantati on. Accel erated fibri nolysi s occurs commonl y i n
patients undergoing hepatic transpl antation. Thi s is probabl y, i n part, the consequence of
decreased clearance of acti vated cl otting factors by the di seased li ver. More importantl y, hepati c
cl earance ceases enti rel y during the anhepati c phase. In addi ti on, wi th reperfusi on of the donor
li ver, there is an explosive rel ease of t-PA into the systemi c ci rcul ation.
211
Aprotinin, EACA, and
TXA have al l been used and reported to reduce bl ood l oss i n hepati c
transpl antati on.
143, 200, 211, 212, 213
Some advocate prophyl acti c administrati on for all pati ents,
200

whi l e others admini ster these agents only i n response to the demonstration, typicall y by
thromboelastography, of hyperfi bri nol ysis.
143, 214

Use of anti fi brinol ytics i n orthopaedic and other surgery. There have been numerous reports of
reduction of transfusi on requi rement in scol iosi s and joi nt replacement surgery
198, 199, 201
However,
meta-anal ysi s has not confi rmed the efficacy i n noncardiac surgery and the avai l abl e data do not
permi t a determi nati on of the rel ati ve efficacy of EACA, TXA, and aprotinin.
197

CONCLUSIONS
The approach to the bl eedi ng patient requi res a knowl edge of the basi c hemostatic mechanism and
common bl eedi ng di sorders, an abi l ity to interpret coagulati on tests, and an appreciati on of the
ri sks involved wi th blood component therapy. The hemostatic bal ance is del icate and compl ex and
it is the responsi bi li ty of the anesthesiol ogi st to antici pate, prevent, and treat disturbances of that
bal ance. Preoperati ve eval uation must i dentify those pati ents whose inherited or acqui red medical
condi ti ons or whose current medi cations may i nfl uence these processes. Wi th respect to
medicati ons, there are a rapi dly i ncreasi ng number of agents that are admi ni stered speci fi cal ly for
the purpose of alteri ng the hemostati c bal ance, for example, cl opi dogrel , t-PA, lowmol ecul ar-
weight hepari n. As the pati ent proceeds through surgery and the postoperati ve peri od, the
anesthesiol ogi st must determi ne whether bl eedi ng is surgi cal i n nature or the result of a
preexi sti ng or evolving hemostatic defect that wil l require the transfusion of hemostatic bl ood
componentspl atel ets, fresh frozen pl asma, or cryopreci pi tateor the admi ni strati on of
pharmacol ogic agents.
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> Tabl e of Contents > Secti on III - Basi c Pri nci pl es of Pharmacol ogy i n Anesthesi a Practi ce > Chapter 11 -
Basi c Pri nci pl es of Cl i ni cal Pharmacol ogy
Chapter 11
Basic Principles of Clinical Pharmacology
Robert J. Hudson
Thomas K. Henthorn
KEY POINTS
Most drugs must pass through cel l membranes to reach their si tes of acti on.
Consequently, drugs tend to be rel ati vel y li pophi li c, rather than hydrophil i c.
Most drugs are either organi c bases or organi c aci ds. A greater extent of
ioni zati on at physi ologic pH wi l l l i mi t the rapi dity of drug uptake and
di stri bution.
The l iver i s the most important organ for metabol i sm of drugs. Hepati c drug
cl earance depends on three factors: the intri nsi c abi li ty of the li ver to
metabol i ze a drug, hepati c blood fl ow, and the extent of bi nding of the drug to
bl ood components.
The ki dneys el i mi nate hydrophi li c drugs and rel ati vel y hydrophi l i c metaboli tes of
li pophi li c drugs. Renal eli mi nation of l ipophi l ic compounds i s negl i gi bl e.
The cytochrome P450 (CYP) superfami l y i s the most important group of enzymes
invol ved in drug metabol i sm. It and other drug-metaboli zi ng enzymes exhi bi t
geneti c pol ymorphi sm.
In pharmacoki netic model s, the vol ume of di stri buti on quanti fi es the extent of
drug di stri buti on. The greater the affi ni ty of ti ssues for the drug, rel ati ve to
bl ood, the greater the vol ume of di stri buti on.
Generall y, more l i pophil i c drugs are more hi ghl y bound to pl asma proteins and
have greater vol umes of di stri buti on.
In pharmacoki netic model s, the el iminati on clearance quanti fi es the abi l ity of
drug-el i mi nating organs to i rreversi bl y remove drugs from the body. Hi gh val ues
for el iminati on clearance indi cate effi ci ent drug el i mi nation.
All el se bei ng equal, an i ncrease in the vol ume of distri buti on of a drug wi l l
Over four decades ago, Dr. E. M. Papper
1
emphasized the i mportance of understandi ng the
pharmacol ogy of anestheti cs:
Cli nical anaestheti sts have admini stered mi ll i ons of anaestheti cs during more
than a century wi th l i ttl e precise i nformati on of the uptake, distri buti on, and
el i mi nation of inhalational and non-ol ati le anaestheti c agents. Consi deri ng how
serious i s the handicap of not knowi ng those fundamental and i mportant facts
about the drugs they have used so often, the record of success and safety in
cl i ni cal anaesthesia i s an extraordi nary accompl ishment indeed. It can in some
measure be attributed to the accumulated experi ence and successful teachi ng of a
hi ghl y devel oped sense of i ntui ti on from generati on to generation of
anaestheti sts. It can al so be attri buted i n part to the abil i ty to learn by error
after observing pati ents come uncomfortably close to i njury and even to death.
In the l ast few years, however, suffi ci ent fundamental informati on has become
avai labl e to expl ain these cli ni cal successes. The empiri cal process of gi ving an
anaestheti c can be better understood because of the speci fi c data provi ded by the
studi es reported i n thi s symposium and by the work of others whi ch has preceded
them.
Knowl edge of the pri nci pl es of pharmacol ogy and speci fi c properties of i ndi vi dual drugs i s even
more i mportant today. New anesthetics, opioi ds, and neuromuscul ar bl ockers have recentl y
increase i ts el i mi nati on hal f-li fe; an increase i n eli mi nati on cl earance wi l l
decrease eli minati on hal f-li fe.
Pharmacol ogic effects can be anal yzed by both dose-response curves and
concentration-response rel ationships. A disadvantage of dose-response curves i s
the inabi l i ty to di sti nguish between pharmacoki netic and pharmacodynami c
vari abi l ity.
Many drugs bi nd to speci fi c receptors. Receptors are dynamic enti ti es that adapt
to thei r envi ronment by changing i n response to exposure their agonists or
antagonists.
During conti nuous infusi ons of drugs that parti ti on rapi dl y and extensi vely i nto
body ti ssues, the rate of ri se to the eventual steady-state pl asma drug
concentration is determined pri maril y by the hal f-li ves of the earl y distri bution
phases,

not the el i mi nation half-li fe. Thus, drug concentrati ons rapidl y approach the
steady-state concentrati on during the first mi nutes, and then ri se much more
sl owly after the first hour, of the i nfusion.
P.248
Target-control led i nfusi ons are achieved wi th computer-control led i nfusi on
pumps i n Europe and Asi a (not yet FDA-approved in the Uni ted States), and
permi t cli ni cians to make use of the drug concentrationeffect relationship,
optimal l y accounting for pharmacoki netics, and predicting the offset of drug
effect.
become avail able. We do not have the benefi t of decades of experi ence with new drugs, so we
must depend on careful ly conducted i nvesti gati ons for the i nformati on needed to use them
opti mal l y. As Dr. Papper wrote:
If the anaesthetist studies the pharmacol ogy of these agents and understands
thei r pharmacoki netic properti es, he can wi th reasonabl e certai nty predi ct whi ch
of these newer anaestheti c agents wi ll hol d promise for cl i ni cal uti li ty the
cl i ni ci an can spare his patients much danger and hi s own work many hardshi ps i f
he i s aware of the physicochemi cal and pharmacol ogi cal [properti es] of new
agents.
Our patients are al so changi ng. Many have comorbidi ties that were once consi dered
contrai ndi cations to anesthesi a and surgery. Therefore, we must consi der the impact of chronic
di seases and associ ated pharmacotherapy on the responses to drugs administered duri ng the
peri operative peri od. Comprehensi ve knowl edge of cli nical pharmacol ogy i s a prerequi si te to the
practi ce of anesthesi ol ogy.
The fi rst secti ons of this chapter di scuss the biol ogi c and pharmacol ogi c factors that i nfluence
drug absorption, distri buti on, and eli mi nation. Quantitati ve anal ysis of these processes i s
di scussed i n the section on pharmacoki netics. The next secti on presents the fundamentals of
pharmacodynami csthose factors that determi ne the rel ati onship between drug concentrati on and
pharmacol ogic effects. Mechanisms of drug interacti ons are then revi ewed. The fi nal section
di scusses cli nical appl icati on of pharmacoki netics and pharmacodynamics, and systems for del i very
of intravenous drugs. Although speci fi c properti es of drugs are used to il l ustrate basic
pharmacol ogic principl es, detai led i nformation regardi ng the pharmacol ogy of drugs used in
anesthesiol ogy is presented in succeedi ng chapters.
TRANSFER OF DRUGS ACROSS MEMBRANES
Drug absorption, di stri buti on, metabol i sm, and excreti on of drugs al l require transfer of
drugs across cel l membranes. Most drugs must also traverse cell membranes to reach thei r
si tes of acti on. Biol ogi c membranes consi st of a l i pid bil ayer wi th a nonpol ar core and polar
el ements on their surfaces. Proteins are embedded i n the l i pi d bi l ayer and are ori ented si mil arl y,
wi th i oni c, pol ar groups on the membrane surfaces and hydrophobi c groups i n the membrane
interior. The nonpol ar core hi nders the passage of water-solubl e molecul es, so that onl y l i pid-
solubl e molecul es easi ly traverse cel l membranes.
Tr anspor t P r ocesses
Drugs can cross cel l membranes ei ther by passi ve processes or by active transport. Passi ve
di ffusion occurs when a concentrati on gradi ent exi sts across a membrane. The rate of passive
transfer i s directl y proporti onal to the concentrati on gradi ent and the l i pi d sol ubi l i ty of the drug.
Passage of water-solubl e drugs is restri cted to small aqueous channels through the membrane.
These channel s are so smal l that onl y molecul es l ess than 200 D pass through them readi l y.
Capi l lary endothel ial cel l s, except those i n the central nervous system (CNS), permi t transfer of
much larger mol ecul es, such as al bumi n (mol ecular wei ght ~67,000 D). Because of these uni que
features, diffusi on of drugs across capi l lary membranes outsi de the CNS is l i mi ted by blood fl ow,
not by l i pi d sol ubi l i ty.
2

Some drugs are transferred through cel l membranes of hepatocytes, renal tubular cel l s, and
others by acti ve transport. Thi s is an energy-requi ri ng process that i s both speci fi c and saturabl e.
Acti ve transport can move compounds agai nst concentrati on gradi ents. Facil i tated diffusi on shares
some characteri sti cs wi th active transport. It i s also carri er mediated, speci fi c, and saturable, but
does not require energy and cannot overcome a concentrati on gradi ent.
2

Ef f ect s of Mol ecul ar P r oper t i es
Most drugs are too large to pass through aqueous membrane channels and must traverse the
li pi d component of membranes. Al most al l drugs are either weak aci ds or weak bases, and are
present i n both i oni zed and noni oni zed forms at physi ol ogi c pH. The noni oni zed form i s more l i pi d
solubl e and able easil y to traverse cel l membranes. The nonioni zed fracti on of weak aci ds, such as
sali cyl ates and barbi turates, i s greater at l ow pH val ues, so aci di c drugs become more l i pi d sol ubl e
as pH decreases. The nonioni zed fracti on of weak bases l i ke opioi ds and local anestheti cs
increases as the pH becomes more al kali ne. The pK
a
is the pH at whi ch exactl y 50% of a weak aci d
or base i s present i n each of the i oni zed and noni oni zed forms. The cl oser the pK
a
is to the
ambi ent pH, the greater the change i n the degree of ioni zation for a gi ven change i n pH. If there
i s a pH gradi ent across a membrane, drug wi l l be trapped on the si de that has the hi gher i onized
fracti on, because onl y the

noni onized drug i s diffusi ble. Thi s phenomenon i s known as ion trappi ng. The total drug
concentration is greater on the side of the membrane wi th the hi gher i onized fracti on. However, at
equil i bri um, the concentration of noni onized drug wi l l be the same. In most situations, the range
of pH val ues i s too smal l to cause major changes i n the degree of i oni zation. However, there are
major pH changes i n the upper gastroi ntestinal (GI) tract, which can affect drug absorption.
DRUG ABSORPTION
Except after intravenous (i v) injecti ons, drugs must be absorbed into the ci rculation before they
can be del i vered to thei r si tes of acti on. Therefore, absorpti on i s an i mportant determi nant of both
the intensi ty and durati on of drug acti on. Incompl ete absorpti on l i mi ts the amount of drug
reaching the si te of acti on, reduci ng the peak pharmacol ogi c effect. Rapi d absorpti on i s a
prerequisi te for rapi d onset of action. In contrast, sl ow absorption permits a sustained durati on of
acti on because of the depot of drug at the absorpti ve si te. The speed of absorpti on depends on
the sol ubi li ty and concentrati on of drug. Al l drugs must di ssolve i n water to reach the ci rculation.
Consequently, drugs i n aqueous sol uti ons are absorbed faster than those i n sol id formulations,
suspensi ons, or organi c sol vents, such as propylene glycol . A high concentrati on of drug faci li tates
absorpti on. Increased bl ood fl ow to the si te of injecti on i ncreases the rate of absorption.
Decreased bl ood fl ow secondary to hypotensi on, vasoconstri ctors, or other factors sl ows drug
absorpti on. Vasoconstri ctors added to l ocal anestheti cs del ay absorpti on after subcutaneous
injecti on. Thi s prol ongs the durati on of acti on at the si te of injecti on and l essens the chance of
systemi c toxi city.
Rout e of Admi ni st r at i on
In general medi cal practice, drugs are most commonl y admi nistered oral l y. The advantages of oral
administrati on are conveni ence, economy, and safety. Disadvantages i nclude the requi rement for a
cooperati ve pati ent, incomplete absorpti on, and metabol i sm of the drug in the GI tract and li ver
before i t reaches the systemi c ci rcul ation.
2
In anesthesi a, drugs are most frequentl y admini stered
via i v and i nhal ati onal routes. Both permi t rapid and reasonabl y predi ctabl e attai nment of the
desi red blood concentrati on.
Oral Administration
Absorpti on from the GI tract i s hi ghl y vari abl e because of the multi ple factors involved. Tabl ets
and capsul es must disi ntegrate before the drug can di ssolve in the GI l umen. The drug must then
cross the GI epithel i um and pass i nto the portal ci rcul ati on. The most i mportant si te of absorpti on
of al l drugs i s the smal l i ntesti ne, because of i ts l arge surface area and the anatomi c
characteri sti cs of i ts mucosa. The noni oni zed fracti on of weak acids such as barbi turates i s hi gher
at l ow pH val ues, whi ch favors absorption from the stomach. However, the effect of pH on
ioni zati on of acidi c drugs i n the stomach i s offset by the small surface area and thi ckness of the
gastri c mucosa and the rapi di ty of gastri c emptyi ng. Basi c drugs are highly i onized at l ow pH, so
they cannot cross the gastric mucosa. The more al kal i ne pH of the smal l intestine i ncreases the
noni onized fraction of basi c drugs such as opi oi ds, faci l itati ng their absorpti on.
Once drugs enter the portal ci rcul ati on, they must traverse the li ver before reaching the systemic
ci rculati on. Some drugs are extensively metabol ized during thi s ini ti al pass through the l i ver, so
P.249
that onl y a smal l fracti on of the drug reaches the systemic ci rcul ati on. This i s cal l ed the fi rst-pass
effect. Dependi ng on the magni tude of the fi rst-pass effect, the oral dose must be proporti onatel y
larger than the iv dose to achi eve the same pharmacol ogi c response. Metabol i sm of some drugs by
the GI mucosa al so contri butes to the first-pass effect.
3

Sublingual Administration
Drug absorbed from the oral mucosa passes directl y i nto the systemi c circul ati on, el iminati ng the
first-pass effect. Because of the smal l surface area for absorption, this route is efficaci ous onl y for
noni onized, hi ghl y li pi d-solubl e drugs, such as ni troglycerin.
Transcutaneous Administration
Only li pi d-solubl e drugs can penetrate i ntact ski n suffi cientl y to produce systemic effects. Drug
patches appl i ed to the ski n are now widel y used. These systems consi st of an adhesi ve
contai ning a reservoi r of drug that is sl owly rel eased after the patch i s appl i ed, produci ng a stabl e
pharmacol ogic effect. Drugs currentl y admi ni stered in thi s fashi on include scopol ami ne (for moti on
si ckness) and ni troglycerin. Opioi d patches are used for treatment of chroni c pain. Transcutaneous
absorpti on of drugs from patches is passi ve, so the onset ti me i s delayed. Thi s di sadvantage can
be overcome by usi ng an el ectri c current to dri ve ioni zed drugs i nto the ski n, a process is cal l ed
iontophoresi s. Transcutaneous iontophoretic admi ni strati on of fentanyl has been described.
4

Intramuscular and Subcutaneous Injection
Absorpti on of drugs from subcutaneous ti ssue i s rel ati vely slow, permitting a sustained effect. The
rate of absorpti on can be al tered by changes i n the drug formulati on. Exampl es of such
mani pul ati ons are the various preparations of i nsul i n and the additi on of vasoconstrictors to l ocal
anesthetic sol utions. Uptake of drugs after intramuscul ar i njection is more rapi d than after
subcutaneous admi ni strati on because of greater bl ood fl ow. Drugs i n aqueous sol ution are very
readil y absorbed. The effect of drugs i n nonaqueous sol utions, such as diazepam i n propyl ene
gl ycol, is l ess predi ctabl e because of errati c absorption.
5

Intrathecal, Epidural, and Perineural Injection
Intrathecal injecti on of l ocal anesthetics or other drugs cl ose to their si tes of acti on i n the spi nal
cord permi ts the use of very l ow doses, eli mi nating the ri sk of adverse systemi c drug effects. Thi s
is not an advantage of epidural anesthesi a or major peri neural regi onal anesthesi a because of the
greater total dose requi red. The major di sadvantage of these routes of injecti on is the expertise
they requi re.
Inhalational Administration
Uptake of inhalational anestheti cs from the pul monary alveol i to the bl ood i s exceedi ngl y rapi d
because of thei r l ow mol ecul ar wei ght and hi gh li pi d sol ubi l ity, and the l arge total al veolar surface
area, and because al veol ar blood flow is almost equal to cardiac output.
Intravenous Injection
Intravenous i njecti on el i mi nates the need for absorption, so that therapeutic bl ood concentrations
are rapi dly attai ned. Thi s is especiall y advantageous when rapi d onset of action is desired. It al so
si mpl i fi es ti trati on of the dose to i ndi vi dual pati ents' responses. Unfortunately, rapi d onset al so
has i ts hazards; shoul d an adverse drug reacti on or overdose occur, the effects are i mmedi ate and
potential ly severe.

Bi oavai l abi l i t y
Bi oavai l abi l i ty is defined as the fracti on of the total dose that reaches the systemic ci rcul ati on.
Bi oavail abil i ty i s reduced by factors such as i ncomplete absorpti on from the si te of i njecti on or GI
P.250
tract, the fi rst-pass effect, or pulmonary uptake of drugs.
Even after i v i njection, the bi oavail abil i ty of drugs formul ated i n li pi d suspensi ons may be l ess
than 100%. These suspensions contai n smal l l ipi d dropl ets. Some, but not al l , of the drug di ffuses
from the l i pi d dropl ets i nto the pl asma. These dropl ets are taken up by the l i ver and metabol i zed.
Presumabl y, some drug i s also metabol i zed before i t i s rel eased back into the ci rculation. The
bi oavai l abi l ity of the leci thin suspensi on of di azepam is 30% less than that of di azepam in
propyl ene gl ycol , even wi th di rect i v injecti on.
6

DRUG DISTRIBUTION
After absorpti on or i njecti on i nto the systemi c circul ation, drugs are di stributed throughout the
body. Hi ghl y perfused organs, such as the brain, heart, lungs, liver, and kidneys, receive most of
the drug soon after injecti on. Deli very to muscl e, ski n, fat, and other l ess wel l perfused ti ssues is
sl ower, and equi l ibrati on of di stributi on i nto these ti ssues may take several hours or even days.
Capi l lary membranes are freel y permeable i n most ti ssues, so drugs pass qui ckl y i nto the
extracel lul ar space. Subsequent distri buti on vari es according to the physi cochemical properties of
the drug. Di stri buti on of hi ghl y pol ar, water-solubl e drugs such as the neuromuscul ar bl ockers i s
essential ly li mited to extracel lular fl ui d. Li pi d-soluble drugs li ke propofol easi ly cross cel l
membranes and are therefore di stributed much more extensi vel y.
Distri buti on of drugs into the CNS i s uni que. Brai n capi ll ari es do not have the l arge aqueous
channel s typical of capil l ari es in other ti ssues. Consequentl y, di ffusion of water-solubl e drugs into
the brai n i s severel y restri ctedhence the term bl ood-brain barrier. In contrast, di stri buti on of
hi ghl y l i pid-solubl e drugs into the CNS is l i mi ted only by cerebral blood fl ow. For more pol ar
compounds, the rate of entry i nto the brai n i s proporti onal to the l ipi d sol ubi l i ty of the noni oni zed
drug.
Drugs accumulate i n ti ssues because of binding to ti ssue components, pH gradi ents, or uptake of
l i pophi l i c drugs i nto fat. These ti ssue stores can act as reservoi rs that prol ong the durati on of
drug action, either i n the same ti ssue, or by del ivery to the si te of acti on el sewhere after
reabsorpti on i nto the ci rculation.
Bi ndi ng of drugs to pl asma protei ns and erythrocytes i nfl uences di stri buti on to other ti ssues. Only
free, unbound drug can cross capillary membranes. The extent of ti ssue uptake of drugs depends
on the affi ni ty of drug bindi ng to blood constituents, rel ative to the overal l affi ni ty of bi ndi ng to
ti ssue components.
Redi st r i but i on
The rapi d entry and equal l y rapi d egress of l i pophil i c drugs from ri chl y perfused organs such as
the brai n and heart i s referred to as redi stri buti on. Thi s phenomenon i s il l ustrated by the events
that fol low an injecti on of thi opental . The brain concentrati on of thi opental peaks within 1 mi nute
because of hi gh bl ood fl ow to the brai n and the hi gh l i pi d sol ubi l i ty of thiopental . As the drug is
taken up by other, l ess well perfused ti ssues, the pl asma l evel rapi dl y decreases. This creates a
concentration gradi ent from cerebral ti ssue to the blood, so that thi opental qui ckl y di ffuses back
i nto the bl ood, where i t i s redi stri buted to other ti ssues that are stil l taki ng up the drug.
Ul ti matel y, adi pose ti ssue contains much of the drug remai ni ng i n the body because of the hi gh
l i pi d sol ubi l i ty of thi opental . However, recovery from a si ngl e dose of thi opental depends
predomi nantly on redi stributi on of thiopental from the brain to muscle, because of the l arger mass
and greater perfusi on of muscl e compared to adi pose tissue.
7, 8

A si ngl e moderate dose of thi opental (<5 to 6 mg/kg) has a very short durati on of acti on because
of redi stri buti on. If repeated i njections are given, the concentration of thi opental bui lds up i n the
peri pheral tissues, and termi nation of drug action becomes i ncreasingly dependent on the much
sl ower process of drug el i mi nati on. Termi nation of the pharmacologi c effects of other li pophi li c
drugs, such as fentanyl and its deri vati ves, and propofol , i s al so governed by these factors.
P l acent al Tr ansf er
Most drugs cross the pl acenta by si mpl e di ffusi on, so propofol and other l i pi d-sol ubl e drugs with
low mol ecul ar wei ghts are most readil y transferred. Hi ghl y pol ar, water-solubl e compounds such
as the neuromuscular blocki ng drugs do not cross the pl acenta to a si gni fi cant extent. Fetal pH i s
sl i ghtly l ower than maternal pH. Thi s pH gradi ent causes the i oni zed fraction of weak bases, such
as opioi ds and local anestheti cs, to be hi gher in the fetus. Therefore, the fetal total drug l evel
may be hi gher than predi cted from the maternal total drug l evel because of i on trappi ng.
9

Different total drug concentrati ons can al so resul t from differences between mother and fetus in
the extent of drug bi ndi ng to pl asma protei ns. However, regardless of the effects of pH and
protei n bi nding, the concentrati on of free, noni oni zed drug is the same on both si des of the
pl acenta once equi l ibri um is reached. For most drugs, thi s i s the most i mportant form, because i t
has the most pharmacol ogi c acti vi ty.
DRUG ELIMINATION
El iminati on is an inclusive term referring to all the processes that remove drugs from the body.
El iminati on occurs ei ther by excreti on of unchanged drug or by metaboli sm (bi otransformation)
and subsequent excreti on of metabol i tes. The l i ver and ki dneys are the most i mportant organs for
drug eli mi nation. The l i ver eli mi nates drugs pri mari l y by metabol ism to l ess acti ve compounds
and, to a l esser extent, by hepatobi l iary excreti on of drugs or thei r metabol ites. The pri mary role
of the ki dneys i s the excreti on of water-sol ubl e, pol ar compounds. Drugs havi ng these properties,
such as some nondepol ari zi ng neuromuscul ar bl ockers, undergo renal excreti on i ntact.
10
The
kidneys also excrete water-solubl e metaboli tes of drugs that i ni tial ly undergo biotransformati on.
Pul monary excretion is the major route for eli minati on of anestheti c gases and vapors.
The term drug cl earance, or el i mi nation cl earance, descri bes the abil i ty to remove drug from
the blood. Drug cl earance i s the theoreti cal volume of bl ood from whi ch drug i s completely and
irreversibl y removed i n a given ti me i nterval . It i s anal ogous to creati ni ne cl earance, which
quantitati vel y descri bes the abi l ity of the ki dneys to eli minate creati ni ne. Like creati ni ne
cl earance, drug clearance has uni ts of flow, mi ll i l iters per mi nute (mL/min). Many drugs are
cl eared by more than one route, and mul ti pl e eli mi nation pathways are addi tive. Consequentl y,
total drug clearance i s equal to the sum of the cl earances of al l of the el iminati on pathways.
Total drug cl earance can be cal cul ated wi th pharmacoki neti c model s of bl ood concentrati on versus
ti me data. However, cl earance by i ndi vi dual organs and the bi ologic factors infl uenci ng drug
el i mi nation cannot be esti mated from blood concentrati on data alone. Addi ti onal data, such as the

hepati c arteri ovenous drug concentrati on difference or the rate of uri nary excretion of the drug,
are needed to determi ne the contri bution of a specific organ to total drug cl earance.
Hepat i c Dr ug Cl ear ance
Drug cl earance by the l iver i s dependent on three factors: (1) hepati c bl ood fl ow, (2) the
intrinsic abi li ty of the l i ver to irreversibl y eli mi nate the drug from the bl ood, and (3) the
extent of drug bindi ng to pl asma protei ns or other bl ood consti tuents. The interrel ati onshi ps
between these factors have been descri bed wi th the venous equi li brati on model of hepati c drug
cl earance.
11, 12
Accordi ng to thi s model, the unbound concentration of drug in hepatic venous blood
is i n equi li bri um wi th the unbound concentrati on i n hepatocytes. Thi s unbound drug wi thin the
li ver i s avai labl e for el i mi nati on by bi otransformati on or bi li ary excretion.
The venous equi li bration model i s based on two assumpti ons: that hepati c drug cl earance i s
l i mi ted by del i very of drug to the l i ver, and that eli mi nation is a first-order process.
11
By
definiti on, first order means that a constant fracti on of the drug i s eli minated per unit time. The
fracti on of the drug removed from the bl ood passi ng through the l iver i s the hepatic extracti on
rati o, E:
P.251

where C
a
is the mi xed hepatic arteri al portal venous drug concentrati on and C
v
is the mi xed
hepati c venous drug concentrati on. The total hepati c drug cl earance, Cl
H
, is:

where Q is hepatic blood flow. Therefore, hepati c clearance i s a functi on of hepatic bl ood flow and
the abi l ity of the li ver to extract drug from the blood. The abil i ty to extract drug depends on the
acti vi ty of drug-metaboli zi ng enzymes and the capaci ty for hepatobi l i ary excreti on.
The concept of intrinsic cl earance was devel oped to account for the effects of bl ood fl ow and drug
bi nding i n the blood on el iminati on.
11
Intri nsi c cl earance represents the abi li ty of the l i ver to
remove drug from the blood i n the absence of any l i mi tations i mposed by bl ood fl ow or drug
bi nding. The rel ati onship of total hepatic drug cl earance to the extraction rati o and i ntrinsi c
cl earance, Cl
I
, is:

The right-hand si de of Equati on 11-3 indicates that if i ntri nsi c cl earance i s very hi gh (many ti mes
l arger than hepati c bl ood fl ow), total hepati c clearance approaches hepati c bl ood fl ow. On the
other hand, if i ntri nsi c cl earance i s very small , hepati c cl earance wi ll be si mi l ar to intrinsic
cl earance. These rel ati onshi ps are shown in Fi gure 11-1.
Thus, hepati c drug cl earance and extraction are determi ned by two i ndependent vari abl es,
intrinsic cl earance and hepati c bl ood flow. Changes in either wi l l change hepati c cl earance.
However, the extent of the change depends on the i ni tial i ntri nsi c cl earance. If the i nherent abi l ity
of the li ver to eli mi nate a drug (intri nsic cl earance) i s doubl ed, then the extracti on ratio al so
increases, but not necessaril y to the same extent. The extracti on ratio and intri nsi c cl earance do
not have a si mple, l i near rel ati onship:
FIGURE 11-1. The relationshi p between hepatic extracti on rati o, intri nsi c cl earance, and
hepati c cl earance at the normal hepati c bl ood fl ow of 1.5 L/min. For drugs with hi gh intri nsic
cl earance (>25 L/min), i ncreasi ng intri nsi c cl earance has li ttl e effect on hepati c extraction
and total hepatic cl earance. The inset demonstrates the rel ati onshi p at l ow val ues of i ntri nsi c
cl earance on an expanded scale. (Repri nted with permi ssi on from Wi l ki nson GR, Shand DG: A
physi ol ogi c approach to hepatic drug cl earance. Cl in Pharmacol Ther 18:377, 1975.)

If the i ni ti al intri nsic cl earance is smal l rel ati ve to hepati c blood fl ow, then the extracti on ratio i s
al so smal l, and Equati on 11-4 indicates that doubl i ng i ntrinsi c clearance wil l produce an al most
proporti onal increment in the extraction rati o, and, consequentl y, cl earance. However, if i ntri nsi c
cl earance is much greater than hepati c bl ood flow, a twofol d change i n i ntrinsic cl earance has a
negli gi bl e effect on the extracti on rati o and drug clearance. In nonmathemati cal terms, high
intrinsic cl earance i ndicates effi cient hepati c eli mi nation. It i s hard to enhance an al ready effici ent
process, whereas i t i s rel ati vel y easy to i mprove on i neffici ent drug cl earance because of l ow
intrinsic cl earance.
The effect of changes i n hepati c bl ood fl ow al so depends on the magni tude of i ntri nsi c clearance.
If extracti on and i ntri nsi c clearance are hi gh, a decrease i n hepati c bl ood flow causes a smal l
increase i n the extracti on ratio (Fi g. 11-2) that is insufficient to offset the effects of reduced
hepati c fl ow (Eq. 11-4). Consequently, changes i n hepati c blood fl ow produce vi rtual l y
proporti onal changes in clearance of drugs wi th hi gh extracti on ratios (Fi g. 11-3). For drugs
havi ng a l ow intri nsi c cl earance, a decrease i n hepati c bl ood fl ow i s associated wi th a larger,
al most proporti onal i ncrease i n the extracti on ratio (see Fi g. 11-2). Thi s largel y offsets the effects
of changes i n bl ood fl ow, so that clearance of drugs wi th l ow extraction rati os i s essenti all y
i ndependent of hepati c bl ood fl ow (see Fi g. 11-3).
FIGURE 11-2. The effect of changes i n hepati c bl ood flow on extracti on of drugs wi th
di fferent extraction ratios. The extraction rati os at the normal hepati c bl ood fl ow of 1.5 L/mi n
are above the correspondi ng curves. (Reprinted with permission from Wood AJJ: Drug
di sposi ti on and pharmacokineti cs. In Wood M, Wood AJJ [eds]: Drugs and Anesthesi a
Pharmacol ogy for Anesthesi ologi sts, p 27. Balti more, Wi l li ams & Wal ki ns, 1990. After
Wi l ki nson GR, Shand DG: A physi ol ogic approach to hepati c drug cl earance. Cl i n Pharmacol
Ther 18:377, 1975.)
Hepati c cl earance of drugs wi th extracti on rati os 30% i s i ndependent of changes i n l i ver bl ood
flow, but very sensi ti ve to the l iver' s abi l ity to metabol i ze the drug, whi ch can vary as a resul t of
pathologi c condi tions, i nhi biti on or i nducti on of drug-metaboli zi ng enzymes, or interi ndi vi dual
di fferences. In contrast, vari ati ons of hepati c cl earance of drugs wi th hi gh extracti on ratios
(>70%) are determined pri maril y by l i ver blood fl ow. Drugs wi th i ntermediate extracti on ratios,
between 30 and 70%, share characteristi cs wi th both the other groups. Drugs can be cl assi fi ed as
havi ng either high, i ntermedi ate, or l ow extracti on ratios (Tabl e 11-1).
FIGURE 11-3. The effect of changes in hepati c bl ood fl ow on hepatic clearance of drugs wi th
di fferent extracti on ratios. The extracti on ratios for each curve at 1.5 L/mi n flow are
i ndi cated. The arrows indi cate the normal physi ol ogic range of hepatic bl ood fl ow. (Repri nted
with permission from Wood AJJ: Drug disposi tion and pharmacoki netics. In Wood M, Wood AJJ
[eds]: Drugs and Anesthesi aPharmacol ogy for Anesthesi ologi sts, p 27. Balti more, Wi l li ams
& Wi lkins, 1990. After Wi l ki nson GR, Shand DG: A physi ol ogic approach to hepati c drug
cl earance. Cl in Pharmacol Ther 18:377, 1975.)
TABLE 11-1 Classification of Drugs Encountered in Anesthesiology According to
Hepatic Extraction Ratios
LOW INTERMEDIATE HIGH
di azepam
lorazepam
methadone
phenytoin
rocuroni um
theophyll i ne
thiopental
al fentani l
methohexital
midazolam
vecuroni um
al prenol ol
bupi vacaine
di l ti azem
fentanyl
ketamine
li docaine
meperi di ne
metoprol ol
morphine
Bi ndi ng of drugs to pl asma proteins and other bl ood components may al so affect drug cl earance.
Whether or not drug bi ndi ng i nfluences drug cl earance depends on the extracti on ratio and the
extent of binding. Three cl asses of hepatic cl earance can be defi ned by i ntegrati ng the effects of
drug bi ndi ng i n the bl ood and the extraction rati o.
13
Cl earance of drugs wi th hi gh extracti on ratios
is fl ow l i mi ted because i t depends onl y on

hepati c perfusi on and i s not affected by changes i n drug bi ndi ng or i ntri nsi c clearance. The
combi nation of a l ow extracti on ratio and a hi gh free fraction resul ts in capaci ty-li mi ted, bi ndi ng-
insensi tive cl earance, whi ch i s affected by changes in i ntri nsi c cl earance but i s not significantly
i nfl uenced by bi ndi ng or hepati c perfusi on. Drugs wi th l ow extracti on rati os and l ow free fracti ons
have capaci ty-li mi ted, bi ndi ng-sensi ti ve cl earance, whi ch i s not greatl y affected by changes i n
hepati c bl ood fl ow but depends on both i ntri nsi c cl earance and the free drug concentration.
El iminati on of drugs wi th i ntermedi ate extracti on ratios and bi ndi ng is i nfluenced by al l three
bi ologi c factorshepati c blood fl ow, i ntri nsi c clearance, and the free drug concentrati on i n the
bl ood. The relative importance of these three factors cannot be predi cted unl ess the extraction
rati o and the unbound fracti on in the blood are known.
Physiologic, Pathologic, and Pharmacologic Alterations in Hepatic
Drug Clearance
At rest, approxi mately 30% of cardi ac output perfuses the l iver. The hepati c artery provides
roughl y 25% of total hepatic flow, with the remai nder suppl i ed vi a the portal vei n. Many
physi ol ogi c and pathol ogi c condi ti ons al ter hepati c bl ood fl ow, but there i s l ittle i nformation
regarding the effect of these changes i n bl ood fl ow on hepati c drug cl earance. The spl anchnic
ci rculati on responds to a vari ety of sti mul i, and splanchni c flow is often sacri fi ced to meet the
demands of other tissues.
Movi ng from the supi ne to the upri ght posi ti on decreases cardi ac output, which produces a refl ex
increase i n systemi c vascul ar resistance. The spl anchnic ci rcul ati on parti ci pates i n this generali zed
vasoconstri cti on, whi ch decreases hepati c bl ood fl ow by 30 to 40%.
12
Cl earance of al dosterone,
whi ch has a high hepatic extracti on rati o, i s decreased i n the upri ght posi ti on.
12
Postural changes
probabl y al so i nfluence clearance of drugs wi th hi gh hepatic extraction ratios, but thi s has not
been systematicall y investi gated.
Exerci se, heat stress, and hypovolemia all decrease splanchnic blood flow i n proporti on to the
associated increase i n heart rate, whi ch suggests that these responses are medi ated by the
sympatheti c nervous system.
12
As expected, these conditi ons decrease clearance of i ndocyani ne
green, whi ch has a high hepatic extracti on ratio. In contrast, the clearance of anti pyri ne, a drug
with a low extraction ratio, i s not affected by these condi ti ons.
14

Decreases in cardi ac output cause refl ex spl anchni c vasoconstri cti on, whi ch reduces hepati c blood
flow in proportion to the reducti on i n cardi ac output.
15
Lidocai ne cl earance i s reduced i n pati ents
naloxone
ni fedi pi ne
propofol
propranolol
sufentani l
verapami l
Drugs el i mi nated pri mari l y by other organs are not i ncluded i n thi s tabl e.
P.252
with congestive cardiac fail ure.
16
Consequentl y, i f usual doses of li docai ne are given to pati ents
wi th heart fai l ure, the ri sk of l i docaine toxi city is increased. Marked

reduction in hepatic bl ood fl ow causes hepatocel l ul ar dysfunction; therefore, severe congestive
heart fail ure decreases drug clearance by reduci ng both intri nsic cl earance and hepati c bl ood
flow.
17
Cardi ovascul ar col l apse severel y compromises both li ver bl ood fl ow and hepatocel l ul ar
function.
12
In experimental hemorrhagic shock, cl earance of li docai ne was decreased by 40%,
whereas hepati c bl ood flow decl ined by 30%.
18
The reducti on i n cl earance i s too large to be
caused sol el y by decreased hepatic perfusion, implying a concomi tant reduction in i ntri nsi c
cl earance secondary to hepati c i schemia.
Li ver di sease can decrease drug cl earance because of hepatocel lular dysfuncti on, al tered hepati c
bl ood flow, or both.
12
Ci rrhosi s reduces cl earance of drugs wi th hi gh extracti on ratios, i ncl udi ng
li docaine,
16
meperi di ne,
19, 20
and propranol ol .
21
Thi s is secondary to decreased hepatic perfusi on,
whi ch can be the resul t of reduced total l iver bl ood fl ow, i ntrahepati c shunti ng, or extrahepatic
shunti ng of portal venous bl ood.
12
Portosystemic shunti ng i ncreases the bioavail abi l i ty of orall y
administered drugs wi th high extracti on rati os.
12
Ci rrhosi s also decreases clearance of drugs wi th
low extraction rati os, such as diazepam,
22, 23
because of i mpai red hepatocel lular functi on, whi ch
decreases intri nsic cl earance. Acute vi ral hepatiti s reduces the cl earance of drugs with both hi gh
(meperi dine,
24
li docai ne
25
) and l ow (di azepam
22
) hepati c extracti on ratios. These observati ons
i ndi cate that both acute and chroni c l iver di seases affect l i ver functi on and bl ood fl ow i n a paral l el
fashi on. Consequently, i n chroni c therapy, doses of any drug cl eared by the l i ver should be
reduced i n pati ents with hepati c di sease.
Drugs that alter spl anchnic hemodynami cs affect cl earance of hi ghl y extracted drugs. Propranol ol
decreases hepati c blood fl ow, thus decreasing i ts own cl earance
12
and the cl earance of
concomi tantl y admi ni stered li docai ne.
26
The volatil e anestheti cs al l decrease hepati c bl ood fl ow,
al though isoflurane does so to a lesser extent than halothane or enfl urane.
27, 28
Intra-abdominal
surgery causes a further decrease in hepatic perfusi on.
27
Hypotensi on produced by spi nal
anesthesia reduces spl anchnic bl ood flow.
29
In contrast to the volatil e anestheti cs, ni trous oxide,
opi oi ds, and barbi turates have l i ttl e effect on hepati c bl ood fl ow.
12
Al though they are potenti al l y of
great cl ini cal importance, the effects of these hemodynamic alterations have not been thoroughl y
investi gated. It is l ogical to assume that the clearance of drugs wi th hi gh hepati c extraction rati os
wi l l be reduced duri ng anesthesi a and surgery.
Renal Dr ug Cl ear ance
Although the kidneys do metaboli ze drugs, thei r major function in drug el i mi nati on i s to
excrete water-solubl e drugs, and metabol i tes produced el sewhere (primaril y the l iver), i nto
the urine. Renal cl earance of drugs i s determi ned by the net effects of three processes:
gl omerul ar fi l trati on, tubular secreti on, and tubul ar reabsorpti on.
30, 31

Gl omerul ar fi l trati on cannot el i mi nate drugs effi ci entl y. The glomerul ar fil trati on rate (GFR) i s
approxi mately 20% of renal pl asma fl ow.
32
Consequentl y, even i f none of the drug i s bound to
pl asma protei ns, only about 20% can be removed by gl omerul ar fi l trati on. Drug bi ndi ng to pl asma
protei ns and erythrocytes reduces the amount fi ltered, because onl y unbound drug can pass
through the gl omerular membrane i nto the renal tubul e. If a drug i s nei ther secreted nor
reabsorbed by the renal tubul es, then renal drug cl earance wi ll be equal to glomerul ar cl earance.
Drugs and metabol ites excreted in thi s fashion have l ow renal extraction rati os, and thei r renal
cl earance depends on the degree of bi ndi ng to bl ood constituents. Therefore, protein bi ndi ng is a
major determi nant of both hepati c and renal cl earance of drugs wi th l ow extracti on rati os.
Proxi mal renal tubul ar cel ls have two discrete mechani sms for secreti ng acidi c and basic organi c
compounds.
30
These processes are carri er medi ated, so they are saturabl e. Drugs wi th simi lar
physi cochemi cal characteristics compete for avai l abl e carrier mol ecules and interfere wi th each
other's secretion. If a drug i s very avidl y secreted by tubul ar cel ls and not subsequentl y
reabsorbed, i t wi l l have a hi gh renal extracti on ratio. Renal clearance of such drugs is l argel y
determi ned by the magni tude of renal blood fl ow.
30
Thi s is anal ogous to the i mportance of l iver
P.253
bl ood flow in the cl earance of drugs with hi gh hepati c extracti on ratios.
Clearance of drugs fil tered by the gl omerul i or secreted by the proxi mal renal tubul e may be
decreased by subsequent reabsorpti on from the renal tubul e. If thi s i s extensi ve, the drug wi l l
have a very l ow renal extraction ratio and negli gi ble renal clearance. Tubul ar reabsorption occurs
by acti ve, carri er-mediated transport that i s simil ar to acti ve secreti on. Drugs can al so be
reabsorbed by passi ve di ffusi on across the tubul ar epi theli um. The progressive reabsorpti on of
water from the renal tubul e faci l itates passi ve reabsorpti on of drugs by creati ng a tubule-to-
pl asma concentrati on gradi ent for the drug. Consequentl y, ol i guria can decrease renal drug
cl earance.
31
Passive reabsorpti on i s determi ned by the l i pi d sol ubi li ty and degree of i oni zati on of a
drug. Hi ghl y l i pophil i c drugs li ke propofol are al most compl etel y reabsorbed and have vi rtual l y no
renal clearance. For l ess l ipophi l ic drugs, the degree of i onizati on i s a major determi nant of the
extent of passive reabsorpti on because onl y the noni oni zed drug readi l y diffuses across the renal
tubul ar epi theli um. Uri ne pH can range from 4.5 to 8.0, which can cause l arge changes i n the
ioni zed fracti on of weak acids and bases, particul arl y if the pK
a
is cl ose to or wi thi n thi s range.
Uri ne pH can be manipul ated to i ncrease renal drug cl earance after overdoses.
Physiologic, Pharmacologic, and Pathologic Alterations in Renal
Drug Clearance
In adul ts, renal bl ood fl ow i s approxi mately 1,200 mL/mi n, so renal pl asma fl ow i s approxi matel y
700 mL/mi n. About one-fifth of the pl asma is fi ltered by the gl omerul us, resulti ng i n an average
GFR of 125 mL/min. Renal blood fl ow and GFR are autoregul ated, so they remain fai rl y constant as
long as mean arterial pressure is between 70 and 160 mmHg.
32
Consequentl y, renal drug
cl earance is more constant than hepatic cl earance, because renal bl ood flow usuall y vari es less
than hepati c bl ood fl ow.
The capacity for excreti ng endogenous and exogenous compounds depends on the number of
functi onal l y i ntact nephrons. Decreased gl omerul ar fi l trati on i s accompani ed by a paral l el l oss of
renal tubul ar functi on. Therefore, clearance of endogenous creati ni ne, whi ch i s essenti al l y
equival ent to the GFR, can be used to esti mate overall renal functi on. It fol l ows that renal drug
cl earance is proporti onal to creati ni ne cl earance, even for drugs eli mi nated pri maril y by tubular
secreti on. Thi s pri nci pl e has been used to devel op nomograms for reduci ng drug doses according
to the creatinine clearance in the presence of renal dysfuncti on.
33
Many drugs, including
li docaine,
34
pancuroni um,
35
and meperi di ne,
36
have pharmacol ogi cal l y acti ve metabol i tes that are
excreted by the kidneys. Therefore, both parent drugs and thei r metabol ites can contribute to
drug toxi city i n pati ents wi th renal fai l ure.
Renal function decreases progressivel y wi th age. By age 80 years, creati ni ne cl earance is reduced
by about 50%.
37
Despi te the age-rel ated decrease i n glomerul ar fil trati on rate, serum creati ni ne is
not el evated in heal thy el derl y patients because muscle mass, the pri mary source of creati ni ne,
al so decreases with age. Therefore, even if serum creati ni ne i s normal, renal cl earance of drugs i s
reduced i n el derl y pati ents.
The ki dneys el i mi nate many drugs encountered i n anestheti c practi ce (Tabl e 11-2). In renal
fai l ure, doses of these drugs must be reduced to avoi d adverse effects. In addi ti on to renal

di sease, other pathologi c processes can impai r ki dney functi on. Low cardi ac output states reduce
renal bl ood fl ow, gl omerul ar fil trati on, and, consequentl y, renal drug cl earance.
30
Advanced
hepati c ci rrhosis al so i nterferes wi th renal function,
30
and thi s combi nation, the hepatorenal
syndrome, reduces el imi nati on of al most al l drugs.
P.254
TABLE 11-2 Drugs with Significant Renal Excretion Encountered in Anesthesiology
Ami noglycosides Pancuroni um
DRUG METABOLISM
Unl ess tolerance develops, termi nation of drug acti on depends on removal of the drug from its
si tes of acti on. (Tolerance i s defi ned as decreasi ng pharmacol ogi c effect wi th sustai ned exposure
to a drug. It resul ts i n hi gher doses [or concentrati ons] bei ng requi red to mai ntai n a gi ven effect.
The mechani sms responsibl e for tol erance are di verse. They i ncl ude adapti ve or refl ex responses
to drug effects that al ter the observed effects and alterations in the number or sensi tivity of
receptors.) Most operati ons are completed wi thi n a rel ati vel y short period (durati on of anesthesi a
<2 to 3 hours). In such cases, drug redi stribution i s the primary mechani sm responsi ble for
reduci ng drug concentrati ons in the bl ood. Thi s, in turn, establ ishes the concentration gradi ent
requi red for removal of drugs from their sites of acti on. Drug metabol ism is more i mportant in
termi nati ng effects of drugs that are not extensivel y redi stri buted, or when l arger, or repeated,
doses are admi ni stered. Thi s coul d occur after prolonged anesthesi a (>4 to 5 hours).
Consi deration of drug metabol ism is al so i mportant i n the therapeutics of cri tical care and pai n
therapy.
Drugs must usual ly cross bi ologi c membranes to reach thei r sites of action, so most are rel ati vel y
li pi d sol ubl e. Thi s property makes thei r excretion difficult, because li pophi l i c compounds are
readil y reabsorbed from the gut and the di stal renal tubul e. Metabol i sm, or bi otransformation of
drugs to more pol ar, water-solubl e compounds, faci l itates the ul ti mate excretion of metaboli tes i n
the bil e and urine. Bi otransformation is a protecti ve mechanism for preventi ng the accumul ati on
and resul tant toxi ci ty of vari ous l i pophi li c compounds acquired from the environment.
Metabol ites are usual l y l ess acti ve pharmacol ogicall y than the parent drug. However, this i s not
al ways true. Many benzodi azepi nes have metabol ites that have si mil ar pharmacol ogi c effects.
5
The
anal gesi c effects of codeine are a result of its bi otransformati on to morphine. Metaboli tes can al so
be toxi c. The major metabol ite of meperidi ne is normeperidi ne, whi ch can cause sei zures.
36
If
metaboli tes are pharmacologicall y active or toxi c, further bi otransformati on or excreti on i s
requi red for terminati on of their effects.
Metabol ism of drugs and other exogenous compounds, known col lectivel y as xenobi oti cs, occurs
pri mari l y i n the li ver. Other organs, including the kidneys, lungs, gut, and ski n, al so metabol ize
drugs, but extrahepati c bi otransformati on i s quantitati vel y unimportant i n most i nstances.
Bi ot r ansf or mat i on React i ons
Bi otransformati on reacti ons have cl assical l y been di vi ded i nto two groups. Phase I reacti ons al ter
the molecul ar structure of xenobiotics by modi fying an exi sti ng functi onal group of the drug, by
addi ng a new functi onal chemi cal group to the compound, or by spl i tti ng the ori ginal mol ecul e into
two fragments. These changes i n mol ecul ar structure resul t from oxidation, reducti on, or
hydrol ysi s of the parent compound. Phase II reacti ons consi st of the coupl i ng, or conjugati on, of a
vari ety of endogenous compounds to pol ar chemi cal groups. The pol ar chemi cal group at whi ch
Atenol ol
Cephal ospori ns
Di goxi n
Doxacuri um
Edrophonium
Nadol ol
Neosti gmi ne
Penici l li ns
Pi pecuronium
Procai nami de
Pyri dosti gmi ne
Rocuronium
Quinol ones
conjugati on occurs is frequentl y the resul t of a previ ous Phase I reaction, hence the Phase I
Phase II nomencl ature. However, not al l drugs are el iminated by thi s sequenti al pathway of
bi otransformation. Oxidation of thiopental produces i ts major metabol i te, thiopental carboxyl i c
acid,
38
whi ch undergoes renal excretion without undergoing a Phase II bi otransformati on.
Morphi ne i s di rectl y conjugated to form morphine gl ucuronide wi thout first undergoi ng a Phase I
reacti on.
Phase I Reactions
Phase I reactions may hydrolyze, oxi dize, or reduce the parent compound. Hydrol ysi s is the
inserti on of a mol ecul e of water i nto another mol ecule, whi ch forms an unstabl e i ntermedi ate
compound that subsequently spli ts apart. Thus, hydrol ysis cl eaves the origi nal substance i nto two
separate molecul es. Hydrol yti c reacti ons are the primary way ami des, such as li docai ne and other
amide l ocal anestheti cs, and esters, such as succi nylchol ine, are metabol i zed.
Many drugs are bi otransformed by oxidative reacti ons. Oxi dati ons are defi ned as reacti ons that
remove el ectrons from a molecul e. The common el ement of most, i f not all , oxi dati ons is an
enzymati cal ly medi ated reaction that i nserts a hydroxyl group (OH) i nto the drug molecul e.
39
In
some i nstances, thi s produces a chemi cal l y stabl e, more pol ar hydroxylated metaboli te. However,
hydroxyl ati on usual ly creates unstable compounds that spontaneousl y spl it i nto separate
mol ecul es. Many di fferent bi otransformati ons are effected by this basi c mechani sm. Deal kyl ati on
(removal of a carbon-contai ning group), deami nation (removal of ni trogen-contai ning groups),
oxi dati on of nitrogen-contai ning groups, desul furati on, dehal ogenati on, and dehydrogenati on al l
fol l ow an i ni tial hydroxyl ati on.
39
Hydrol ysi s and hydroxyl ati on are comparabl e processes. Both
have an i ni tial , enzymaticall y medi ated step that produces an unstabl e compound that rapidl y
di ssociates i nto separate molecul es.
Some drugs are metabol i zed by reductive reacti ons, that i s, reacti ons that add el ectrons to a
mol ecul e. In contrast to oxi dati ons, where el ectrons are transferred from NADPH to an oxygen
atom, the el ectrons are transferred to the drug mol ecule. Oxi dati on of xenobi otics requi res
oxygen, but reducti ve bi otransformati on i s inhi bi ted by oxygen, so i t is facil i tated when the
intracel lular oxygen tensi on i s low.
40

The Cytochromes P450. The cytochromes P450 (CYP) are enzymes that catal yze most
bi otransformations. These hemoproteins, when reduced by carbon monoxi de, have an absorpti on
spectrum wi th a peak at the 450-nm wavelength, hence their name. CYP are i ncorporated into the
smooth endopl asmi c reticulum of hepatocytes. The endoplasmi c reticulum i s an intracel l ul ar
network of tubul es si mi l ar i n ul trastructure to cel lul ar membranes. Other ti ssues, i ncl udi ng the
lungs, ki dneys, and ski n, al so contai n CYP, but i n much smal ler amounts.
41
Upper intestinal
enterocytes contain high concentrati ons of CYP, whi ch contri butes to the fi rst-pass effect by
metabol i zi ng drugs absorbed from the GI tract before they reach the systemi c circul ati on.
3, 41, 42

CYP are capabl e of metabol i zi ng hundreds of compounds, i ncluding endogenous substances such

as steroi ds and ami nes, as wel l as drugs and other exogenous compounds acqui red from the
envi ronment.
42
CYP i soenzymes oxi dize thei r substrates pri mari ly by the inserti on of an atom of
oxygen in the form of a hydroxyl group, whil e another oxygen atom i s reduced to water.
CYP i s a superfami l y of rel ated enzymes.
43
More than 2,000 CYP isoenzymes have been
identi fi ed i n pl ants, animal s, and mi crobi ologic species.
44
In humans, 57 CYP members,
grouped i nto 42 subfami l ies and 18 famil i es according to ami no acid sequences, have been
identi fi ed.
45
CYP fami l i es share
40% sequence identi ty and are denoted by an Arabi c numeral

(i .e., CYP2, CYP3). Subfami l i es share 55% i denti ty and are desi gnated sequenti al l y usi ng a l etter
(CYP3A, CYP3B, etc.). Indi vi dual members of a famil y are assi gned a second numeral (such as
CYP3A4, CYP3A5).
45

Several constituti ve CYPs are i nvol ved in the producti on of vari ous endogenous compounds, such
as cholesterol, steroi d hormones, prostagl andi ns, and eicosanoi ds.
45
In additi on to the constituti ve
forms, producti on of vari ous CYPs can be i nduced by a wi de variety of xenobi oti cs.
46
CYP drug-
metaboli zi ng activity increases after exposure to various exogenous chemicals, i ncl udi ng many
P.255
drugs.
44, 47
The number and type of CYPs present at any ti me depends on exposure to di fferent
xenobi oti cs. The CYP system i s abl e to protect the organi sm from the del eteri ous effects of
accumulation of exogenous compounds because of i ts two fundamental characteristicsbroad
substrate speci fi ci ty and the capabi li ty to adapt to exposure to di fferent substances by i nducti on
of different CYP i soenzymes.
Bi otransformati ons can be inhi bi ted i f different substrates compete for the drug-bi nding site on
the same CYP member. The effect of two competing substrates on each other' s metaboli sm
depends on their relative affi ni ti es for the enzyme. Bi otransformati on of the compound wi th the
lower affinity is inhi bi ted to a greater degree. Thi s is the mechani sm by whi ch the H
2
receptor
antagonist cimeti di ne i nhi bits the metabol ism of many drugs, i ncludi ng meperi di ne, propranol ol ,
and di azepam.
48, 49, 50
The newer H
2
antagoni st rani ti di ne has a di fferent structure and causes
fewer cl i ni cal ly significant drug i nteracti ons.
51
Other drugs, notabl y cal ci um channel bl ockers and
anti depressants, al so i nhibi t oxidative drug metabolism in humans.
52, 53
Informati on regardi ng both
i nducti on and i nhi bi ti on of di fferent CYP i soenzymes by specifi c compounds has become
avai labl e.
53
Thi s informati on all ows cl i ni cians to predi ct whi ch combinati ons of drugs are more
li kel y to lead to cl i ni cal ly significant i nteracti ons because of al tered drug metabol ism by the
cytochrome P450 system.
CYP i soenzymes from fami l i es 1, 2, and 3 effect 70 to 80% of al l Phase I metaboli sm of al l
cl i ni cal ly used drugs.
54
CYP3A4 is the single most i mportant enzyme, accounting for 40 to 45% of
al l CYP-medi ated drug metabol i sm.
54
The CYP2 famil y accounts for a si mi lar percentage of CYP-
medi ated bi otransformati on.
54
Tabl es 11-3 and 11-4 group drugs encountered i n anestheti c
practi ce accordi ng to the CYP i soenzymes responsibl e for thei r biotransformati on.
41, 55
Some drugs
are metabol i zed by more than one CYP isoenzyme.
TABLE 11-3 Substrates of CYP3A4 Encountered in Anesthesiology
Acetaminophen
Al fentani l
Al prazol am
Bupi vacai ne
Ci sapri de
Codeine
Cortisol
Diazepam
Di gi toxi n
Di l ti azem
Fel odi pi ne
Fentanyl
Grani setron
Li docai ne
Methadone
Mi dazolam
Ni cardipi ne
Ni fedi pi ne
Omeprazol e
Pantoprazole
Ropi vacaine
Stati ns
Sufentani l
Verapami l
Warfari n
Compil ed from references 41 and 55.
TABLE 11-4 Substrates of the CYP2 Family Encountered in Anesthesiology
CYP2D6 captopri l
codeine
hydrocodone
metoprol ol
ondansetron
propranolol
ti molol
CYP2C9 di cl ofenac
ibuprofen
indomethaci n
CYP2C19 di azepam
omeprazol e
propranolol
Inducti on and i nhi bi ti on of hepati c drug-metaboli zi ng enzyme systems change the intri nsi c hepati c
cl earance of drugs. Thi s i s most i mportant for drugs with low hepati c extraction ratios, because
intrinsic cl earance i s the pri mary determi nant of their hepatic cl earance. Altered drug-
metaboli zi ng enzyme activity has li ttl e effect on drugs wi th high hepatic extraction rati os because
thei r cl earance depends pri mari ly on hepatic bl ood fl ow.
Phase II Reactions
Phase II reacti ons are also known as conjugation or syntheti c reacti ons. Many drugs do not have a
pol ar chemical group sui tabl e for conjugati on, so conjugati on occurs onl y after a Phase I reaction.
Other drugs, such as morphine, already have a pol ar group that serves as a handl e for
conjugati on, and they undergo these reacti ons di rectl y. Vari ous endogenous compounds can be
attached to parent drugs or thei r Phase I metaboli tes to form different conjugati on products.
56

These endogenous substrates i nclude gl ucuronic acid, acetate, and ami no aci ds. Mercapturi c aci d
conjugates resul t from the bi ndi ng of exogenous compounds to glutathi one. Other conjugati on
reacti ons produce sul fated or methyl ated deri vati ves of drugs or thei r metabol ites. Li ke the
cytochrome P450 system, the enzymes that catal yze Phase II reacti ons are i nduci bl e.
47
Phase II
reacti ons produce conjugates that are pol ar, water-solubl e compounds. Thi s faci l itates the
ul ti mate excretion of the drug via the kidneys or hepatobi li ary secreti on. Li ke CYP, there are
di fferent fami li es and superfami li es of the enzymes that catalyze Phase II biotransformati ons.
56

Fact or s Af f ect i ng Bi ot r ansf or mat i on
Drug metabol ism vari es substantial ly between i ndi vi dual s because of vari abi l i ty in the genes
control li ng the numerous enzymes responsibl e for biotransformati on. For most drugs, i ndi vi dual
subjects' rates of metabol i sm have a unimodal

di stri bution. However, distinct subpopul ations with different rates of el imi nati on of some drugs
have been identi fi ed. The resul ting mul ti modal di stri bution of i ndi vi dual rates of metabol ism is
known as pol ymorphi sm. For exampl e, different genotypes result i n either normal, low, or (rarel y)
absent pl asma pseudochol inesterase activity, accounting for the wel l -known differences i n
individual s' responses to succi nylchol ine, which i s hydrol yzed by thi s enzyme. Many drug-
metabolizing enzymes exhibi t geneti c pol ymorphi sm, including CYP and vari ous transferases that
catal yze phase II reacti ons.
54, 56, 57, 58, 59

Drug metabol ism al so vari es with age. The fetus and neonate have less capaci ty for most
bi otransformations, especi all y those catal yzed by the CYP superfami l y.
60
Neonates al so have less
capaci ty for most phase II bi otransformation, wi th the excepti on of sulfate conjugati on.
60
Impai red
conjugati on of bil i rubin causes physi ol ogi c jaundice. Bi otransformati on capaciti es rapi dl y i n the
postpartum period, reachi ng adult capaci ty by 1 year of age.
60

warfari n
Compil ed from references 41 and 55.
P.256
Metabol ism of some drugs may also be decreased i n geri atri c pati ents, al though i t i s di ffi cul t to
separate the effects of age per se from the effects of organ dysfuncti on, whi ch i s more prevalent
in the el derl y. Some, but not all , i nvesti gati ons suggest decreased CYP acti vi ty i n the el derl y.
61

Conjugation capaci ty has l ittle or no age-rel ated changes.
61

Men have greater capaci ty for most Phase II reacti ons, and for Phase I reacti ons catal yzed by
CYP2E1.
62, 63
There do not appear to be any sex-rel ated di fferences i n CYP2C9 or CYP2C19
acti vi ty.
62, 63
CYP3A i soenzymes metabol i ze the l argest number of medi cations. Whether there are
any cli nicall y rel evant differences between men and women i n CYP3A acti vi ty i s controversial .
62, 63

Exposure to vari ous forei gn compounds can al ter drugmetabol i zi ng enzyme acti vi ty. Barbiturates,
phenytoin, macrol ide anti bi otics, i mi dazol e anti fungal agents, and corti costeroi ds can cause drug
interactions secondary to induction of hepati c drug-metaboli zi ng enzymes.
47
Chroni c ethanol
consumpti on i nduces enzyme activity, but acute i ntoxi cation inhi bi ts the bi otransformati on of
some drugs.
64
Smoki ng i ncreases the metabol ism of many drugs secondary to enzyme inducti on by
pol ycycli c hydrocarbons in tobacco smoke.
65

Liver di sease profoundly affects drug di sposi ti on. It is di ffi cul t to di sti ngui sh the i mpact of al tered
bi otransformation per se from other effects of l iver di sease: al tered bi ndi ng of drugs to pl asma
protei ns and decreased l i ver bl ood fl ow. Nonethel ess, hepatic di sease decreases clearance of drugs
with low hepati c extracti on ratios,
13, 66
whi ch impli es i mpaired bi otransformati on. Decreased in
vitro acti vi ty i n ci rrhoti c l i vers of some, but not al l , CYP i soforms has been reported, al though thi s
al so depends on the severi ty of the hepati c i mpai rment.
67
Congestive heart fail ure decreases
metaboli sm of li docai ne and theophyll i ne.
17
Renal fai l ure decreases CYP acti vi ty not only i n the
kidneys, but al so i n the i ntestines and li ver.
68
Thi s is pri mari l y because of downregul ati on of CYP
gene expressi on.
68
Hepati c Phase II bi otransformati on i s also reduced by renal fai l ure.
Presumabl y, substances that decrease biotransformati on enzyme acti vi ty and downregul ate gene
expressi on accumulate in pati ents wi th renal fail ure.
68

Effects of Anesthesia and Surgery on Biotransformation
Drug disposi tion is al tered in the perioperative peri od. Although many other factors are probabl y
al so i nvol ved, bi otransformation reacti ons are affected by anesthesi a and surgery. In dogs
anesthetized wi th hal othane, the intri nsi c hepati c cl earance of propranol ol i s decreased, whi ch
impli es that hepati c drug-metaboli zi ng abi l ity is i mpai red.
69
Hal othane i nhibi ts demethyl ati on of
aminopyri ne i n a dose-dependent fashi on. Isofl urane has l ess effect, and enfl urane does not affect
aminopyri ne bi otransformati on.
70

Many i nvestigators have studi ed the effects of anesthesia and surgery on anti pyri ne clearance.
Antipyri ne, an antipyretic that is no longer used therapeuti cal ly, does not bi nd to pl asma protei ns,
has a l ow hepatic extracti on ratio, and is not cleared by the ki dneys. Therefore, cl earance of
anti pyrine i s sol el y dependent on the acti vi ty of hepati c drug-metaboli zi ng enzymes. Thi s permi ts
the use of antipyri ne cl earance as an indicator of hepati c drug-metaboli zi ng activity.
71
Cl earance
of anti pyri ne i s general l y i ncreased after surgery conducted wi th a wide vari ety of general
anesthetic techni ques,
72, 73
al though there are excepti ons to thi s rul e. General anesthesi a wi th
enfl urane does not appear to i ncrease antipyri ne cl earance.
74
After operations l asti ng more than 4
hours, anti pyri ne cl earance i s decreased.
75
Presumabl y, major surgi cal trauma i nterferes wi th drug
metaboli sm, al though the preci se mechanisms are not known. Anti pyrine clearance i s also
increased after spi nal anesthesi a.
73
Therefore, general anesthesi a is not a prerequi site for
increased rates of biotransformati on i n the postoperati ve peri od, and other peri operati ve factors
al so affect drug metabol i sm. For exampl e, the cal ori c source of i v nutri tional regi mens infl uences
anti pyrine clearance. It i s decreased when the onl y cal oric source i s 5% dextrose, and i ncreased
when ami no aci ds are substi tuted for dextrose.
76

Factors other than altered rates of bi otransformati on, such as decreased hepati c bl ood fl ow duri ng
surgery,
27, 28
can affect drug el i mi nation in the perioperati ve peri od. In many pati ents the
magni tude of these changes is too smal l to cause any cl inicall y evi dent probl ems. However, i n
some patients cli nicall y si gni fi cant changes in drug eli mi nation coul d occur. Decreased drug
cl earance can resul t i n higher concentrati ons of drugs and increase the ri sk of adverse effects,
especi al l y after prol onged surgery. Cli nici ans must be aware of the potential for excessive
pharmacol ogic effects and must tail or doses accordingly.
BINDING OF DRUGS TO PLASMA PROTEINS
Drugs are present i n the blood in two fractions. Some are si mply dissol ved i n plasma water; the
rest i s bound to various components of whol e blood, such as pl asma protei ns and red bl ood cel l s.
Ideall y, drug concentrati ons shoul d be measured i n whol e bl ood because drugs are transported i n
bl ood, not pl asma, and drugs equil i brate between erythrocytes and pl asma very qui ckl y.
77

Unfortunatel y, measurement of total drug l evel s and drug bi ndi ng i n whol e bl ood i s techni cal ly
more difficult than in plasma or serum, so few i nvesti gators have di rectly measured whol e blood
bi nding. As a compromi se, the blood:pl asma concentrati on rati o can be used to estimate whole
bl ood bi ndi ng.
Drugs bi nd to pl asma protei ns i n a reversi bl e fashion that obeys the l aw of mass acti on. The rate
constants of the association and dissoci ati on reacti ons are k
1
and k
2
, respecti vel y. These reactions
are very rapi d, havi ng half-li ves of a few mi ll i seconds. Bi ndi ng of drugs to bl ood consti tuents
other than proteins, such as erythrocytes, proceeds i n an analogous fashi on. The equi li brium
di ssociation constant, k
d
, quanti fi es the affinity of drug-protei n bi ndi ng:

The di ssoci ati on constant has uni ts of mol es per l i ter (mol/L), and is the drug concentrati on at
whi ch 50% of the binding sites are occupi ed. The degree of bi ndi ng i s dependent on the affi ni ty of
the protei n for the drug, the protei n concentrati on, and the concentrati on of drug avai l abl e for
bi nding.
The extent of pl asma drug bindi ng can be expressed as the percentage of drug bound, which is the
percentage of the total drug present that i s bound to pl asma proteins. Al ternati vel y,

the free fracti on, whi ch i s the percentage of drug not bound to pl asma protei ns, can be used. For
example, approximately 83% of fentanyl i s bound to pl asma protei nsthus, the free fracti on i s
about 17%.
78, 79

Protei n bi ndi ng i s affected by many factors, i ncluding temperature and pH.
77
At hi gh drug
concentrations, bi ndi ng si tes become saturated and the free fraction i ncreases. There are also
qual i tati ve di fferences between speci es i n pl asma proteins that affect drug bi ndi ng, and bi ndi ng to
puri fi ed human al bumi n may not correl ate wi th bi ndi ng i n pl asma.
77
Consequentl y, to provi de
cl i ni cal ly useful i nformation, in vi tro measurement of drug bi ndi ng must be conducted at
physi ol ogi c temperature and pH, wi th human pl asma, and at concentrations withi n the usual
therapeutic range.
Drugprotei n bi ndi ng has i mportant pharmacol ogi c i mpli cations, because onl y unbound drug can
cross cel l membranes to reach i ts si tes of acti on. Al so, free drug i s more readi l y avai labl e for
el i mi nation. Thi s has led to the frequentl y hel d misconcepti on that drug bound to pl asma protei ns
and other bl ood constituents i s pharmacol ogi cal ly i nert. Thi s is not the case. As soon as unbound
drug leaves circul ati on, the l aw of mass action dictates that some drug wi ll di ssociate from bindi ng
si tes, whi ch tends to restore the free drug concentrati on. Thi s occurs al most instantaneousl y, so
that the bound fracti on of drug serves as a dynami c reservoi r that buffers acute changes i n the
free drug concentrati on.
As di scussed earl i er, cl earance of some drugs depends on the degree of protei n bi ndi ng. The
extent of distri buti on of drugs throughout the body al so depends on the degree of bi ndi ng. At
equil i bri um, the porti on of the total drug in the body that i s in extravascular si tes is determined
by the relative affinity of bl ood bi ndi ng versus bi ndi ng to all other ti ssues. A drug that i s hi ghl y
bound to pl asma protei ns or erythrocytes cannot be extensi vel y di stri buted unl ess i t has even
greater affi ni ty for extravascul ar bi ndi ng si tes.
P.257
Bi ndi ng P r ot ei ns
Two pl asma protei ns are pri mari l y responsi bl e for drug bindi ng: al bumi n and
1
-aci d gl ycoprotei n
(AAG). Drugs also bi nd to other plasma proteins, such as globul i ns or l i poprotei ns, and to
erythrocytes. Drugs can bind to more than one protei n. For exampl e, fentanyl and sufentani l bi nd
to al bumi n, AAG, gl obul i ns, and al so to red bl ood cel l s.
79

Albumi n i s the most i mportant drug-bi ndi ng protei n. In addi ti on to a wi de range of drugs,
i ncl udi ng barbi turates, benzodi azepi nes, and peni ci l l i ns, al bumi n bi nds endogenous compounds
such as bil i rubin. Many drugs bi nd to more than one si te on the albumi n mol ecul e, and most drugs
have one or two hi gh-affinity, pri mary bi ndi ng si tes and a vari abl e number of secondary, low-
affinity si tes. Studies wi th radioactively l abel ed drugs indicate that al bumi n has at least three
di screte, hi gh-affinity drug-bi nding sites. Di azepam, di gi toxi n, and warfari n each bi nd to a
di fferent si te. The sites at whi ch other drugs bind to al bumin and the affinity of the drugal bumin
bond can be determi ned by usi ng these three markers.
80
Thi s permits predi cti on of the l i kel ihood
of drug interacti ons as a resul t of one drug di spl aci ng another. Drugs that compete for the same
bi nding site are more li kel y to di spl ace one another than drugs that bind at different si tes, and the
drug wi th the l ower affinity for the bi ndi ng site wi l l be more easil y displ aced.
Fact or s Af f ect i ng Dr ug Bi ndi ng
The physi cochemi cal properti es of drugs i nfl uence bi ndi ng to pl asma protei ns. Al bumi n i s the
major bi ndi ng protei n for organi c aci ds, such as peni ci l li ns and barbi turates. Basi c drugs al so bi nd
to albumi n, but to a l esser extent. The pri mary bi ndi ng protei n for many basi c drugs i s AAG (Tabl e
11-5). Basi c drugs al so bi nd to l i poproteins and globul i ns. AAG i s an acute phase reactant, and i ts
concentration increases i n many acute and chroni c i ll nesses.
In general , the greater the l i pi d sol ubi l i ty of a drug, the greater the bi ndi ng to pl asma protei ns
(Tabl e 11-6).
79, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99
Water-solubl e drugs, such as
neuromuscul ar bl ocki ng agents, are bound to a substanti al l y l esser extent than l ipi d-sol ubl e drugs,
li ke propofol. Thi s i s al so true for drugs that bel ong to the same cl ass. The degree of bi ndi ng of
opi oi ds parall el s thei r l ipi d sol ubil i ty: morphi ne is the least bound, fentanyl and i ts deri vati ves are
hi ghl y bound, and meperi dine i s intermedi ate.

Si mi l arl y, bupi vacai ne i s bound to a greater extent than l i docai ne.
TABLE 11-5 Drugs Binding to
1
-Acid Glycoprotein

Al fentani l
Alprenolol
Bupi vacai ne
Di sopyrami de
Fentanyl
Li docai ne
Meperi di ne
Methadone
Propranolol
Quinidi ne
Ropi vacaine
Sufentani l
Verapami l
P.258
TABLE 11-6 Plasma Protein Binding of Some Drugs Used in Anesthesiology
CLASS/DRUG PERCENTBOUND REFERENCE
Opi oi ds
Al fentani l 92 79
Fentanyl 84 79
Meperi di ne 5363 81
Methadone 6090 82
Morphine 2035 82,83,84
Sufentani l 92 79
I nt r avenous Anest het i cs
Methohexi tal 73 85
Propofol 98 86
Thiopental 85 87
Neur omuscul ar Bl ock er s
Pancuroni um 1129 88,89
Rocuroni um 46 90
Vecuroni um 30 88
Local Anest het i cs
a
Bupi vacai ne 95 91
Li docai ne 70 91
Ropivacaine 94 92
Many physi ol ogi c and pathol ogi c states cause quanti tative and qual i tati ve changes i n the pri mary
drug-bi ndi ng pl asma protei ns, albumi n and AAG. Drug bi ndi ng may al so be affected by aci d-base
di sturbances that al ter the degree of i oni zati on of drugs and protei ns, and by accumul ati on of
endogenous compounds that compete for drug-bi ndi ng si tes.
Maternal and Neonatal Drug Binding
Bi ndi ng of drugs i n pregnancy and i n the fetus or neonate has received much attenti on because of
its impact on pl acental drug transfer. Pregnant women have reduced l evel s of al bumi n, and the
bi nding of many organi c aci ds, such as phenytoi n, i s decreased at term.
100
Al though thi opental i s
al so an organic acid, unli ke phenytoin, the free fracti on of thi opental is not i ncreased i n patients
undergoi ng cesarean secti on,
101
so that usual doses of thi opental do not resul t in excessi ve free
drug level s. This i s fortunate, because hi gh free drug l evel s woul d i ncrease the ri sk of si de effects
and enhance pl acental transfer of the drug. The free fracti on of di azepam, whi ch binds pri maril y to
al bumin, i s increased at term.
102
AAG levels are not changed duri ng pregnancy.
102
However, the
free fracti ons of li docai ne and propranol ol are, nonethel ess, i ncreased at term.
102

Neonates have decreased l evels of al bumin and AAG,
100, 101, 102, 103
and neonatal albumi n has less
affinity for some drugs.
100, 103
Consequentl y, the free fracti on of many drugs, especi al l y those that
bi nd to AAG, i s hi gher i n the neonate than in the mother.
103
Al though bi ndi ng of many drugs is
decreased i n neonates, thi s does not affect the unbound concentration of drugs transferred across
Benzodi azepi nes
Diazepam 9799 93
Lorazepam 8892 94
Mi dazol am 96 95
Car di ovascul ar Dr ugs
Di goxi n 2030 96
Di l ti azem 7780 97
Esmol ol 55 98
Ni fedi pi ne 9698 97
Propranolol 89 99
Verapami l 8491 97
a
At nontoxi c concentrati ons. At toxi c plasma concentrati ons, bindi ng of l ocal anestheti c
decreases, leadi ng to a marked increase i n the free drug concentrati on.
the placenta. Under near steady-state condi ti ons, maternal and fetal free drug concentrati ons are
the same, al though the total fetal level i s l ower. Because the free drug is the more
pharmacol ogicall y acti ve species, the decrease in maternal pl asma protein drug bi ndi ng i s of
greater consequence as far as placental transfer of drugs i s concerned. Decreased drug bi ndi ng
must be consi dered i n neonatal therapeuti cs.
60

Age and Sex
The pl asma concentrati ons of the pri mary drug-bi ndi ng proteins change wi th i ncreasi ng age:
al bumin decreases sli ghtl y, whereas AAG tends to increase.
104, 105, 106
The free fracti ons of
l i docai ne, meperi di ne, and propranol ol, al l of which bind to AAG, are not changed i n the
el derl y.
81, 106, 107
Si mi l arl y, bi ndi ng of drugs to al bumin i s mi ni mal ly altered. The bi ndi ng of
mi dazol am does not change,
95
and di azepam bi ndi ng may decrease sl ightl y.
22, 104, 108
The typi cal
magni tude of age-associated decreases in drug bi ndi ng i s i l l ustrated by thi opental . The average
free fracti on of thi opental of 18% i n young adul ts only i ncreases to 22% in geriatri c pati ents.
109

Cli nicall y si gni fi cant changes i n drug bi ndi ng in el derl y pati ents are more often caused by
pathologi c processes than by age per se. Age-rel ated changes i n drugprotei n bi nding are usual l y
not cl ini cal ly si gnificant.
110

Studies compari ng drug bi nding i n men and women have not found any cl i ni cal l y si gni fi cant
di fferences between the sexes. This i s not surprisi ng, because the concentrati ons of albumi n and
AAG in men and women do not di ffer si gni fi cantl y.
105

Hepatic Disease
The pl asma al bumi n concentrati on i s often decreased i n pati ents wi th l i ver di sease. Drug bi ndi ng
may also be affected by qual itati ve changes i n the albumin molecule that decrease affi ni ty for
drugs, and by accumul ati on of endogenous substances, such as bi li rubi n, that compete for drug-
bi nding si tes.
13
Al though hepati c di seases vary wi dely in pathophysiol ogy and severi ty, i t i s
possi bl e to make some general izati ons regardi ng thei r i mpact on drug bindi ng. The free fracti ons
of drugs that bi nd pri mari l y to albumi n are increased. Thi s i s true for organic bases such as
di azepam
22, 111
and morphi ne,
83
and for the organi c aci ds phenytoin
83
and thi opental.
112, 113
The
free fracti ons of basi c drugs, such as meperi di ne
24
and l i docai ne,
25
are not i ncreased in pati ents
with acute viral hepati tis, whi ch suggests that drug bi ndi ng to AAG i s mi ni mal l y affected by l i ver
di sease.
Renal Disease
Albumi n l evel s tend to decrease i n al l types of renal disease. However, even when al bumi n l evel s
are normal , bi nding of phenytoi n
83
and thi opental
87
is decreased. The free fracti on of phenytoi n is
correlated wi th both the albumi n concentrati on and the severity of renal dysfuncti on.
83
Thi s
indicates that renal fai lure reduces the affi ni ty of albumi n for organi c aci ds. Di al ysi s does not
restore the affini ty of albumi n for thi opental or phenytoi n.
83, 87
The pl asmaprotei n bi ndi ng of
many other organi c aci ds is also decreased i n renal fail ure.
114

The effect of renal di sease on the bi nding of basi c drugs depends on whether the drug binds
pri mari l y to al bumin or to AAG, and on the type of renal di sease. The free fracti on of di azepam,
whi ch bi nds pri mari ly to al bumin, is i ncreased i n the nephroti c syndrome, renal fai l ure, and after
renal transplantati on.
115
Si mi l arl y, bi ndi ng of morphine i s decreased i n uremia.
83
Bi ndi ng of other
basic drugs varies accordi ng to the changes i n AAG i n di fferent types of renal di sease. Li docai ne
bi nding i ncreases i n renal fai lure and after renal transplantati on, condi ti ons associ ated wi th
increased AAG l evel s.
115
Likewi se, propranolol bi ndi ng i s i ncreased in pati ents wi th renal di sease
and elevated concentrati ons of AAG.
99
Li docai ne bi ndi ng i s not al tered i n nephroti c pati ents who
have normal level s of AAG.
115

Other Diseases, Surgery, and Trauma
Patients with infl ammatory di seases, such as rheumatoi d arthriti s and Crohn' s di sease, have
increased l evel s of AAG and, consequently, decreased free fracti ons of drugs that bi nd to thi s
protei n.
99, 116
Mal i gnant di sease is al so associ ated with elevated levels of AAG, and i ncreased
bi nding of l idocai ne, propranol ol , and other basic drugs has been demonstrated in pati ents wi th
cancer.
117
In contrast, al bumi n tends to decrease i n patients wi th mali gnanci es, whi ch can
decrease bi ndi ng of aci di c drugs.
116
After acute myocardi al i nfarcti on, AAG l evel s double and
remai n el evated for about 3 weeks.
118
Consequentl y, the bi nding of l i docai ne and propranol ol i s
increased.
118, 119

The catabol ic state that foll ows surgery and trauma decreases plasma albumi n level s.
120
In
contrast, the concentrati on of AAG i ncreases after trauma
121
and surgery
122
and remains el evated
for several weeks. These changes result i n al terati ons i n drug bi nding. The free fracti on of
phenytoin i ncreases after surgery, probabl y secondary to decreased l evels of al bumi n, al though
the contemporaneous i ncrease i n free fatty aci ds may resul t i n competi ti on for bindi ng si tes.
120

Higher AAG level s i ncrease bindi ng of basic drugs, such as l i docai ne and propranol ol , after
trauma
121
and surgery.
123, 124

PHARMACOKINETIC PRINCIPLES
The concentrati on of a drug at its site or si tes of acti on i s a fundamental determinant of i ts
pharmacol ogic effects. Because drugs are transported to and from thei r si tes of action i n the
bl ood, the concentrati on at the acti ve site i s in turn a function of the concentrati on i n the blood.
The change i n drug concentration over ti me i n the blood, at the si te of action, and in other ti ssues
is a result of compl ex i nteracti ons of multi ple bi ologi c factors wi th the physi cochemi cal
characteri sti cs of the drug. Together, these factors determi ne the rate, extent, and pattern

of drug absorpti on, di stri buti on, metabol ism, and excreti on. The term pharmacokinetics, deri ved
from the Greek words pharmakon (medici ne) and ki nesis (movement), refers to the quantitati ve
anal ysi s of the rel ati onshi p between the dose of a drug and the ensui ng changes i n drug
concentration in the bl ood and other ti ssues.
Earl y pharmacoki neti c studi es of i ntravenous and inhal ati onal anestheti cs used physi ol ogi c or
perfusi on model s. In these models, body ti ssues are classi fi ed accordi ng to simil ari ties i n
perfusi on and affinity for drugs.
125
Hi ghl y perfused ti ssues, i ncl udi ng the brai n, heart, l ungs, li ver,
and ki dneys, make up the vessel -ri ch group. Muscl e and ski n compri se the l ean ti ssue group, and
fat i s consi dered as a separate group. The vessel -poor group, whi ch has mi nimal effect on drug
di stri buti on and el i mi nati on, i s composed of bone and cartil age. Physi ologic pharmacoki netic
models made major contri buti ons to understandi ng the factors infl uenci ng recovery from
thiopental . These model s establi shed that awakeni ng after a si ngle dose was pri mari l y the resul t
of redi stri buti on of thi opental from the brai n to muscl e and ski n.
7, 8
Di stri buti on to other ti ssues
and metabol ism played minor rol es. Thi s fundamental concept, redi stri buti on, al so appl i es to al l
l i pophi l i c drugs. Physi ol ogi c model s have al so contri buted greatl y to our understandi ng of the
uptake and di stri buti on of i nhal ati onal anesthetics.
126

Physi ol ogi c pharmacoki netic model s provi de much i nsi ght i nto factors affecti ng drug action. They
can predi ct the effects of physi ologi c changes, such as al tered regi onal bl ood fl ows or reduced
cardi ac output, on drug di stri buti on and el i mi nati on. The di sadvantage of perfusi on-based model s
is their compl exity. Veri fi cation of these model s requi res measurement of drug concentrati ons i n
many different ti ssues, whi ch i s rarel y practi cal .
125
Because of these di sadvantages, si mpler
pharmacokineti c models have been devel oped. In these model s the body i s envi saged as composed
of one or more compartments. Drug concentrati ons in the bl ood are used to define the rel ati onshi p
between dose and the ti me course of changes of the drug concentrati on.
127
It i s cri ti cal l y
important to understand that the different compartments of a compartmental pharmacoki netic
model cannot be equated wi th the tissue groups that make up physi ol ogi c pharmacoki netic
model s. Compartments are theoreti cal enti ti es that are used to deri ve pharmacoki netic
parameters, such as cl earance, vol ume of distributi on, and hal f-l i ves. These parameters quanti fy
drug di stri buti on and el i mi nati on.
Although the si mpl ici ty of compartmental model s, compared to physi ol ogic pharmacoki neti c
P.259
model s, has i ts advantages, i t also has some disadvantages. For exampl e, cardi ac output i s not a
parameter of compartmental models, and compartmental model s therefore cannot be used to
predi ct di rectly the effect of cardiac fail ure on drug disposi tion. However, compartmental
pharmacokineti c models can stil l quanti fy the effects of reduced cardi ac output on the di spositi on
of a drug if a group of patients with cardi ac fail ure i s compared to a group of otherwi se healthy
subjects.
The di sci pl i ne of pharmacoki netics i s, to the despai r of many, mathemati cal l y based. In the
succeeding secti ons, formul as are used to il l ustrate the concepts needed to understand and
interpret pharmacoki netic studi es. Readers are encouraged to concentrate on the concepts, not
the formul as.
P har macoki net i c Concept s
Rate Constants and Half-Lives
The di spositi on of most drugs fol l ows first-order ki netics. A first-order kineti c process i s one in
whi ch a constant fracti on of the drug i s removed duri ng a fi ni te peri od of ti me. Thi s fracti on i s
equival ent to the rate constant of the process. Rate constants are usual ly denoted by the l etter k
and have units of inverse time, such as min
-1
or h
-1
. If 10% of the drug i s eli mi nated per
mi nute, then the rate constant i s 0.1 mi n
-1
. Because a constant fracti on i s removed per uni t of
ti me i n fi rst-order kineti cs, the absolute amount of drug removed i s proporti onal to the
concentration of the drug. It foll ows that, i n fi rst-order kineti cs, the rate of change of the
concentration at any given ti me i s proportional to the concentrati on present at that time. When
the concentration is hi gh, i t wi l l fal l faster than when i t i s low. Fi rst-order kineti cs appl y not onl y
to el iminati on, but also to absorpti on and di stri buti on.
127

Rather than usi ng rate constants, the rapidi ty of pharmacoki neti c processes is often descri bed
with hal f-li vesthe ti me requi red for the concentrati on to change by a factor of 2. Half-li ves are
calculated directl y from the correspondi ng rate constants wi th thi s si mple equati on:

Thus, a rate constant of 0.1 min
-1
translates i nto a hal f-li fe of 6.93 minutes. The hal f-li fe of any
first-order kineti c process, including drug absorpti on, di stribution, and eli minati on, can be
calculated. Fi rst-order processes asymptoti cal l y approach compl eti on, because a constant fracti on
of the drug, not an absol ute amount, is removed per unit of time. However, after five half-lives,
the process wi l l be al most 97% compl ete (Tabl e 11-7). For practi cal purposes, thi s is cl ose enough
to 100% and can be consi dered as such.
TABLE 11-7 Half-Lives and Percent of Drug Removed
NUMBER OF HALF-
LIVES
PERCENT OF DRUG
REMAINING
PERCENT OF DRUG
REMOVED
0 100 0
1 50 50
2 25 75
3 12.5 87.5
Volumes of Distribution
The vol ume of di stri buti on quantifies the extent of drug distri buti on. The physi ol ogic factor
that governs the extent of drug distri buti on i s the overall capaci ty of ti ssues versus the
capaci ty of bl ood for that drug. Overall tissue capaci ty for uptake of a drug is in turn a function of
the total mass of the tissues i nto whi ch a drug di stri butes and their average affi ni ty for the drug.
In compartmental pharmacoki neti c model s, drugs are envi saged as di stributi ng into one or more
boxes, or compartments. These compartments cannot be equated di rectl y wi th speci fi c ti ssues.
Rather, they are hypothetical entiti es that permit anal ysi s of drug di stri bution and el iminati on and
descri ption of the drug concentrati on versus ti me profi le.
The vol ume of di stri buti on i s an apparent vol ume because i t represents the si ze of these
hypotheti cal boxes, or compartments, that is necessary to expl ain the concentrati on of drug in a
reference compartment, usual ly cal l ed the central or pl asma compartment. The vol ume of
di stri bution, Vd, rel ates the total amount of drug present to the concentrati on observed i n the
central compartment:

Thi s formula i s l ogi cal . If a drug i s extensi vely di stri buted, then the concentrati on wi l l be lower
rel ati ve to the amount of drug present, whi ch equates to a l arger volume of di stri buti on. For
example, if a total of 10 mg of drug i s present and the concentrati on i s 2 mg/L, then the apparent
vol ume of distri buti on i s 5 L. On the other hand, if the concentrati on was 4 mg/L, then the vol ume
of di stri buti on woul d be 2.5 L.
Simply stated, the apparent volume of di stri bution is a numeri c index of the extent of drug
di stri bution that does not have any rel ati onshi p to the actual vol ume of any ti ssue or group
of ti ssues. It may be as smal l as pl asma vol ume, or, if overall ti ssue uptake is extensi ve, the
apparent vol ume of di stributi on may greatly exceed the actual total vol ume of the body (Fi g. 11-
4). In general , l i pophil i c drugs have larger vol umes of di stri buti on than hydrophi l ic drugs (see Fi g.
11-4). Because the vol ume of di stributi on i s a mathemati cal approximati on, i t cannot be di rectl y
correlated wi th the anatomic and physi ol ogic factors that i nfl uence drug di stri buti on.
Determi nati on of the volume of di stri bution from a compartmental model does not provi de any
information regardi ng the ti ssues into whi ch the drug actual l y di stri butes or the concentrati ons in
those tissues. Despite these l imitati ons, the vol ume of di stri buti on provi des useful i nformation.
For example, an i ncrease in the vol ume of di stri buti on means that a larger l oadi ng dose wi l l be
requi red to fil l up the box and achieve the same concentration. Vari ous pathol ogi c condi tions can
al ter the vol ume of di stri buti on, necessi tati ng therapeuti c adjustments.
4 6.25 93.75
5 3.125 96.875
P.260
Total Drug Clearance
In compartmental pharmacoki neti c model s, the abi l ity of the system as a whol e to
irreversibl y el i mi nate a drug is quanti fi ed by the total drug clearance or el i mi nation
cl earance. El i mi nati on cl earance is the porti on of the vol ume of distri buti on from which drug i s
compl etel y and irreversibl y removed during a given ti me i nterval . It i s anal ogous to creati ni ne
cl earance, and, l i ke creati ni ne cl earance, drug cl earance has uni ts of fl ow. Drug cl earance is often
corrected for wei ght or body surface area, in which case the uni ts are mL/mi n/kg or mL/mi n/m
2
,
respectively.
El iminati on clearance, Cl , can be cal cul ated from the decl i ni ng bl ood l evel s observed after an i v
i njecti on, as fol l ows:

Agai n, this formula i s intui ti vel y l ogical. If a drug i s rapi dl y removed from the pl asma, i ts
concentration wi ll fal l more quickl y than the concentrati on of a drug that is l ess readi l y
el i mi nated. Thi s resul ts in a smal l er area under the concentrati on versus time curve, which
equates to greater cl earance.
A si gnificant l imitati on of calcul ati ng eli mi nation cl earance from compartmental pharmacoki neti c
model s i s that the relative contributi on of different organs to drug el i mi nati on cannot be
determi ned. Nonetheless, esti mati on of drug clearance wi th these models has made i mportant
contri buti ons to cl inical pharmacol ogy. In parti cul ar, these model s have provi ded a great deal of
cl i ni cal ly useful information regardi ng al tered drug el imi nati on i n vari ous pathol ogi c conditi ons.
Compar t ment al P har macoki net i c Model s
One-Compartment Model
Although for most drugs the one-compartment model i s an oversimpli fi cati on, i t does serve to
il l ustrate the basic relationshi ps among cl earance, vol ume of distri buti on, and the el i mi nation half-
l i fe. In thi s model , the body i s envi saged as a si ngl e homogeneous compartment. Drug di stributi on
after injecti on i s assumed to be i nstantaneous, so there are no concentrati on gradi ents withi n the
FIGURE 11-4. The vol ume of di stri buti on of some drugs used i n anesthesi ol ogy.
compartment. The concentrati on can decrease only by elimination of drug from the system. The
pl asma concentrati on versus ti me curve for a hypotheti cal drug with one-compartment ki netics is
shown i n Fi gure 11-5. With the concentrati on pl otted on a logari thmi c scale, the concentrati on
versus ti me curve becomes a strai ght l ine. The sl ope of the l ogari thm of concentrati on versus ti me
is equal to the fi rst-order eli mi nation rate constant.
Immedi atel y after i njecti on, before any drug can be eli minated, the amount of drug present is
equal to the dose. Therefore, by modi fying Equati on 11-7, the vol ume of di stri buti on can be
calculated:

In the one-compartment model , drug cl earance, Cl , i s equal to the product of the el i mi nati on rate
constant, k
e
, and the vol ume of di stri buti on:

Combini ng Equati ons 11-6 and 11-10 yi el ds:

Therefore, the greater the cl earance, the shorter the el iminati on hal f-li fe, whi ch i s easy to
understand. Less obvi ous i s the impact of the vol ume of di stri buti on on the eli mi nation half-
li fe. It i s easiest to understand i f the physi ol ogi c correl ate of a l arge vol ume of di stri buti on i s
consi dered. A l arge vol ume of di stributi on refl ects extensive ti ssue uptake of a drug, so that onl y
a smal l fracti on of the total amount of drug is i n the bl ood and accessi bl e to the organs of
el i mi nation. Consequently, the greater the volume of di stri bution, the l onger the el i mi nation half-
li fe. For drugs that exhi bi t mul ticompartment pharmacokineti cs, the rel ati onshi p among cl earance,
vol ume of di stributi on, and the el iminati on hal f-li fe i s not a si mpl e l i near one such as Equati on 11-
11. However, the same pri nci ples appl y. Al l el se bei ng equal , the greater the cl earance, the
shorter the el imi nati on hal f-li fe; the larger the vol ume of di stri buti on, the longer the el imi nati on
half-li fe. Thus, the el iminati on hal f-li fe depends on two other vari abl es, clearance and vol ume of
di stri bution, that characteri ze, respecti vel y, the extent of drug distri buti on and effi ci ency of drug
FIGURE 11-5. The pl asma concentrati on, pl otted on both l i near (, left vertical axis) and
logari thmi c (---, ri ght verti cal axis) scal es, versus ti me for a hypotheti cal drug exhibi ting
one-compartment, fi rst-order pharmacoki netics.
P.261
el i mi nation.
Two-Compartment Model
For many drugs, a graph of the logari thm of the plasma concentration versus time after an iv
injecti on i s si mi l ar to the schemati c graph shown i n Fi gure 11-6. There are two discrete phases in
the decl i ne of the pl asma concentrati on. The first phase after injecti on i s characteri zed by a very
rapi d decrease i n concentrati on. The rapi d decrease i n concentrati on during thi s di stri bution
phase is l argel y caused by passage of drug from the pl asma i nto tissues. The distri buti on phase i s
fol l owed by a sl ower decl i ne of the concentration owi ng to drug el i mi nati on. El iminati on also
begi ns i mmedi atel y after i njection, but i ts contri bution to the drop i n pl asma concentrati on is
initi al l y much smal l er than the fall i n concentration because of drug di stributi on.
To account for thi s bi phasi c behavi or, one must consi der the body to be made up of two
compartments, a central (or plasma) compartment and a peri pheral compartment (Fi g. 11-7). Thi s
two-compartment model assumes that it i s the central compartment i nto whi ch the drug is
injected and from which the bl ood sampl es for measurement of concentrati on are obtai ned, and
that drug i s eli minated onl y from the central compartment. Drug distri buti on wi thin the central
compartment is considered to be i nstantaneous. In real ity, thi s l ast assumption cannot be true.
However, drug uptake i nto some of the hi ghl y perfused ti ssues i s so rapi d that i t cannot be
detected as a discrete phase on the pl asma concentrati on versus time curve.
FIGURE 11-6. A schemati c graph of the pl asma concentrati on, on a logari thmi c scale, versus
ti me for a drug wi th a di stri buti on phase precedi ng the el i mi nation phase (two-compartment
or bi exponenti al ki neti cs). See text for expl anati on.
The di stri buti on and el i mi nati on phases can be characterized by graphi c analysi s of the pl asma
concentration versus ti me curve, as shown in Fi gure 11-6. The el i mi nati on phase l i ne i s
extrapol ated back to time zero (the ti me of i njection). At any time, the di fference between the
total concentrati on and the concentration on the extrapol ated el i mi nation phase li ne is equal to a
correspondi ng poi nt, at that ti me, on the di stri buti on phase li ne. In Fi gure 11-6, the zero ti me
intercepts of the di stri buti on and el i mi nation l i nes are poi nts A and B, respecti vel y. The hybrid
rate constants, and , are equal to the sl opes of the two l ines, and are used to cal cul ate the
di stri bution and el iminati on hal f-li ves; and are cal led hybrid rate constants because they
depend on both di stri buti on and eli mi nation processes.
At any time after an i v injecti on, the pl asma concentration of drugs wi th two-compartment ki netics
is equal to the sum of two exponenti al terms:

where t = ti me, Cp
(t )
= pl asma concentration at time t, A = y-axi s i ntercept of the distri buti on
phase l i ne, = hybrid rate constant of the di stri buti on phase, B = y-axi s i ntercept of the
el i mi nation phase l i ne, and = hybrid rate constant of the el iminati on phase. The first term
characteri zes the di stributi on phase and the second term characteri zes the el iminati on phase.
Immedi ately after injecti on, the first term represents a much larger fracti on of the total plasma
concentration than the second term. After several di stri buti on hal f-li ves, the value of the fi rst
term approaches zero, and the plasma concentrati on i s essenti al l y equal to the value of the
second term (see Fi g. 11-6).
In multi compartment models, the drug is i niti al l y di stributed onl y wi thin the central compartment.
Therefore, the i ni ti al apparent volume of distri buti on i s the volume of the central compartment.
Immedi ately after injecti on, the amount of drug present i s the dose, and the concentrati on i s the
extrapol ated concentrati on at ti me t = 0, whi ch i s equal to the sum of the i ntercepts of the
di stri bution and el iminati on l ines. The vol ume of the central compartment, V1, is cal cul ated by
modi fyi ng Equati on 11-7:

The vol ume of the central compartment is i mportant i n cl i ni cal anesthesi ol ogy because i t i s the
pharmacokineti c parameter that determi nes the peak plasma concentrati on after an iv bol us
injecti on. Hypovol emi a, for example, reduces the vol ume of the central compartment. If doses are
not correspondi ngl y

reduced, the hi gher pl asma concentrati ons wi ll i ncrease the i nci dence of adverse pharmacol ogi c
effects.
Immedi ately after i v i njection, al l of the drug is i n the central compartment. Si multaneousl y, three
processes begi n. Drug moves from the central to the peri pheral compartment, which al so has a
volume, V2. Thi s intercompartmental transfer i s a fi rst-order process, and i ts magni tude i s
quantified by the rate constant k
12
. As soon as drug appears i n the peri pheral compartment, some
passes back to the central compartment, a process characteri zed by the rate constant k
21
. The
transfer of drug between the central and peri pheral compartments i s quanti fi ed by the
di stri butional or intercompartmental cl earance:

= V
2
k
21

The thi rd process that begins i mmediately after admi ni strati on of the drug i s irreversi bl e removal
FIGURE 11-7. A two-compartment pharmacoki netic model . See text for expl anati on.
P.262
of drug from the system via the central compartment. As i n the one-compartment model , the
el i mi nation rate constant i s k
e
, and el i mi nation cl earance is:

The rapi di ty of the decrease i n the central compartment concentrati on after i v i njection depends
on the magni tude of the compartmental volumes, the i ntercompartmental clearance, and the
el i mi nation cl earance.
At equil i bri um, the drug is di stri buted among the central and the peri pheral compartment, and by
definiti on, the concentrati ons i n the compartments are equal. Therefore, the ulti mate vol ume of
di stri bution, termed the vol ume of di stri buti on at steady-state (V
ss
), i s the sum of V1 and V2.
Extensive tissue uptake of a drug i s reflected by a l arge vol ume of the peri pheral compartment,
whi ch, i n turn, results i n a large V
ss
. Consequentl y, V
ss
can greatl y exceed the actual vol ume of
the body.
As i n the singl e-compartment model , i n multi compartment models the eli mi nation cl earance i s
equal to the dose di vi ded by the area under the concentrati on versus ti me curve. Thi s area, as
well as the compartmental vol umes and i ntercompartmental cl earances, can be cal cul ated from the
intercepts and hybri d rate constants, wi thout havi ng to reach steady-state condi ti ons.
128

Three-Compartment Model
After i v i njecti on of some drugs, the i ni ti al, rapid distri buti on phase is fol lowed by a second,
sl ower di stri buti on phase before the el iminati on phase becomes evi dent. Therefore, the plasma
concentration is the sum of three exponenti al terms:

where t = ti me, Cp
(t )
= pl asma concentration at time t, A = i ntercept of the rapi d di stribution
phase l i ne, = hybrid rate constant of the rapi d di stri buti on phase, B = i ntercept of the sl ower
di stri bution phase line, = hybrid rate constant of the slower distributi on phase, G = i ntercept of
the eli mi nation phase li ne, and = hybrid rate constant of the eli minati on phase. Thi s tri phasi c
behavi or i s expl ai ned by a three-compartment pharmacokineti c model (Fi g. 11-8). As i n the two-
compartment model , the drug i s injected i nto and el imi nated from the central compartment. Drug
is reversi bly transferred between the central compartment and two peripheral compartments,
whi ch accounts for two distri buti on phases. Drug transfer between the central compartment and
the more rapidl y equil i brating, or shal l ow, peri pheral compartment i s characteri zed by the fi rst-
order rate constants k
12
and k
21
. Transfer i n and out of the more sl owly equi l ibrati ng, deep
compartment is characteri zed by the rate constants k
13
and k
31
. In thi s model, there are three
compartmental volumes: V1, V2, and V3, whose sum equals V
ss
; and three cl earances: the rapi d
intercompartmental clearance, the sl ow i ntercompartmental cl earance, and eli mi nation cl earance.
The pharmacoki neti c parameters of interest to cl i ni ci ans, such as cl earance, vol umes of
di stri buti on, and di stri buti on and el i mi nation half-li ves, are determi ned by cal cul ati ons anal ogous
to those used in the two-compartment model. Accurate estimates of these parameters depend on
accurate characteri zation of the measured plasma concentrati on versus ti me data. A frequentl y
encountered probl em i s that the durati on of sampli ng i s not l ong enough to defi ne accurately the
el i mi nation phase.
129
Si mi lar problems ari se i f the assay cannot detect low concentrations of the
drug. Whether a drug exhi bi ts two- or three-compartment ki netics is of no cl i ni cal consequence. In
fact, some drugs have two-compartment ki netics in some pati ents and three-compartment ki netics
in others.
108, 130
In selecting a pharmacoki netic model , the most important factor i s that i t
accurately characteri ze the measured concentrations. In general , the model with the small est
number of compartments or exponents that accuratel y reflects the data i s used.
Almost al l earl ier pharmacoki neti c studi es used two-stage model i ng. With this techni que,
pharmacokineti c parameters were esti mated i ndependently for each subject and then averaged to
provi de esti mates of the typi cal parameters for the popul ati on. One probl em with thi s approach i s
that i f outl iers are present, averagi ng parameters coul d resul t i n a model that does not accurately
predi ct typi cal drug concentrati ons. Currentl y, most pharmacokineti c model s are devel oped usi ng
popul ati on pharmacoki neti c model i ng, which has been made feasi bl e because of advances in
model i ng software and i ncreased computi ng power. Wi th these techni ques, the pharmacoki neti c
parameters are esti mated using all the concentrati on versus ti me data from the enti re group of
subjects i n a si ngl e stage, usi ng sophi sti cated nonl i near regressi on methods. This model i ng
technique provi des si ngl e esti mates of the typi cal parameter val ues for the popul ati on.
Ef f ect s of Hepat i c or Renal Di sease on P har macoki net i c
P ar amet er s
As di scussed earl i er, hepati c and renal di sease not onl y affect the abi l ity to el iminate drugs, but
al so change the bi ndi ng of drugs to pl asma protei ns. Consequently, the effects of al tered protei n
bi ndi ng and the effects of i mpai red organ function must be considered to understand ful ly the
impact of hepati c or renal disease on pharmacokineti c vari ables.
The extent of drug di stri buti on depends on the relati ve affini ty of blood versus ti ssues for the
drug. Therefore, i f the free fraction i n pl asma increases, the vol ume of di stributi on must al so
increase. The magni tude of the change depends on the

initi al free fraction and vol ume of distri buti on. An i ncrease i n the free fraction wi ll produce the
greatest increase i n the vol ume of di stri buti on for drugs that are hi ghl y bound to pl asma protei ns
and have small volumes of distri buti on. In contrast, changes in pl asma protei n bi ndi ng of drugs
with large volumes of distribution have minimal effects on the vol ume of di stri buti on, because so
li ttl e of the total amount of drug i s in the pl asma.
131

In theory, a paral l el change in ti ssue bi ndi ng woul d cancel the effect of changes in pl asma
bi ndi ng. However, thi s appears to be uncommon. Increased vol umes of distri buti on of di azepam
22

and propranol ol
132
associ ated wi th i ncreased free fracti ons have been observed i n patients wi th
hepati c di sease. Decreased bi ndi ng of thi opental i n patients with renal fai lure al so i ncreases the
vol ume of di stri buti on.
87

The effect of al tered protei n bi nding on total drug cl earance also depends on the i ni tial magni tude
of the cl earance. Increases i n the free fracti on of drugs with low hepati c extracti on ratios and
drugs el i mi nated pri maril y by gl omerular fi ltration cause a proporti onal i ncrease in clearance. In
contrast, al tered protei n bi ndi ng has l i ttl e effect on drugs wi th hi gh hepati c or renal cl earance.
The effect of an i ncreased free fracti on on eli mi nation depends on the net effect on cl earance and
the volume of di stri buti on.
131
The el i mi nati on hal f-li fe wil l increase i f increased vol ume of
FIGURE 11-8. A three-compartment pharmacoki netic model . See text for expl anati on.
P.263
di stri bution is the paramount change, or decrease i f i ncreased cl earance predomi nates.
Diverse pathophysi ologi c changes preclude preci se prediction of the pharmacoki netics of a given
drug i n i ndi vi dual pati ents wi th hepatic or renal disease. However, some generali zations can be
made. Bi ndi ng of drugs to al bumi n i s decreased, so that doses of drugs gi ven as an i v bol us, such
as thi opental , shoul d be reduced. In pati ents wi th hepatic di sease, the el i mi nati on hal f-li fe of
drugs metabol i zed or excreted by the l i ver is often i ncreased because of decreased clearance, and,
possi bl y, i ncreased vol ume of distri buti on. Repeated doses of such drugs as benzodi azepi nes,
opi oi ds, and barbi turates may accumul ate, l eadi ng to excessi ve and prol onged pharmacol ogic
effects. Recovery from small doses of drugs such as thi opental and fentanyl i s l argel y the resul t of
redi stri buti on, so recovery from conservati ve doses wi l l be mi ni mal l y affected. In pati ents with
renal fail ure, si mi l ar concerns apply to the admini stration of drugs excreted by the ki dneys. It i s
al most al ways better to underesti mate a pati ent' s dose requi rement, observe the response, and
gi ve addi ti onal drug i f necessary.
Nonl i near P har macoki net i cs
The physi ol ogi c and compartmental model s thus far discussed are based on the assumpti on that
drug di stri buti on and el i mi nati on are first-order processes. Therefore, thei r parameters, such as
cl earance and el iminati on hal f-li fe, are independent of the dose or concentrati on of the drug.
However, the rate of el iminati on of a few drugs i s dose dependent, or nonl inear.
El iminati on of drugs i nvol ves interacti ons with either enzymes catal yzing bi otransformati on
reacti ons or carri er protei ns for transmembrane transport. If suffici ent drug i s present, the
capaci ty of the drug-el i mi nating systems can be exceeded. When thi s occurs, it i s no l onger
possi bl e to excrete a constant fracti on of the drug present to the eli minati ng system, and a
constant amount of drug i s excreted per unit ti me. Phenytoi n is a wel l -known exampl e of a drug
that exhibi ts nonl inear el imi nati on at therapeutic concentrati ons. In theory, al l drugs are cleared
in a nonl i near fashi on. In practi ce, the capacity to el imi nate most drugs i s so great that this i s
usuall y not evident, even with toxi c concentrati ons.
PHARMACODYNAMIC PRINCIPLES
In i ts broadest sense, pharmacodynamics i s the study of the effects of drugs on the body.
Classi cal l y, pharmacol ogi c effects have been quantified by dose-response studi es. Advances in
drug assay techni ques and data anal ysis now al l ow defi ni ti on of the rel ati onshi p between the drug
concentration and the associ ated pharmacol ogi c effect in vi vo. As a result, the term
pharmacodynami cs has acqui red a more speci fi c defi ni ti on: the quanti tati ve anal ysi s of the
rel ati onship between the drug concentrati on i n the bl ood, or at the site of acti on, and the
resul tant effects of the drug on physi ol ogi c processes.
133

Dose- Response Cur ves
Dose-response studi es determi ne the rel ationship between i ncreasing doses of a drug and the
ensui ng changes i n pharmacologic effects. Schemati c dose-response curves are shown i n
Fi gure 11-9, wi th the dose plotted on both l i near and l ogari thmic scal es. There is a curvi l inear
rel ati onshi p between dose and the intensi ty of response. Low doses produce l ittle pharmacol ogic
effect. Once effects become evident, a smal l increase i n dose produces a rel ati vel y l arge change in
effect. At near-maxi mal response, large increases i n dose produce l ittle change i n effect. Usual l y
the dose i s pl otted on a l ogari thmi c scale (see Fi g. 11-9, ri ght panel ), whi ch demonstrates the
li near rel ati onship between the l ogari thm of the dose and the i ntensity of the response between 20
and 80% of the maxi mum effect.
Dose-response curves provide i nformation regardi ng four aspects of the rel ati onshi p of dose and
pharmacol ogic effect. The potency of the drugthe dose requi red to produce a gi ven effecti s
determi ned. Potency i s usuall y expressed as the dose requi red to produce a gi ven effect i n 50% of
subjects, the ED50. The sl ope of the curve between 20 and 80% of the maxi mal effect indicates
the rate of increase in effect as the dose is increased. The maxi mum effect is referred to as the
effi cacy of the drug. Finally, if curves from multi ple subjects are generated, the variabi li ty in
potency, effi cacy, and the slope of the dose-response curve can be esti mated.
The dose needed to produce a given pharmacologi c effect vari es consi derably, even i n normal
patients. The pati ent most resistant to the drug usual l y requi res a dose two- to threefol d greater
than the pati ent with the lowest dose requi rements. Thi s vari abi l ity i s caused by di fferences
between indi vi duals i n the rel ati onshi p between drug concentrati on and pharmacologic effect,
superi mposed on differences i n pharmacokineti cs.

Dose-response studi es have the di sadvantage of not bei ng abl e to determi ne whether vari ati ons i n
pharmacol ogic response are caused by differences i n pharmacokineti cs, pharmacodynami cs, or
both.
Concent r at i on- Response Rel at i onshi ps
Ideall y, the concentrati on of drug at its site of acti on shoul d be used to define the concentrati on-
response rel ationship. Unfortunatel y, these data are rarely avai l abl e, so the rel ati onshi p between
the concentration of drug in the bl ood and pharmacologic effect i s studied i nstead. Thi s
rel ati onship is easi est to understand i f the changes in pharmacol ogi c effect that occur duri ng and
after an i v i nfusion of a hypothetical drug are consi dered. If a drug i s infused at a constant rate,
the plasma concentrati on i ni ti all y increases rapi dl y and asymptoti cal l y approaches a steady-state
level after approxi mately fi ve eli mi nation hal f-li ves have el apsed (Fi g. 11-10). The effect of the
drug ini ti al l y i ncreases very slowl y, then more rapi dly, and eventual ly al so reaches a steady state.
When the infusi on i s disconti nued, i ndi cated by point C in Fi gure 11-10, the pl asma concentrati on
i mmedi atel y decreases because of drug distri buti on and el i mi nati on. However, the effect stays the
same for a short peri od, and then al so begi ns to decreasethere i s al ways a time l ag between
changes i n pl asma concentrati on and changes i n pharmacol ogi c response. Fi gure 11-10 al so
demonstrates that the same pl asma concentrati on is associated wi th di fferent responses i f the
concentration is changi ng. At poi nts A and B in Fi gure 11-10, the pl asma concentrati ons are the
FIGURE 11-9. Left panel: A schemati c curve of the effect of a drug pl otted agai nst dose.
Right panel: The same curve, replotted with dose on a logari thmi c scal e. Thi s yi elds the
famil i ar si gmoid dose-response curve, whi ch is l i near between 20 and 80% of the maxi mal
effect.
P.264
same, but the effects at each time di ffer. When the concentrati on i s increasi ng, there is a
concentration gradient from blood to the si te of acti on. When the infusi on is di sconti nued, the
concentration gradient is reversed. Therefore, at the same plasma concentrati on, the
concentration at the si te of acti on i s hi gher after, compared to duri ng, the i nfusi on. Thi s i s
associated wi th a correspondingl y greater effect.
In theory, there must be some degree of temporal disequi l i bri um between plasma concentrati on
and drug effect for all drugs with extravascular si tes of action. However, for some drugs, the ti me
l ag may be so short that i t cannot be demonstrated. The magni tude of thi s temporal di sequi li brium
depends on several factors:
1. perfusi on of the organ on whi ch the drug acts
2. the ti ssue:bl ood parti ti on coeffi ci ent of the drug
3. the rate of diffusi on or transport of the drug from the bl ood to the cell ul ar si te of action
4. the rate and affi ni ty of drugreceptor bi ndi ng
5. the ti me requi red for processes i ni ti ated by the drug-receptor interacti on to produce changes
in cel l ul ar functi on
The consequence of thi s ti me lag between changes i n concentration and changes i n effects i s that
the plasma concentrati on wi l l have an unvaryi ng rel ati onshi p wi th pharmacol ogi c effect only under
steady-state condi ti ons. At steady state, the pl asma concentrati on i s i n equil i bri um wi th the
concentrations throughout the body, and i s thus di rectl y proporti onal to the steady-state
concentration at the si te of acti on. Pl otti ng the logari thm of the steady-state plasma concentrati on
versus response generates a curve i dentical i n appearance to the dose-response curve shown i n
the ri ght panel of Fi gure 11-9. The Cp
ss
50, the steady-state plasma concentrati on produci ng 50%
of the maxi mal response, is determined from the concentrati on-response curve. Like the ED50, the
Cp
ss
50 is a measure of sensi tivity to a drug, but the Cp
ss
50 has the advantage of bei ng unaffected
by pharmacoki neti c vari abi l ity. Because i t takes fi ve el i mi nation hal f-li ves to approach steady-
state condi ti ons, i t i s not practi cal to determi ne the Cp
ss
50 di rectl y. For drugs wi th l ong
el i mi nation half-li ves, the pseudoequi li brium duri ng the el iminati on phase can be used to
FIGURE 11-10. The changes i n pl asma drug concentrati on and pharmacol ogi c effect duri ng
and after an intravenous i nfusion. See text for expl anati on. (Repri nted wi th permi ssi on from
Stanski DR, Shei ner LB: Pharmacoki netics and pharmacodynami cs of muscl e rel axants.
Anesthesi ol ogy 51:103, 1979.)
approxi mate steady-state condi ti ons, because the concentrations i n plasma and at the site of
acti on are changi ng very sl owly.
The onset and durati on of pharmacol ogi c effects depend not only on pharmacoki netic factors but
al so on the pharmacodynami c factors governi ng the degree of temporal disequi l i bri um between
changes i n concentrati on and changes in effect. The magni tude of the pharmacol ogi c effect is a
functi on of the amount of drug present at the site of acti on, so increasi ng the dose i ncreases the
peak effect. Larger doses have a more rapi d onset of acti on because pharmacol ogicall y active
concentrations at the site of acti on occur sooner. Increasing the dose al so increases the durati on
of acti on because pharmacologi cal ly effecti ve concentrati ons are maintai ned for a l onger ti me.
Integrated pharmacoki neticpharmacodynami c models ful ly characteri ze the rel ati onshi ps between
ti me, dose, pl asma concentrati on, and pharmacologi c effect.
133
Thi s i s accompl i shed by addi ng an
effect compartment to a standard compartmental pharmacoki netic model. The effect
compartment is also cal l ed the bi ophase. Transfer of drug between central compartment and the
effect compartment, or bi ophase, i s assumed to be a fi rst-order process, and the pharmacol ogi c
effect i s assumed to be di rectl y related to the concentrati on in the bi ophase. By quantifying the
ti me l ag between changes i n pl asma concentrati on and changes i n pharmacol ogic effect, these
model s can also defi ne the Cp
ss
50, even without steady-state condi tions. These model s have
contri buted greatl y to our understandi ng of factors i nfl uenci ng the response to i ntravenous
anesthetics,
134, 135
opi oids,
136, 137
and nondepol arizing muscl e relaxants
138, 139
in humans.

Dose-response and concentration-response rel ationships can be al tered by many factors, such as
drug interactions or pathol ogi c conditi ons. They are al so affected by the devel opment of tol erance,
whi ch i ncreases the ED50 and Cp
ss
50. When tol erance devel ops rapi dl y, i t i s referred to as
tachyphylaxi s, or acute tol erance.
Dr ug Recept or I nt er act i ons
The bi ochemi cal and physi ologic effects of drugs, neurotransmi tters, and hormones resul t from the
bi nding of these compounds to receptors, whi ch i ni tiates changes i n cel l ul ar function. In additi on
to the wel l -known muscari ni c and nicoti ni c choli nergi c receptors, and - and -adrenoceptors,
there are specific receptors for hi stami ne, serotonin, dopami ne, eicosanoids, pepti de hormones,
steroid hormones, endorphi ns and exogenous opi ates, benzodi azepines, and cal cium channel
bl ockers, to name a few. Subtypes of many of these receptors have been characteri zed. Most
receptors are protei n molecul es

si tuated i n the cel l membrane, al though some are l ocated withi n the cell .
Bi ndi ng of drugs to receptors, l i ke the bi ndi ng of drugs to pl asma protei ns, is usual l y reversi ble,
and foll ows the l aw of mass acti on:

The hi gher the concentration of free drug or unoccupi ed receptor, the greater the tendency to
form the drug-receptor compl ex. Pl otting the percentage of receptors occupi ed by a drug agai nst
the logari thm of the concentrati on of the drug yi el ds a si gmoi d curve, as shown i n Fi gure 11-11.
P.265
It i s often assumed that the percentage of the maximal effect observed at any gi ven drug
concentration is equal to the percentage of receptors occupi ed by the drug. However, thi s is not
al ways the case. At the neuromuscul ar juncti on, onl y 20 to 25% of the postjuncti onal ni cotinic
chol i noceptors need to bind acetyl choli ne to produce contracti on of all the fi bers i n the muscle.
140

Thus, 75 to 80% of the receptors can be consi dered spare receptors. The presence of spare
receptors has two i mportant consequences. Equati on 11-17 indicates that the hi gher the
concentration of unoccupi ed receptors, the greater the tendency to form the drugreceptor
compl ex. Therefore, spare receptors permi t near-maxi mal effects at very low concentrati ons of
drugs or neurotransmi tters.
141
The other corol lary of the existence of spare receptors i s that most
of the receptors must be occupi ed by an antagoni st before transmi ssi on i s affected. This accounts
for the margi n of safety of neuromuscul ar transmission.
140

The bi ndi ng of drugs to receptors and the resulti ng changes i n cel l ul ar function are the l ast two
steps in the compl ex seri es of events between admini stration of the drug and producti on of i ts
pharmacol ogic effects. There are two pri mary mechanisms by which the bi ndi ng of an agoni st to a
receptor changes cel l ul ar function: receptor-li nked membrane i on channels call ed ionophores, and
guani ne nucl eoti de bi ndi ng protei ns, referred to as G-protei ns. The nicoti ni c choli noceptor in the
neuromuscul ar postsynaptic membrane is one example of a receptor-ionophore compl ex. Binding
of acetylchol ine opens the cati on i onophore, l eadi ng to an i nfl ux of Na
+
ions, propagati on of an
acti on potential, and, ulti matel y, muscle contracti on.
142
The -amino butyri c aci d (GABA)
receptorchlori de i onophore complex i s another exampl e of thi s type of effector mechani sm.
Bi ndi ng of ei ther endogenous neurotransmi tters (GABA) or exogenous agoni sts (benzodi azepi nes
and iv anestheti cs) i ncreases Cl
-
conductance, which hyperpol ari zes the neuron and decreases its
exci tabi l ity.
143
-Adrenoceptors are the prototypi cal receptors that alter cel l ul ar function via G-
protei ns. G-protei ns change the intracel l ul ar concentrati ons of vari ous so-call ed second
messengers, such as Ca
2+
and cycli c AMP.
144

Receptors are not stati c entiti es. Rather, they are dynami c cel l ul ar components that adapt to thei r
envi ronment. For example, admi ni strati on of -adrenergi c agonists leads to desensiti zati on of -
FIGURE 11-11. Schemati c dose-response curves representing vari ous conditi ons. Ei ther dose
or concentrati on is pl otted on the x-axi s, and ei ther effect or the number of receptors
occupi ed on the y-axis. Curve A i s a typi cal dose-response curve. Curve B is a paral lel
ri ghtward shi ft of the curve and represents a drug that i s l ess potent than the drug depi cted
by curve A, but i s a ful l agoni st and thus capabl e of producing the same maximal effect.
Curve B woul d also resul t i f the drug used to generate curve A was studi ed i n the presence of
a competiti ve antagoni st. Curve C is shi fted to the ri ght, wi th a reducti on i n sl ope and the
maximal effect. This is the curve observed wi th parti al agonists and also when a full agoni st
(curve A) i s studied in the presence of a noncompeti ti ve antagoni st.
adrenoceptors.
145
Thi s occurs by several mechani sms: reduced abi l ity to combine wi th G-protei ns;
sequestrati on, whi ch is the removal of receptors from the cel l membrane so they are no longer
accessibl e to agoni sts; and by downregul ati on, a decrease i n the total number of receptors.
Admi ni strati on of adrenoceptor antagoni sts i ncreases the number of receptors.
145

Agonists, Partial Agonists, and Antagonists
Drugs that bi nd to receptors and produce an effect are cal l ed agoni sts. Drugs may be capabl e
of produci ng the same maxi mal effect, al though they may di ffer i n potency. Agoni sts that
di ffer i n potency but bi nd to the same receptors wil l have paral lel concentrati on-response curves
(curves A and B in Fi g. 11-11). Differences i n potency of agoni sts refl ect di fferences in affinity for
the receptor. Parti al agoni sts are drugs that are not capabl e of producing the maxi mal effect, even
at very high concentrati ons (curve C in Fi g. 11-11).
Compounds that bind to receptors wi thout produci ng any changes i n cel l ul ar function are referred
to as antagonists. Bi ndi ng of agoni sts to receptors i s i nhi bi ted by antagoni sts. Competi ti ve
antagoni sts bi nd reversi bl y to receptors, and thei r bl ocki ng effect can be overcome by hi gh
concentrations of an agoni st. Therefore, competiti ve antagoni sts produce a parall el shi ft i n the
dose-response curve, but the maxi mum effect is not altered (see Fi g. 11-11, curves A and B).
Noncompeti tive antagoni sts bind i rreversi bly to receptors. This has the same effect as reduci ng
the number of receptors and shi fts the dose-response curve downward and to the ri ght, decreasi ng
both the sl ope and the maxi mum effect (curves A and C in Fig. 11-11). The effect of
noncompeti ti ve antagoni sts is reversed onl y by synthesis of new receptor mol ecul es.
Agonists produce a structural change i n the receptor molecul e that ini ti ates changes i n cel lular
functi on. Partial agonists may produce a quali tati vel y di fferent change i n the receptor, whereas
antagoni sts bi nd wi thout produci ng a change i n the receptor that resul ts i n al tered cel lular
functi on. The underlying mechani sms by whi ch di fferent compounds that bi nd to the same receptor
act as agoni sts, partial agoni sts, or antagoni sts are not ful ly understood.
DRUG INTERACTIONS
Taki ng into account premedi cati on, peri operati ve anti biotics, i v agents used for i nducti on or
maintenance, inhalational anestheti cs, opi oi ds, muscl e rel axants, the drugs used to restore
neuromuscul ar transmi ssi on, and postoperati ve anal gesi cs, 10 or more drugs may be gi ven for a
rel ati vely routine anesthetic. Consequently, thorough understandi ng of the mechanisms of drug
interactions and knowl edge of speci fi c interactions with drugs used in anesthesi a are essenti al to
the safe practi ce of anesthesiol ogy. Indeed, anesthesi ol ogi sts often del i beratel y take advantage of
drug interactions. For exampl e,

when chol i nesterase i nhi bitors are gi ven to reverse the effects of neuromuscul ar bl ockers on
ni cotinic chol inoceptors, atropi ne or glycopyrrol ate i s administered concomitantly to avoid such
undesi rabl e si de effects as bradycardi a and bronchospasm, whi ch woul d result from increased
acetylchol ine bi ndi ng to muscari ni c choli noceptors.
Drug i nteracti ons because of physi cochemical properti es can occur in vi tro. Mi xi ng acidi c drugs,
such as thiopental , and basi c drugs, such as opi oids or muscle rel axants, resul ts i n the formation
of insol ubl e sal ts that preci pitate.
146
Another type of in vi tro reacti on i s absorption of drugs by
pl asti cs. Exampl es incl ude the uptake of ni troglycerin by pol yvi nyl chl oride infusi on sets
147
and the
absorpti on of fentanyl by the apparatus used for cardi opul monary bypass.
148

Drugs can al ter each other' s absorption, distri buti on, and eli mi nation. Absorpti on from the GI tract
i s al tered by drugs l i ke rani tidi ne, whi ch al ters gastri c pH,
51
and metoclopramide, which speeds
gastri c emptying.
149
Vasoconstri ctors are added to local anestheti c sol uti ons to prol ong thei r
duration of action at the si te of injecti on and to decrease the ri sk of systemi c toxi city from rapid
absorpti on.
Drugs that compete for bi ndi ng si tes on plasma protei ns have compl ex interactions.
77

Displ acement of a drug from plasma proteins affects i ts di stributi on. The i ncrease in the free drug
P.266
concentration increases tissue uptake of the drug, i ncreasi ng the volume of distri buti on. The
extent of the effect on drug di stributi on depends on the fracti on of the total drug i n the body that
i s bound to pl asma proteins. The change i n di stri buti on wi l l be greatest when drugs wi th rel ati vel y
l arge bound fracti ons and smal l vol umes of di stri buti on are di spl aced. Di spl acement of one drug by
another may produce toxi c-free-drug concentrations. When a steady state is reestabli shed, the
effect of decreased bi ndi ng on total and free drug concentrati ons depends on the rate of clearance
of the drug. For drugs wi th l ow extracti on ratios, clearance varies with the degree of bi ndi ng, and
cl earance increases proporti onately to the increase i n free fracti on. Therefore, when a steady
state i s reestabl ished, the total drug concentration wi ll be l ower, but the free drug l evel wi l l be
the same as the l evel before di splacement. Clearance of drugs wi th hi gh extracti on rati os i s not
restricted to the free fracti on and is not affected by changes i n bi ndi ng. Consequentl y, when a
new steady state i s reached, the total drug concentrati on i s unchanged, and the hi gher free drug
level wi l l persi st. Adverse interacti ons are thus most li kel y to occur i f the displ aced drug has hi gh
(nonrestri cti ve) cl earance, a small vol ume of di stri buti on, and rel ati vel y hi gh bi ndi ng to pl asma
protei ns.
Drugs that i nhibi t or i nduce the enzymes that catal yze biotransformati on reacti ons can affect
cl earance of other concomitantly admini stered drugs. Clearance can al so be affected by drug-
i nduced changes i n hepati c bl ood fl ow. Drugs that are cleared by the kidneys and have si mi l ar
physi cochemi cal characteristics compete for the transport mechanisms i nvol ved i n renal tubular
secretion.
Pharmacodynami c interacti ons fal l i nto two broad cl assifi cati ons. Drugs can interact, ei ther
di rectl y or i ndirectl y, at the same receptors. Opi oi d antagoni sts di rectl y displ ace opioi ds from
opi ate receptors. Chol inesterase inhi bi tors i ndi rectl y antagoni ze the effects of neuromuscul ar
bl ockers by increasi ng the amount of acetyl choli ne, which displ aces the bl ocki ng drug from
ni cotinic receptors. Pharmacodynamic i nteracti ons can also occur i f two drugs affect a physiol ogi c
system at di fferent si tes. Benzodi azepines and opi oids, each acting on thei r own speci fi c
receptors, appear to interact synergisticall y.
150, 151
Al though receptors and mechanisms are not as
well defined as for the benzodiazepi neopi oi d i nteracti on, thi s i s presumabl y how volatil e
anesthetics i ncrease sensi tivity to neuromuscul ar blocking drugs
138
and also how premedi cation
increases sensi ti vity to i nhal ati onal anesthetics.
152

CLINICAL APPLICATION OF PHARMACOKINETICS AND
PHARMACODYNAMICS TO ADMINISTRATION OF INTRAVENOUS
AGENTS
Whil e no new i nhaled anesthetics have been synthesi zed since the 1960s, i ntravenous drugs that
act on the central nervous system conti nue to be developed. Anesthesi ol ogi sts have become
accustomed to the exquisi te control of anestheti c blood (and effect si te) concentrati ons afforded
by modern vol ati le anestheti c agents and thei r vapori zers, coupl ed to end-ti dal anestheti c gas
moni tori ng. To achi eve si mi lar degrees of control of i ntravenously admi ni stered anestheti c drug
concentrati ons i n bl ood and i n the central nervous system, new technol ogies aimed at i mprovi ng
intravenous i nfusi on devices, as well as new software to manage the daunti ng pharmacoki netic
pri nci pl es i nvol ved, are needed. Thi s section examines the current state of i nfusion devices and
the pharmacoki neti c and pharmacodynami c pri nci ples speci fi cal l y requi red for preci se deli very of
anesthetic agents.
I nf usi on P umps
Origi nal ly designed over 30 years ago to control intravenous nutri ti on, i nfusion pumps have been
developed for the large intensi ve care uni t (ICU) and hospi tal -based market for an ever-widening
vari ety of drugs. Anesthesi a-specific pumps remai n a rel ati ve rari ty because the overal l market is
smal l er. Anesthesi a is the onl y arena i n whi ch a highly trained i ndi vi dual conti nuousl y moni tors
both the infusi on pump and the pati ent. Opti mall y, the control i nterface for infusi on pumps woul d
be anal ogous to the swi tches, knobs, and di al s found on anesthesi a machi nes, all owi ng for rapi d
adjustments with a minimum number of steps to actuate the new i nfusi on rate.
153
However, most
pumps currentl y avai l abl e i n hospi tal s are designed for safe management by personnel wi th
varyi ng skil l level s and protecti on from those wi th no ski l l level , that i s, pati ents, fami ly members,
and so on. These systems often feature ti me-consuming, menu-dri ven, double-checked
programmi ng; detecti on of mi nute ai r bubbl es; and al arms when the pump is left on pause or
standby mode, none of whi ch are necessari ly required or desi red by anesthesi ol ogi sts.
153

Since the therapeutic i ndices and the need to accuratel y predict emergence are l argely simil ar for
inhaled and intravenous agents, simil ar preci si on i n the drug del i very systems i s requi red. Tabl e
11-8 li sts the theoreti cal attri butes of an i deal anesthesia-specific infusi on pump. Whil e
el i mi nation of the aforementi oned safety features is desi rable, i n many ways such pumps shoul d
be more sophi sti cated than generic infusi on pumps. Specificall y, they shoul d di splay i nformation
rel evant to the conduct of an anestheti c, including assurance that the correct drug is bei ng
del i vered precisel y as programmed. The l atter is a parti cular probl em wi th most currentl y used
pumps, resul ti ng in underdosi ng and pati ent awareness, as wel l as other
misadventures.
154, 155, 156, 157
Other i mprovements from standard hospi tal pumps shoul d i nclude a
di fferent set of al arm conditi ons, the abi l i ty to variabl y set ai r detecti on l i mi ts, and a mechani sm
for rapi dl y effecti ng changes i n pump programmi ng. A pump with these speci fi cations woul d
obvi ously require the continuous presence of a hi ghl y trai ned i ndi vi dual. However, drugs bei ng
del i vered vi a an anesthesi a-specific pump woul d l ikely not be acceptabl e in other uni ts wi thin the
hospi tal unl ess a pump were to have dual setti ngs, one for anesthesia and one for the rest of the
hospi tal . Drugs del i vered by an anesthesi a-specific

pump that woul d continue to be i nfused outsi de of the OR, for example, anestheti c agents and
vasoactive drugs, woul d then need to be swi tched to another i nfusi on devi ce upon arri val at
another care setting.
P.267
TABLE 11-8 Desirable Features for Intravenous Infusion Devices
Low acqui siti on and operati ng costs
Accuracy over a wi de range of flow rates to al l ow use wi th mul ti pl e drug formul ati ons in
adul t and pedi atric patients
Small si ze and battery backup for transporti ng patients
Controls that al l ow rapi d changes i n drug del i very
Pause function wi thout al arm
Programmabi l ity:
Drug identification
Abi l ity to enter pati ent wei ght and drug concentrati on, al lowi ng user to set dose in
mass units rather than volumes (i .e., mg/h or g/kg/min instead of mL/h)
Preset bol us dose i n mass uni ts or volume, with reversion to conti nuous infusi on rate
after compl etion of bol us
Computer i nterface for data acqui si ti on and control
Target-control led infusi on capabi li ty
Di spl ays:
Al l programmed parameters
Current i nfusion rate and cumul ati ve dose
Vi sibl e i n low ambi ent l i ght
Safety features:
Drug i denti fi cati on (anal ogous to vaporizer)
Audi o and vi sual al arms for empty drug reservoi r, air i nl i ne, occl usi on, i mpendi ng
battery depl eti on, nonspeci fi c mal functi on
Vari able ai r detecti on li mits
Sensi ng and control ci rcui ts to detect discrepanci es between programmed and actual
fl ow rates
Mi croprocessor-based i ntegrati on of drug identi fi cati on, pati ent wei ght, and set dose
P har macoki net i c and P har macodynami c P r i nci pl es of Dr ug
I nf usi ons
Whil e pharmacoki neti c and pharmacodynami c pri nci ples and data have contri buted greatl y to our
understandi ng of drug action in anesthesi a, thei r pri mary uti l ity and ul ti mate purpose are to
determi ne opti mal dosi ng wi th as much mathematical precisi on and cl inical accuracy as possi ble.
In most pharmacotherapeutic scenari os outside of anesthesia care, the ti me scal es for onset of
drug effect, its mai ntenance, and i ts offset are measured i n days, weeks, or even years. In such
cases, gl obal pharmacoki neti c vari abl es such as total vol ume of distri buti on (V
SS
), eli mi nation
cl earance (Cl
e
), and hal f-li fe (t
1/2
) are suffi cient and uti li tari an parameters for cal culating dose
regi mens.
158
However, in the OR and ICU, the temporal tol erances for onset and offset of desi red
drug effects are measured i n mi nutes. Consequentl y, these gl obal vari ables are i nsuffi ci ent to
descri be the detai l s of ki netic behavior of drugs in the minutes fol l owing i ntravenous
administrati on. Thi s is parti cul arly true of l i pi d-sol ubl e hypnoti cs and opi oi ds that rapi dl y and
extensi vel y di stri bute throughout the vari ous tissues of the body, because di stri buti on processes
domi nate pharmacoki netic behavior during the ti me frame of most anesthetics. Addi ti onall y, the
therapeutic i ndi ces of many intravenous anestheti c drugs are smal l and two-tail ed (i .e., an
underdose, resulti ng i n awareness, is a toxi c effect). Opti mal dosi ng in these si tuati ons requi res
use of al l the variabl es of a mul ticompartmental pharmacoki netic model to account for drug
di stri buti on i n bl ood and other ti ssues.
It i s not easy to intui t the pharmacoki netic behavi or of a multi compartmental system by si mpl e
examinati on of the kineti c vari ables.
159
Computer si mul ati on i s requi red to meani ngful l y interpret
dosing or to accuratel y devi se new dosi ng regimens. In addi ti on, there are several
pharmacokineti c concepts that are uni quel y appl i cabl e to i ntravenous admini stration of drugs wi th
mul ticompartmental ki netics and must be taken i nto account when admi nisteri ng i ntravenous
infusi ons.
Ri se t o St eady- St at e Concent r at i on
The drug concentrati on versus time profi l e for the ri se to steady state i s the mirror i mage of its
el i mi nation profi le. In a one-compartment model wi th a decl i ne i n concentrati on versus ti me that
is mono-exponential foll owi ng a si ngle dose, the rise of drug concentrati on to the steady-state
concentration (C
SS
) i s l ikewi se mono-exponential duri ng a conti nuous i nfusi on. That is, i n one
el i mi nation half-li fe an infusi on i s halfway to its eventual steady-state concentrati on, i n another
half-li fe i t reaches hal f of what remai ns between hal fway and steady state (i .e., 75% of the
eventual steady state is reached i n two el imi nati on hal f-li ves), and so on for each hal f-li fe
increment. The equati on descri bi ng thi s behavi or i s:

where Cp
(t )
= the concentration at time t, k is the rate constant rel ated to the el i mi nati on hal f-
to alert user of potenti al overdoses
li fe, and t i s the ti me from the start of the i nfusi on. Thi s rel ati onshi p can al so be descri bed by:

in which Cp(n) is the concentration at n hal f-li ves. Equati on 11-19 indicates that during a constant
infusi on, the concentrati on reaches 90% of C
SS
after 3.3 hal f-li ves, which i s usuall y deemed close
enough for cl inical purposes.
However, for a drug such as propofol, whi ch parti tions extensi vel y to pharmacol ogi cal l y i nert body
ti ssues (e.g., muscl e, gut), a mono-exponential equati on, or si ngle-compartment model , i s
insuffi cient to describe the ti me course of propofol concentrati ons i n the fi rst mi nutes and hours
after begi nni ng drug admi ni strati on. Instead, a mul ti compartmental or multi exponential model
must be used.
158
With such a model , the pi cture changes drastically for the pl asma drug
concentration ri se toward steady state. The rate of ri se toward steady state i s determi ned by the
di stri bution rate constants to the degree that thei r respective exponenti al terms contri bute to the
total area under the concentration versus ti me curve. Thus, for the three-compartment model
descri bi ng the pharmacokineti cs of propofol , Equati on 11-18 becomes:

in which t = ti me; Cp
(t )
= pl asma concentration at time; A = coeffi ci ent of the rapi d di stri buti on
phase and = hybrid rate constant of the rapi d di stri buti on phase; B = coeffi ci ent of the sl ower
di stri bution phase and = hybrid rate constant of the sl ower di stri buti on; and G = coeffi ci ent of
el i mi nation phase and = hybrid rate constant of the eli minati on phase. A + B + G is the sum of
the coeffi cients of al l the exponenti al terms. For most l i pophil i c anestheti cs and opi oids, A is

typi cal l y one order of magni tude greater than B, and B is in turn an order of magni tude greater
than G. Therefore, distri buti on-phase kineti cs for i ntravenous anestheti cs have a much greater
infl uence on the ti me to reach C
SS
than do el iminati on-phase ki netics.
For example, wi th propofol having an el i mi nati on half-li fe of approximatel y 6 hours,
160
the simple
one-compartment rule i n Equation 11-19 tel ls us that i t woul d take 6 hours from the start of a
constant rate i nfusi on to reach even 50% of the eventual steady-state propofol plasma
concentration and 12 hours to reach 75%. In contrast, wi th a full three-compartment propofol
ki neti c model ,
160
Equation 11-20 accurately predi cts that 50% of steady state is reached in l ess
than 30 mi nutes and 75% wi ll be reached in l ess than 4 hours. This example emphasi zes the
necessity of using mul ti compartment models to descri be the cl ini cal pharmacoki netics of
intravenous anestheti cs.
Concent r at i on- Ef f ect Rel at i onshi p
The fundamental goal dri vi ng the advances i n pharmacoki netics and pharmacodynami cs during the
past three decades has been to better understand and predi ct drug concentrationeffect
rel ati onships. For i nhaled anesthetics, end-ti dal concentrati on measurements all ow a very cl ose
approxi mati on of thi s goal i n the cl i ni cal setting. For drugs that are not i nhal ed, cli ni ci ans must
operate at the level of the dose-effect relationship, that i s, cl i ni cians observe the effect resul ting
from an admi ni stered because i t is not possi ble to know the drug concentrati on at the ti me of the
observed effect. Dose-effect rel ati onshi ps are i nherently more diffi cult to interpret and control
because of the mul ti pl e pharmacokineti c factors affecting the relationshi p between the dose of
drug admini stered and the concentrati on at the effect si te. For thi s reason anesthesi ol ogi sts have
not generall y been able to take ful l advantage of the advances i n our understandi ng of the cl i ni cal
pharmacol ogy of i ntravenous anestheti cs.
P.268
I soconcent r at i on Nomogr am
The rise toward steady state descri bed by a mul ti compartmental system can be both vi sual i zed
and put to cl i ni cal use by a concept introduced by Shafer i n 1994 cal l ed an i soconcentrati on
nomogram (Fi g. 11-12).
161
Thi s graphi cal tool all ows users to empl oy concentrati on-effect, rather
than dose-effect, rel ationships when determi ning opti mal dosi ng of i ntravenous anestheti c agents.
The nomogram is constructed by calcul ati ng the pl asma drug concentrati on versus ti me curve for a
constant-rate infusion from a set of pharmacoki neti c vari abl es for a particul ar drug. From thi s
si ngl e simul ati on, one can readi l y visual ize (and esti mate) the ri se toward steady-state pl asma
drug concentrati on descri bed by the drug' s pharmacokineti c model . By simul ati ng a range of
potential i nfusi on rates a seri es of curves of identi cal shape are then pl otted on a single graph
with drug concentrati ons at any ti me that are directl y proporti onal to the infusi on rate.
By pl aci ng a hori zontal l i ne at the desi red pl asma drug concentrati on (y-axi s) the times (x-axi s) at
whi ch the hori zontal i ntersects the l i ne for a particul ar i nfusi on rate wi ll represent the ti mes at
whi ch the infusi on rate shoul d be set to the rate on the i ntercepting l i ne.
162
In the example shown
(see Fi g. 11-12) with 25 g/kg/mi n i ncrements, the predi cted pl asma propofol concentrati ons
remai n withi n 10% of the target from 2 mi nutes onward wi th a bi as of underesti mation. If never
al lowi ng the esti mated concentration to fal l bel ow the target is desired, then the time to decrease
to the next lower i nfusi on shoul d be at the mi dpoi nt of the subsequent i nterval . Extending the
infusi ons to the subsequent midpoi nt times wil l i ntroduce a maxi mum overesti mati on bi as of
approxi mately 17% wi th the i l l ustrated i nfusion increments (Fi g. 11-13). Bi ases woul d be
FIGURE 11-12. Isoconcentration nomogram for determini ng propofol i nfusi on rates desi gned
to mai ntai n a desi red pl asma propofol concentrati on. Thi s nomogram i s based on the
pharmacokineti cs of Schni der et al
160
and pl otted on a l ogl og scal e to better del ineate the
early ti me poi nts. Curved l i nes represent the pl asma propofol concentration versus ti me
pl ots, resul ti ng from the vari ous conti nuous infusi on rates i ndi cated al ong the ri ght and
upper borders (uni ts i n g/kg/mi n). A hori zontal li ne is pl aced at the desi red target plasma
propofol concentrati on (3 g/mL i n thi s case) and verti cal li nes are placed at each
intersection of a curved concentrati on-ti me pl ot. The verti cal l i nes i ndi cate the times that the
i nfusi on rate shoul d be set to the one represented by the next i ntersected curve as one
moves from l eft to ri ght al ong the hori zontal l ine drawn at 3 g/mL. In thi s exampl e the
infusi on rate woul d be reduced from 300 g/kg/mi n to 275 g/kg/mi n at 2.5 mi nutes, to 250
g/kg/mi n at 3 mi nutes, to 225 g/kg/mi n at 4.5 minutes, and so on until i t is turned to 100
g/kg/mi n at 260 minutes.

increased or decreased by constructing nomograms with larger or smal ler i nfusion increments,
respectively.
The nomogram can al so be used to i ncrease or reduce the targeted pl asma propofol concentration.
To target a new plasma drug concentrati on, a new hori zontal li ne can be drawn at the desi red
concentration. The i nfusion rate that i s closest to the current time i ntersect i s the one that shoul d
be used ini ti all y, fol l owed by the decremental rates di ctated by the subsequent intercept ti mes.
For best results when i ncreasing the target concentrati on, a bol us equal to the product of V1 (the
central compartment vol ume) and the incremental change i n concentration should be
administered. Li kewi se, when decreasi ng the concentration the best strategy is to turn off the
i nfusi on for the durati on predi cted by the appl i cabl e context-sensi ti ve decrement ti me and resume
the infusion rate predicted for the current time plus the context-sensi ti ve decrement ti me. For
instance, i f after 30 minutes one wi shes to decrease the target pl asma propofol concentrati on
from 3 g/mL to 2 g/mL (a 33% decrement at a ti me context of 30 mi nutes), one would shut off
the infusi on for 1 mi nute and 10 seconds to l et the concentrati on fal l by 33% and then restart at
75 g/kg/mi n. The esti mated pl asma propofol concentrati ons from thi s nomogram-gui ded dosi ng
scheme is shown i n Fi gure 11-13.
Tar get - Cont r ol l ed I nf usi ons
A more comprehensi ve means of bri dgi ng the gap between dose-effect and concentrati on-effect
came with the i ntroducti on of the concept of target-control led i nfusi ons (TCI), which was fi rst
descri bed by Schwi lden et al
163, 164
in earl y 1980s. Other software systems were developed i n
North America by groups at Stanford Uni versi ty
165
and Duke Universi ty.
166
By the l ate 1990s a
commercial ly avai l abl e TCI system for propofol (Di prifusor) was i ntroduced. Thi s greatl y
increased both anesthesi ol ogi sts' i nterest i n thi s mode of del ivery and thei r understandi ng of the
concentration-effect relationships for hypnoti cs and opi oi ds.
P.269
FIGURE 11-13. Si mul ated pl asma propofol concentrati on history resul ti ng from the
information in the isoconcentration nomogram in Fi gure 11-12 and extendi ng the ti mes to
swi tch the i nfusi on to the next l ower i ncrement to the mi dpoint of the subsequent ti me
segment (i .e., the switch from 250 to 225 g/kg/mi n was at 5 minutes, rather than at 4.5
mi nutes). Note that for the fi rst 30 mi nutes, thi s sequence predi cts pl asma propofol
concentrations that are always sl i ghtly above 3 g/mL (see text). At 30 mi nutes the target i s
adjusted to 2 g/mL and so the infusion is stopped for 1 mi nute and 10 seconds to al low for
the concentration to fal l by one-thi rd (see text) before resumi ng an infusi on at 75 g/kg/mi n.
The i nfusi on i s stopped at 60 minutes in thi s case.
To accompl i sh target-control led i nfusi ons, the mathemati cal calcul ati ons of the
pharmacokineti c events that convert a dose i nto a plasma or effect site concentrati on are
interfaced between the anesthesi a provi der and the i nfusi on pump by means of a computer. With
TCI, the cli ni cian prescri bes a desi red concentrati on (the target) and the computer-control led
pump cal cul ates and produces the drug i nfusi on rates requi red to reach and mai ntai n the desi red
concentration. The success of thi s approach is i nfluenced by the extent to whi ch the drug
pharmacokineti c and pharmacodynami c parameters programmed i nto the computer match those of
the parti cul ar patient at hand. Whi le this same l imi tati on appl ies to the more rudi mentary (non-
TCI) dosi ng done routi nel y i n every cl i ni cal setti ng, we must exami ne the speci al rami fi cations of
pharmacokineti cpharmacodynami c model mi sspecifi cati on wi th TCI i n any discussion of its future
importance i n the cl i ni cal setti ng.
The mathematical pri nci ples governi ng TCI are actuall y qui te si mple. For a computer-control pump
to produce and mai ntai n a pl asma drug concentrati on it must fi rst admi ni ster a dose equal to the
product of the central compartment V1 and the target concentrati on. Then for each moment after
that, the amount of drug to be administered i nto the central compartment to maintai n the target
concentration is equal to drug eli mi nated from the central compartment pl us drug di stri buted from
the central compartment to peripheral compartments mi nus drug returni ng to the central
compartment from peri pheral compartments. The software keeps track of the esti mated drug i n
each compartment over time and appli es the rate constants for i ntercompartmental drug transfer
from the pharmacoki netic model to these amounts to determine drug movement at any gi ven ti me.
It then matches the estimated concentrati ons to the target concentrati on at any ti me to determi ne
the amount of drug that should be infused. The software can also predi ct future concentrati ons,
usuall y wi th the assumption that the i nfusi on wi ll be stopped so that emergence from anesthesia
or the di ssi pati on of drug effect wi ll occur optimal l y accordi ng to the context-sensi ti ve recovery
ti me, or hal f-li fe.
167, 168

Because there i s a del ay or hysteresi s between the attai nment of a drug concentrati on i n the
pl asma and the producti on of a drug effect, i t is advantageous to have the mathematics of thi s
del ay i ncorporated into TCI. By addi ng the ki neti cs of the effect si te i t i s possibl e to target effect
si te concentrati ons as woul d be i n keepi ng wi th the pri nci pl e of worki ng as cl osely to the rel evant
concentration-effect relationship as possi ble. A dose scheme that targets concentrations i n a
compartment remote from the central compartment (i .e., the effect si te) has no cl osed form
solution for cal cul ati ng the infusi on rate(s) needed. Instead, the soluti on i s sol ved numeri cal ly and
invol ves some addi tional concepts that must be consi dered, namel y the ti me to peak effect, T
MAX
,
and the vol ume of di stri buti on at peak effect, V
DPE
. These are di scussed l ater. In pri nci pl e,
targeting the effect si te necessitates produci ng an overshoot i n pl asma drug concentrati ons during
inducti on and for subsequent target increases. Thi s i s si mi l ar i n concept to overpressuri zi ng
inhaled anesthetic concentrati ons to achi eve a targeted end-ti dal concentrati on. However, unli ke
the inspiratory li mb of an anesthesi a circui t, the plasma compartment seems to be cl osely l inked
to cardiovascular effects, and large overshoots i n pl asma drug concentration may produce
unwanted si de effects.
The performance of TCI i s i nfl uenced by the vari ance between pharmacoki netic parameters
determined from group or popul ati on studi es and the i ndivi dual pati ent. Medi an absol ute
performance errors for fentanyl,
165
al fentani l ,
169
sufentani l ,
170
midazolam,
171, 172
and propofol
172, 173

are in the range of 30% when li terature val ues for pharmacokineti c parameters are used to dri ve
the TCI devi ce and fal l to approximatel y 7% when the average ki neti cs of the test subjects
themsel ves are used.
169
Di vergence (the percentage change of the absolute performance error) is
general ly qui te low (approxi matel y 1%) when target concentrati ons remai n rel ati vel y stabl e, but
increase to nearl y 20% when the frequency of concentration steps i s as frequent as every 12
mi nutes.
173
These data suggest that whil e a considerabl e error may exi st (30%) between the
targeted drug concentrati on and the one actuall y achi eved i n a pati ent, the concentrati on attained
wil l not vary much over ti me. Thus, i ncremental adjustments i n the target shoul d resul t i n
incremental and stabl e new concentrations i n the pati ent as long as the incremental adjustments
are not too frequent.
In Europe and Asi a, devi ces for del i veri ng propofol by TCI are commerci al l y avail able from at l east
three compani es (Graseby, Al ari s, and Freseni us) wi th simil ar performance parameters.
174
In the
Uni ted States, there are stil l no FDA-approved devices. For i nvestigational purposes, STANPUMP
(devel oped by Steve Shafer at Stanford Uni versity) can be i nterfaced via an RS232 port to an
i nfusi on pump. STANPUMP currently provi des pharmacoki neti c parameters for 19 different drugs,
but has the abil i ty to accept any ki netic model for any drug provided by the user. (Informati on
regardi ng STANPUMP i s avai l abl e at http://0-
www.anesthesi a.stanford.edu.i nnopac.up.ac.za:80/pkpd/. Accessed August 27, 2004.) RUGLOOP
is TCI software (developed by Michel Struys of Ghent Uni versi ty), whi ch is si mi lar to STANPUMP
but operates i n Wi ndows rather than DOS and is capabl e of controll i ng mul tipl e drug i nfusions
si multaneously. (Information regardi ng RUGLOOP i s avai l abl e at http://www.anesthesi a-
uzgent.be/rugl oop.htm. Accessed August 27, 2004.)
Whil e the pharmacol ogic principl e of relati ng a concentration rather than a dose i s sci enti fi cal ly
sound, few studi es have actual l y attempted to determine whether TCI i mproves cl i ni cal
performance or outcome. Onl y a few li mited studies

have actual ly compared manual i nfusion control versus TCI. Some have shown better control and a
more predictabl e emergence wi th TCI,
175, 176
whereas others have si mply shown no
advantage.
177, 178

TCI pri nci pl es conti nue to be devel oped beyond the scope of intravenous anesthesi a techni ques.
TCI has been used to provi de postoperati ve anal gesia wi th al fentani l.
179, 180
In thi s system a
desi red target pl asma alfentanil concentrati on was set i n the range of 40 to 100 ng/mL. A demand
by the pati ent automaticall y increased the target l evel by 5 ng/mL. Lack of a demand caused the
system to gradual ly reduce the targeted l evel . The quali ty of anal gesi a was judged to be superi or
to standard morphine PCA.
Si mi l arl y, TCI has been used to provi de pati ent-control led sedati on wi th propofol.
181
The TCI was
set to 1 g/mL and a demand by the pati ent i ncreased the l evel by 0.2 g/mL. As wi th the TCI
anal gesi a system, the l ack of a demand caused the system to gradual l y reduce the targeted
pl asma propofol concentrati on. The ti ming and i ncrement of the decrease were adjusted by the
cl i ni ci an. Over 90% of pati ents were satisfi ed wi th thi s method of sedation.
TIME TO MAXIMUM EFFECT COMPARTMENT CONCENTRATION
(T
MAX
)
Earl ier i n this chapter, the del ay between attai ni ng a pl asma concentrati on and an effect si te
concentration was descri bed. Thi s del ay, or hysteresis, i s presumed to be a resul t of transfer of
drug between the pl asma compartment, V1, and an effect compartment, V
e
. By si mul taneousl y
model i ng the pl asma drug concentrati on versus time data (pharmacokineti cs) and the measured
drug effect (pharmacodynamics), an esti mate of the drug transfer rate constant, k
e0
, between
pl asma and the putative effect si te can be esti mated.
138
However, esti mates of k
e0
, l ike al l rate
constants, are model speci fi c.
182
That i s, k
e0
cannot be transported from one set of kineti c
parameters determi ned i n one speci fic pharmacoki neticpharmacodynami c study to any another
set of pharmacoki neti c parameters. Li kewi se, it i s not vali d to compare estimates of k
e0
among
studies of the same drug or across different drugs and, therefore, one shoul d not be surpri sed
that reported val ues for k
e0
for the same drug vary markedly among studi es. The model -
independent parameter that characteri zes the del ay between the pl asma and effect si te i s the ti me
to maximal effect, or T
MAX
.
182
Accordingly, if the T
MAX
and the pharmacoki neti cs for a drug are
known from i ndependent studi es, a k
e0
can be esti mated by numeric techni ques for the
independent ki neti c set that woul d produce the known effect si te T
MAX
.
The concept of a transportabl e, model -independent parameter that characteri zes the kineti cs of
the effect site is important for robust effect si tetargeted, computer-control led i nfusi ons. Thi s is
because there many more pharmacoki netic studi es characteri zi ng a wider vari ety of pati ent types
and groups i n the l i terature than there are complete pharmacoki neticpharmacodynami c studi es.
By making the generall y val i d assumption that i ntrai ndi vi dual differences are smal l in a drug' s rate
of effect si te equi li bration, it i s possibl e wi th a known T
MAX
to esti mate effect si te ki neti cs for a
P.270
drug across a wi de vari ety of pati ent groups where only the pharmacoki neti cs are known. Thi s
cannot be done i n a vali d manner usi ng k
E0
or t
1
/
2KE0
al one.
182

V
DPE

Whil e the pl asma concentrati on can be brought rapi dl y to the targeted drug concentrati on by
administeri ng a bol us dose to the central compartment (C V1) and then held there by a
computer-control led i nfusi on (Fi g. 11-14), the ti me for the effect si te to reach the target
concentration wi ll be much longer than T
MAX
(4 mi nutes for propofol effect site concentrati on to
reach 95% of that targeted). It i s possibl e to cal culate a bol us dose that wi l l attai n the esti mated
effect site concentrati on at T
MAX
wi thout overshoot i n the effect si te. However, plasma drug
concentration wi ll overshoot (Fi g. 11-15). Thi s i s done by combi ni ng the concept of descri bi ng
drug di stri buti on as an expandi ng vol ume of di stri buti on that starts at V1 and approaches V
(the
apparent vol ume of di stri buti on duri ng the el i minati on phase) over time wi th the concept of
T
MAX
.
183, 184

FIGURE 11-14. This is a simulation of a target-control led i nfusi on (TCI) i n whi ch the plasma
concentration is targeted at 5 g/mL. The soli d l i ne represents the predi cted pl asma propofol
concentration of 5 g/mL, which in theory is attai ned at time t = 0 and is then mai ntai ned by
a vari abl e rate i nfusi on. The dashed l i ne is the predi cted effect site concentrati on under the
condi ti ons of a constant pseudosteady-state plasma concentrati on. Note that 95% of the
target concentrati on i s reached in the effect si te at approximatel y 4 mi nutes.
Vol ume of di stri buti on over ti me is cal cul ated by di vi di ng the total amount of drug remai ni ng in
the body by the pl asma

drug concentration at each time t. The ti me-dependent vol ume at the ti me of peak effect (or T
MAX
)
is V
DPE
. The product of the targeted effect site concentrati on and V
DPE
plus the amount l ost to
el i mi nation in the time to T
MAX
becomes the proper bolus dose that wi ll attain the target
concentration at the effect site as rapi dly as possi bl e wi thout overshoot. In practi cal terms this
bol us i s given at ti me t = 0, after whi ch the infusi on stops unti l ti me t = T
MAX
. It then resumes
infusi ng drug in i ts normal stop loss manner.
Some software programs for control li ng target-control led i nfusi ons include thi s concept in thei r
al gori thms. In the case of the propofol kineti cs used to construct the i soconcentrati on nomogram
in Fi gure 11-13, the pharmacoki neti cpharmacodynami c parameter set of Schni der et al
160

predi cts a T
MAX
of 1.6 mi nutes, a V
DPE
of 16.62 L, and an eli mi nation loss of 23.8% of the dose
over 1.6 minutes in a 70-kg man. Thus the proper propofol bolus for a targeted effect site
propofol concentrati on of 5 g/mL i s 109 mg. The computer-control led i nfusion pump wi l l del i ver
thi s dose as rapi dl y as possi bl e and then begi n a targeted i nfusion for 5 g/mL at t = 1.6 mi nutes
(see Fi g. 11-15).
Fr ont end P har macoki net i cs
The term frontend pharmacokineti cs refers to the i ntravascular mi xi ng, pul monary uptake, and
recircul ati on events that occur in the fi rst few mi nutes duri ng and after i ntravenous drug
administrati on.
185
These ki netic events and the drug concentrati on versus ti me profil e that resul ts
are important because the peak effect of rapi dl y acti ng drugs occurs during thi s temporal
window.
186, 187
Al though i t has been suggested that frontend pharmacoki neti cs be util i zed to gui de
drug dosi ng,
188
current TCI does not incorporate frontend ki neti cs i nto the model s from whi ch drug
infusi on rates are cal cul ated. Not doing so may i ntroduce further error.
189

TCI rel ies on pharmacokineti c models that are based on the si mpli fyi ng assumpti on of
instantaneous and compl ete mi xi ng wi thin V1. However, the determi nation of V1 i s routinely
overesti mated in most pharmacokinetic studies. Overestimati on of V1, when used to calcul ate TCI
infusi on rates, resul ts in pl asma drug concentrati ons that overshoot the desi red target
concentration, especial ly i n the fi rst few minutes after begi nni ng TCI. Furthermore, correct
descri ption of drug distri buti on to ti ssues i s dependent on an accurate V1 estimate, so
inaccuraci es caused by not taki ng frontend pharmacoki netics i nto account may be persistent and
resul t in undershoot as wel l as overshoot. Si mul ati on i ndi cates that pharmacokineti c parameters
deri ved from studi es i n whi ch the drug is admini stered by a short (approxi matel y 2 mi nutes)
infusi on better esti mate V1 and tissue-di stri bution ki netics than those from a rapi d i ntravenous
bol us i nfusion.
189
When the latter drug admi nistrati on method i s used, ful l characteri zati on of the
frontend reci rcul atory pharmacoki netics i s requi red to obtai n val i d esti mates of V for use i n TCI.
189

Cl osed- Loop I nf usi ons
When a val i d, and nearly conti nuous, measure of drug effect is avai l abl e, drug del i very can be
automati cal l y ti trated by feedback control . Such systems have been used experi mentall y for
FIGURE 11-15. Thi s i s a si mul ati on of a target controll ed i nfusion (TCI) i n whi ch the effect
si te concentrati on is targeted at 5 g/mL. The soli d li ne represents the predicted pl asma
propofol concentrati on that resul ts from a bol us dose, gi ven at ti me t = 0, that i s predi cted
to purposel y overshoot the plasma propofol concentrati on target unti l time t = T
MAX
(1.6
minutes). At T
MAX
pseudo-equi l i brati on between the effect site and the plasma occurs and
both concentrati ons are then predicted to be the same unti l the target i s changed. Note that
the effect si te attai ns the target i n l ess than hal f the ti me with effect si te targeti ng compared
to the pl asma concentration targeting seen i n Fi gure 11-14.
P.271
control of bl ood pressure,
190
oxygen del i very,
191
bl ood gl ucose,
192
neuromuscul ar bl ockade,
193
and
depth of anesthesi a.
193, 194, 195, 196, 197, 198, 199
A target val ue for the desi red effect measure (the
output of the system) i s sel ected and the rate of drug del ivery (the i nput i nto the system) i s
dependent on whether the effect measure i s above, bel ow, or at the target value. Thus the output
feeds back and control s the i nput. Standard control lers (referred to as proporti onal-integral -
deri vati ve [or PID] control lers) adjust drug del i very based on both the integral, or magni tude, of
the devi ation from target and the rate of devi ati on, or the derivati ve.
Under a range of responses, standard PID control l ers work quite well. However, they have been
shown to develop unstabl e characteri sti cs in situati ons where the output may vary rapi dl y and
widel y. Schwi lden et al
200
have proposed a control ler i n whi ch the output (measured response)
control s not onl y the i nput (drug i nfusion rate), but al so the pharmacokineti c model dri vi ng the
infusi on rate. Thi s i s a so-call ed model -dri ven or adapti ve cl osed-loop system. Such a system has
performed wel l in cli ni cal trial s,
201
and i n a si mulati on of extreme condi ti ons i t was demonstrated
to outperform a standard PID control ler.
196

Closed-loop systems for anesthesi a are the most di ffi cul t to desi gn and i mpl ement because the
precise defi ni tion of anesthesia remai ns el usive, as does a robust monitor for anesthetic depth.
Because modi fi cation of consciousness must accompany anesthesi a, processed EEG parameters
that correl ate wi th l evel of consci ousness, such as the Bi spectral Index (BIS),
201, 202

el ectroencephal ographi c entropy,
203
and auditory evoked potenti al s,
198
make i t possi bl e to
undertake cl osed-loop control of anesthesi a. There i s keen i nterest i n further devel opi ng these
tool s to make them more reli abl e because, advances i n pharmacoki netic model ing, i ncl udi ng the
effect compartment, the implementati on of such model s into drug del i very systems, and the
creati on of adaptive control l ers based on these model s, has made routi ne cl osed-l oop del i very of
anesthesia i magi nable.
204
So far i t has been di ffi cult to bri ng a true cl osed-l oop system to market
in medi cal appli cati ons, because of the regul atory agency hurdl es. From a regul atory poi nt of
view, an open-loop TCI system is much easi er to attai n and offers many of the benefi ts of actual
cl osed-loop systems. Unl ess there is a regul atory or a desi gn breakthrough, cl osed-loop systems
for anesthesi a wi l l li kel y remain i n the theoreti cal and experi mental realms.
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Title: Clinical Anesthesia, 5th Edition
Autonomi c Nervous System: Physi ol ogy and Pharmacol ogy
Chapter 12
Autonomic Nervous System: Physiology and
Pharmacology
Noel W. Lawson
Joel O. Johnson
KEY POINTS
AUTONOMIC PHARMACOLOGY
Anesthesi ol ogy i s the practice of autonomic medici ne. Drugs that produce anesthesi a al so produce
potent autonomic si de effects. The greater part of our trai ning and practice i s spent acqui ring
ski l l s i n averting or util i zi ng the autonomic nervous system (ANS) si de effects of anestheti c drugs
under a vari ety of pathophysiol ogi c condi tions. The success of any anestheti c depends on how wel l
homeostasi s is mai ntained. The numbers that we fai thful l y record during the course of anesthesi a
refl ect ANS functi on and not necessari l y the presence of surgi cal anesthesia.
AUTONOMIC NERVOUS SYSTEM PURPOSE
The ANS i ncl udes that part of the central and peri pheral nervous system concerned with
invol untary regul ati on of cardi ac muscl e, smooth muscle, glandular, and visceral functi ons.
ANS activity refers to vi sceral reflexes that functi on essential ly below the conscious l evel . The
term autonomi c remains the best descri pti on of thi s ubi quitous system, as opposed to automatic.
ANS impli es sel f-control li ng, whereas automati c i mpl ies nonrefl exi c or i ntri nsi c responses;
The autonomic nervous system (ANS) parti cipates in nearl y al l of the
physi ol ogi c processes of the human body and an understandi ng of i ts function is
essential for anesthesi ol ogi sts.
The functi on of the ANS i s i nti matel y ti ed to neurohumeral mechani sms covered
el sewhere i n the text.
Peri operative -bl ockade has been proven to be benefi ci al i n certai n pati ents
with compromi sed cardi ovascul ar functi on.
Knowl edge of the effects of prescri bed oral medi cation on the ANS i s essenti al i n
the peri operati ve management of the surgical pati ent.
Angi otensi n-converting enzyme (ACE) inhi bi tors may preci pi tate hypotensi on i n
the peri operati ve pati ent.
however, the use of autonomy to describe this nervous system is i l lusory. The ANS is al so

responsi ve to changes in somati c motor and sensory acti vi ti es of the body. The physi ol ogi c
evidence of vi sceral reflexes as a resul t of somatic events i s abundantl y cl ear. Psychosomatic
di sease i s an expression of this connection. The ANS i s therefore not as di sti nct an enti ty as the
term suggests. Nei ther somati c nor ANS acti vi ty occurs in i sol ati on.
1
The ANS organizes visceral
support for somatic behavi or and adjusts body states i n anti cipation of emoti onal behavior or
responses to the stress of di sease (i .e., fight or fl i ght).
Traditi onal l y, the ANS has been vi ewed as strictl y a peri pheral , efferent (motor) system. Thi s
concept is no l onger tenabl e. Afferent fibers from vi sceral structures are the fi rst l ink i n the reflex
arcs of the ANS, whether rel aying vi sceral pai n or changes in vessel stretch. Most ANS efferent
fi bers are accompani ed by sensory fi bers that are now commonl y recogni zed as components of the
ANS. However, the afferent components of the ANS cannot be as di sti ncti vel y di vi ded as can the
efferent nerves. ANS vi sceral sensory nerves are anatomi cal l y i ndi sti ngui shabl e from somati c
sensory nerves. The cl ini cal importance of vi sceral afferent fi bers i s more cl osely associ ated wi th
chroni c pai n management.
FUNCTIONAL ANATOMY
The ANS falls into two divisions by anatomy, physi ol ogy, and pharmacol ogy. Langl ey di vi ded
this nervous system i nto two parts in 1921. He retai ned the term sympatheti c (SNS)
introduced by Wi ll i s in 1665 for the fi rst part and i ntroduced the term parasympatheti c
(parasympatheti c nervous system, PNS) for the second. The term autonomi c nervous system was
adopted as a comprehensi ve name for both. Ordinari ly, acti vati on of the SNS produces
expendi ture of body energy, whereas the PNS produces conservati on or accumul ati on of energy
resources. Tabl e 12-1 li sts the compl ementary effects of SNS (adrenergi c) and PNS (chol i nergi c)
acti vi ty of organ systems.
P.276
TABLE 12-1 Homeostatic Balance Between Adrenergic and Cholinergic Effects
ORGAN SYSTEM
RESPONSE
ADRENERGIC CHOLINERGIC
HEART
Sinoatri al node Tachycardi a Bradycardi a
Atri oventri cul ar node Increased conduction Decreased conducti on
His-purkinje Increased automati ci ty and
conducti on vel oci ty
Mi nimal
Myocardi um Increased contracti li ty, conduction
velocity, automatici ty
Mi nimal decrease in
contracti l ity
Coronary vessel s
Constriction (
1
) and di l ati on (
1
)
Di l ati on and
constri cti on?
a
BLOOD VESSELS
Skin and mucosa Constriction Dilation
Skeletal muscle
Constriction (
1
) > di lation (
2
)
Dilation
Pul monary Constriction ?Dilation
BRONCHIAL SMOOTH
MUSCLE
Rel axati on Contracti on
GASTROINTESTINAL TRACT
Gal l bl adder and ducts Rel axati on Contracti on
Gut moti l ity Decreased Increased
Secreti ons Decreased Increased
Sphincters Constriction Rel axati on
BLADDER
Detrusor Rel axes Contracts
Tri gone Contracts Rel axes
GLANDS
Nasal Vasoconstri cti on and reduced
secretion
Stimulation of
secretions
Lacri mal
Paroti d
Submandi bul ar
Gastric
Pancreati c

SWEAT GLANDS Diaphoresi s (chol inergi c) None
APOCRINE GLANDS Thi ck, odi ferous secreti on None
Central Autonomic Organization
Pure central ANS or somatic centers are not known. An extensi ve overl ap of functi on occurs.
Integrati on of ANS acti vi ty occurs at all l evel s of the cerebrospinal axi s. Efferent ANS

acti vi ty can be i niti ated l ocal l y and by centers located i n the spi nal cord, brai nstem, and
hypothal amus. The cerebral cortex is the hi ghest l evel of ANS i ntegration. Fai nti ng at the sight of
bl ood i s an exampl e of thi s hi gher level of somati c and ANS i ntegrati on. ANS functi on has al so
been successful l y modulated through consci ous, intentional efforts demonstrati ng that somati c
responses are al ways accompanied by vi sceral responses and vi ce versa.
The pri nci pal si te of ANS organi zati on i s the hypothal amus. SNS functi ons are controll ed by nucl ei
in the posterol ateral hypothal amus. Sti mul ati on of these nucl ei resul ts in a massi ve di scharge of
the sympathoadrenal system (Tabl e 12-2). PNS functi ons are governed by nuclei i n the mi dl ine
and some anterior nucl ei of the hypothal amus. The anteri or hypothal amus is i nvol ved with
regul ati on of temperature. The supraopti c hypothal ami c nucl ei regul ate water metabol i sm and are
anatomicall y and functional ly associ ated wi th the posterior l obe of the pi tui tary (see Interaction of
Autonomic Nervous System Receptors section). This hypothalami cneurohypophyseal connection
represents a central ANS mechani sm that affects the kidney by means of antidi uretic hormone.
Long-term bl ood pressure control , reactions to physi cal and emotional stress, sl eep, and sexual
refl exes are regul ated through the hypothal amus.
EYE
Pupi l Mydri asi s Mi osi s
Cil i ary muscle Relaxation for far vision Contracti on for near
vision
a
See the Interacti on of Autonomi c Nervous System Receptors section.
P.277
TABLE 12-2 Hypothalamic Nuclei
ANTERIOR POSTERIOR
PARAVENTRICULAR NUCLEUS
Oxytocin rel ease
Water conservation
MEDIAL PREOPTIC AREA
Bl adder contraction
Decreased heart rate
Decreased blood pressure
SUPRAOPTIC NUCLEUS
Water conservati on
POSTERIOR PREOPTIC AND ANTERIOR
HYPOTHALAMIC AREA
POSTERIOR
HYPOTHALAMUS
Increased bl ood pressure
Pupi l l ary di l ati on
Shi veri ng
Corti cotropi n
DORSOMEDIAL NUCLEUS
Gastroi ntesti nal sti mul ation
PERIFORNICAL NUCLEUS
Hunger
Increased bl ood pressure
The medull a oblongata and pons are the vi tal centers of acute ANS organizati on. Together, they
integrate momentary hemodynamic adjustments and maintai n the sequence and automati ci ty of
ventil ati on. Integration of afferent and efferent ANS i mpul ses at thi s central nervous system
(CNS) l evel is responsibl e for the toni c acti vi ty exhi bi ted by the ANS. Control of peri pheral
vascul ar resi stance and blood pressure i s an example of this toni c acti vi ty. Tonici ty hol ds vi sceral
organs in a state of intermedi ate acti vi ty that can either be di mi ni shed or be augmented by
al teri ng the rate of nerve fi ri ng. The nucl eus tractus sol itari us, l ocated wi thin the medul la, i s the
pri mary area for rel ay of afferent chemoreceptor and baroreceptor information from the
gl ossopharyngeal and vagus nerves. Increased afferent i mpul ses from these two nerves inhi bi t
peri pheral SNS vascul ar tone, produci ng vasodi l ati on, and increase vagal tone, produci ng
bradycardia. High spinal cord transecti on eli mi nates the medull a and results i n hypotensi on.
Studi es of pati ents wi th high spi nal cord l esi ons show that a number of refl ex changes are
mediated at the spi nal or segmental l evel. ANS hyperreflexia i s an exampl e of spinal cord
mediation of ANS reflexes wi thout i ntegration of functi on from higher i nhi bitory centers.
1

Peripheral Autonomic Nervous System Organization
The peri pheral ANS is the efferent (motor) component of the ANS and consi sts of two
complementary parts: the SNS and the PNS. Most organs recei ve fi bers from both di vi si ons (Fi g.
12-1). In general , activiti es of the two systems produce opposi te but complementary effects (see
Tabl e 12-1). Acti ons of the two subdivisi ons are suppl ementary i n some ti ssues such as the
sali vary gl ands. A few tissues, such as sweat glands and spl een, are innervated by onl y SNS
fi bers. Al though the anatomy of the somatic and ANS sensory pathways i s identi cal , the motor
pathways are characteristicall y different. The efferent somati c motor system, l i ke somatic
afferents, i s composed of a si ngl e (unipol ar) neuron with its cel l body in the ventral gray matter of
the spi nal cord. Its myel inated axon extends directl y to the vol untary striated muscl e unit. In
contrast, the efferent (motor) ANS i s a two-neuron (bipol ar) chai n from the CNS to the effector
organ (Fi g. 12-2). The fi rst neuron of both the SNS and PNS ori gi nates wi thin the CNS but does
not make di rect contact wi th the effector organ. Instead, i t rel ays the i mpulse to a second station
known as an ANS gangli on, whi ch contai ns the cel l body of the second ANS (postgangl i onic)
neuron. Its axon contacts the effector organ. Thus, the motor pathways of both divisi ons of the
ANS are schemati cal l y a seri al , two-neuron chain consisting of a pregangl ioni c neuron and a
postgangl i onic effector neuron (Fi g. 12-3).
Body temperature regulation
Panti ng
Sweating
Thyrotropi n i nhi biti on
Rage
VENTROMEDIAL NUCLEUS
Sati ety
MAMMILLARY BODY
Feedi ng refl exes
LATERAL HYPOTHALAMIC
AREA
Thi rst and hunger
FIGURE 12-1. Schemati c di stributi on of the crani osacral (parasympathetic) and
thoracolumbar (sympathetic) nervous systems. Parasympathetic pregangl i oni c fi bers pass
di rectl y to the organ that is i nnervated. Thei r postgangl i oni c cel l bodi es are si tuated near or
within the i nnervated vi scera. Thi s li mi ted distri buti on of parasympatheti c postgangl i oni c
fibers is consistent wi th the di screte and li mited effect of parasympatheti c functi on. The
postgangl i onic sympatheti c neurons ori ginate i n either the pai red sympathetic gangl i a or one
of the unpai red col lateral pl exuses. One pregangl ioni c fi ber i nfl uences many postgangli oni c
neurons. Acti vati on of the SNS produces a more di ffuse physi ol ogi c response rather than
di screte effects.
FIGURE 12-2. Compari son of somatic and autonomic refl ex arcs. Somati c arcs are uni pol ar
and autonomi c arcs are bi pol ar.
Pregangl i oni c fi bers of both subdi vi sions are myel inated with diameters of l ess than 3 mm.
1

Impul ses are conducted at a speed of 3 to 15 m/s The postgangl i oni c fi bers are unmyeli nated and
conduct i mpulses at sl ower speeds of less than 2 m/s. They are si mi l ar to unmyel i nated visceral
and somati c afferent C fi bers (Tabl e 12-3). Compared wi th the myel inated somati c nerves, the
ANS conducts impul ses at speeds that precl ude i ts parti cipati on i n the i mmedi ate phase of a
somati c response.
FIGURE 12-3. Schemati c di agram of the efferent ANS. Afferent i mpul ses are i ntegrated
central l y and sent refl exl y to the adrenergi c and choli nergi c receptors. Sympatheti c fi bers
ending i n the adrenal medull a are pregangl i oni c, and acetyl chol i ne (ACh) is the
neurotransmitter. Sti mulation of the chromaffin cell s, acti ng as postgangli oni c neurons,
rel eases epi nephri ne (EPI) and norepi nephri ne (NE).

Sympathetic Nervous System or Thoracolumbar Division
The efferent SNS i s referred to as the thoracolumbar nervous system. The ori gi n of i ts
pregangl i oni c fi bers provi des the anatomi c basi s for thi s desi gnati on. Fi gure 12-1 demonstrates
the di stri buti on of the SNS and i ts i nnervati on of visceral organs.
The pregangl i oni c fibers of the SNS (thoracol umbar divisi on) ori ginate i n the intermedi ol ateral
gray col umn of the 12 thoraci c (T1-12) and the fi rst three lumbar segments (L1-3) of the spi nal
cord. The myeli nated axons of these nerve cel l s leave the spi nal cord wi th the motor fibers to form
the whi te (myel i nated) communi cating rami (Fi g. 12-4). The rami enter one of the pai red 22
sympatheti c gangli a at thei r respecti ve segmental l evel s. On enteri ng the paravertebral gangl ia of
the lateral sympatheti c chain, the pregangli oni c fi ber may fol low

one of three courses: (1) synapse wi th postgangli oni c fi bers i n gangl i a at the l evel of exi t, (2)
course upward or downward in the trunk of the SNS chai n to synapse in gangl i a at other l evel s, or
(3) track for vari abl e di stances through the sympathetic chai n and exi t without synapsi ng to
termi nate i n an outl yi ng, unpaired, SNS coll ateral gangl i on (see Fig. 12-4). The adrenal gl and i s
an excepti on to the rule. Pregangl i onic fi bers pass directl y i nto the adrenal medul la wi thout
synapsi ng i n a gangl i on (see Fi g. 12-3). The cell s of the medul la are deri ved from neuronal tissue
and are analogous to postgangl i onic neurons.
TABLE 12-3 Classification of Nerve Fibers
P.278
P.279
The sympathetic postgangl ioni c neuronal cel l bodi es are l ocated i n gangli a of the pai red l ateral
SNS chai n or unpaired col l ateral gangli a i n more peri pheral pl exuses. Col lateral gangli a, such as
the cel i ac and i nferi or mesenteri c gangli a (plexus), are formed by the convergence of
pregangl i oni c fi bers wi th many postgangl i oni c neuronal bodies. SNS gangl i a are al most al ways
located cl oser to the spi nal cord than to the organs they innervate. The sympatheti c
postgangl i onic neuron can therefore ori ginate i n ei ther the paired lateral paravertebral SNS
gangli a or one of the unpai red coll ateral pl exus. The unmyel i nated postgangl i onic fibers then
proceed from the gangli a to terminate wi thin the organs they i nnervate.
Many of the postgangl i onic fi bers pass from the l ateral SNS chain back into the spi nal nerves,
formi ng the gray (unmyeli nated) communi cati ng rami at al l level s of the spi nal cord (see Fi g. 12-
4). They are di stri buted di stal l y to sweat gl ands, pi l omotor muscl e, and blood vessel s of the skin
and muscl e. These nerves are unmyeli nated C type fibers (see Tabl e 12-3) and are carri ed wi thi n
the somatic nerves. Approxi matel y 8% of the fi bers i n the average somati c nerve are
sympatheti c.
1

The fi rst four or fi ve thoraci c spinal segments generate pregangl i onic fi bers that ascend i n the
neck to form three speci al pai red gangli a. These are the superi or cervical, mi ddl e cervi cal , and
cervi cothoraci c gangli a. The last is known as the stel l ate gangl i on and i s actuall y formed by the
fusi on of the i nferi or cervi cal and fi rst thoraci c SNS gangl ia. These gangli a provi de sympathetic
innervati on of the head, neck, upper extremi ti es, heart, and lungs. Afferent pai n fibers al so travel
with these nerves, accounting for chest, neck, or upper extremity pai n wi th myocardi al i schemi a.

Acti vati on of the SNS produces a di ffused physi ol ogic response (mass reflex) rather than discrete
FIGURE 12-4. The spi nal refl ex arc of the somati c nerves is shown on the l eft. The different
arrangements of neurons i n the sympatheti c system are shown on the ri ght. Pregangl i onic
fibers coming out through white rami may make synapti c connecti ons foll owing one of three
courses: (1) synapse i n gangli a at the l evel of exi t, (2) course up or down the sympatheti c
chai n to synapse at another level , or (3) exi t the chai n without synapsi ng to an outl ying
coll ateral gangli on.
P.280
effects. Functi on fol l ows desi gn. SNS postgangl i oni c neurons outnumber the pregangl i onic neurons
in an average rati o of 20:1 to 30:1.
2
One pregangl i onic fiber i nfl uences a l arger number of
postgangl i onic neurons, whi ch are dispersed to many organs. In addi ti on, the SNS response i s
augmented by the hormonal release of epinephrine (EPI) from the adrenal medull a.
Parasympathetic Nervous System or Craniosacral Division
The PNS, l i ke the SNS, has both pregangli oni c and postgangl i oni c neurons. Thi s di vi si on i s
sometimes cal led the crani osacral outfl ow because the pregangl i onic cell bodi es ori gi nate in the
brainstem and sacral segments of the spi nal cord. PNS pregangl i oni c fi bers are found i n crani al
nerves III (ocul omotor), VII (faci al ), IX (glossopharyngeal), and X (vagus). The sacral outflow
origi nates i n the i ntermediolateral gray horns of the second, thi rd, and fourth sacral nerves.
Fi gure 12-1 shows the di stri buti on of the PNS di vi si on and i ts i nnervati on of visceral organs.
The vagus (crani al nerve X) nerve has the most extensive distri buti on of all the PNS, accounting
for more than 75% of PNS acti vi ty. The pai red vagus nerves suppl y PNS i nnervati on to the heart,
lungs, esophagus, stomach, smal l i ntesti ne, proxi mal hal f of the col on, l i ver, gal l bl adder,
pancreas, and upper porti ons of the ureters. The sacral fi bers form the pel vi c vi sceral nerves, or
nervi eri gentes. These nerves supply the remainder of the vi scera that are not i nnervated by the
vagus. They suppl y the descending col on, rectum, uterus, bladder, and l ower porti ons of the
ureters and are pri maril y concerned wi th emptyi ng. Vari ous sexual reacti ons are also governed by
the sacral PNS. The PNS i s responsi bl e for peni l e erecti on, but SNS sti mulation governs
ejacul ati on.
In contrast to the SNS divisi on, PNS pregangl i oni c fi bers pass directl y to the organ that i s
innervated. The postgangli oni c cel l bodi es are si tuated near or within the i nnervated vi scera and
general ly are not vi sibl e. The proximity of PNS gangli a to or wi thi n the viscera provi des a l imited
di stri buti on of postgangl i oni c fi bers. The rati o of postgangl i oni c to pregangl i onic fi bers i n many
organs appears to be 1:1 to 3:1, compared with the 20:1 found i n the SNS system. Auerbach's
pl exus in the di stal col on i s the excepti on, wi th a rati o of 8,000:1. The fact that PNS pregangl i onic
fibers synapse with only a few postgangli oni c neurons is consistent wi th the di screte and l imi ted
effect of PNS functi on. For exampl e, vagal bradycardi a can occur wi thout a concomi tant change i n
intesti nal motil i ty or sali vation. Mass refl ex action is not a characteristic of the PNS. The effects of
organ response to PNS sti mulation are outl i ned i n Tabl e 12-1.
Autonomic Innervation
Heart
The heart i s wel l suppl i ed by the SNS and PNS. These nerves affect cardiac pumping i n three
ways: (1) by changi ng the rate (chronotropi sm), (2) by changi ng the strength of contracti on
(i notropi sm), and (3) by modul ating coronary bl ood fl ow. The PNS cardiac vagal fibers approach
the stel late gangli a and then joi n the efferent cardi ac SNS fi bers; therefore, the vagus nerve to
the heart and l ungs i s a mi xed nerve contai ni ng both PNS and SNS efferent fi bers. The PNS fi bers
are di stri buted mai nl y to the si noatri al and atrioventricular (AV) nodes and to a l esser extent to
the atri a. There i s li ttl e or no distri buti on to the ventri cles. Therefore, the mai n effect of vagal
cardi ac sti mulation to the heart is chronotropi c. Vagal sti mul ati on decreases the rate of sinoatri al
node discharge and decreases excitabi l i ty of the AV junctional fi bers, slowi ng impul se conducti on
to the ventri cl es. A strong vagal discharge can compl etel y arrest sinoatri al node firi ng and bl ock
impul se conducti on to the ventricl es.
3

The physi ol ogi c i mportance of the PNS on myocardi al contracti li ty is not as wel l understood as that
of the SNS. Chol i nergi c bl ockade can doubl e the heart rate (HR) wi thout al teri ng contracti l ity of
the left ventri cle. Vagal sti mulation of the heart can reduce l eft ventri cul ar maximum rate of
tensi on devel opment (dP/dT) and decrease contracti l e force by as much as 10 to

20%. However, PNS sti mul ati on i s rel ati vel y unimportant i n thi s regard compared wi th its
P.281
predomi nant effect on HR.
The SNS has the same supraventri cul ar di stributi on as the PNS, but wi th stronger representati on
to the ventri cl es. SNS efferents to the myocardi um funnel through the pai red stel late gangli a. The
ri ght stel l ate gangl i on di stri butes pri maril y to the anteri or epi cardial surface and the
interventri cul ar septum. Right stell ate sti mul ati on decreases systol i c duration and i ncreases HR.
The l eft stel late gangli on suppl i es the posteri or and l ateral surfaces of both ventricl es. Left
stell ate stimul ati on i ncreases mean arteri al pressure and l eft ventri cul ar contracti li ty without
causi ng a substanti al change in HR. Normal SNS tone mai ntains contractil i ty approximatel y 20%
above that in the absence of any SNS sti mul ati on.
4
Therefore, the domi nant effect of the ANS on
myocardial contractil i ty i s mediated pri maril y through the SNS. Intrinsic mechanisms of the
myocardium, however, can maintai n ci rculation qui te well without the ANS, as evi denced by the
success of cardi ac transplants (see Denervated Heart).
5

Earl y i nvesti gations, performed in anestheti zed, open-chest ani mals, demonstrated that cardi ac
ANS nerves exert onl y sl ight effects on the coronary vascul ar bed; however, more recent studies
on chroni cal l y i nstrumented, intact, consci ous animal s show consi derabl e evi dence for a strong
SNS regul ati on of the small coronary resi stance and l arger conductance vessel s.
6
(See Adrenergic
Receptors section.)
Different segments of the coronary arteri al tree react di fferentl y to various stimul i and drugs.
Large conductance vessel s, the pri mary locati on for atheromatous plaques, are found on the
epi cardi al surface, whereas the smal l , precapi ll ary resistance vessel s are found wi thi n the
myocardium. Normall y, the l arge conductance vessels contri bute l ittl e to overall coronary vascul ar
resistance. Fl uctuati ons i n resistance refl ect changes i n lumen si ze of the small , precapi ll ary
vessel s. Bl ood fl ow through the resistance vessels i s regul ated pri mari l y by the l ocal metaboli c
requi rements of the myocardi um. The larger conductance vessel s, however, can constri ct markedl y
with neurogeni c sti mulation. Neurogeni c infl uence al so assumes a greater rol e i n the resistance
vessel s when they become hypoxic and l ose autoregulation. There is a strong interacti on between
SNS and PNS nerves i n organs with dual, antagoni sti c innervati on.
Peripheral Circulation
The SNS nerves are by far the most i mportant regul ators of the peri pheral ci rcul ati on. The PNS
nerves pl ay onl y a mi nor rol e i n this regard. The PNS di l ates vessel s, but onl y i n li mited areas
such as the geni tal s. SNS sti mulation produces both vasodil ati on and vasoconstri cti on, wi th
vasoconstri ctor effects predomi nating. The effect is determined by the type of receptors on which
the SNS fi ber termi nates (see Receptors). SNS constri ctor receptors are di stri buted to al l
segments of the ci rculation. Thi s di stri buti on i s greater i n some tissues than in others. Blood
vessel s in the ski n, ki dneys, spl een, and mesentery have an extensive SNS di stri buti on, whereas
those i n the heart, brai n, and muscl e have less SNS i nnervation. SNS sti mulation of the coronary
arteries may produce vasoconstri cti on or vasodil ati on, dependi ng on the predomi nant receptor
acti vi ty at the ti me of stimul ati on (see Tabl e 12-1). Vagal sti mulation may also produce coronary
vasoconstri cti on (see -Adrenergic Receptors secti on). However, l ocal autoregul atory factors
usuall y have the predominant infl uence on coronary vascul ar tone.
Basal vasomotor tone is mai ntained by i mpul ses from the l ateral porti on of the vasomotor center
in the medul la oblongata that conti nuall y transmi ts i mpul ses through the SNS, mai ntai ni ng parti al
arteriol ar and venul ar constri cti on. Circul ati ng EPI from the adrenal medull a has addi tive effects.
Thi s basal ANS tone mai ntains arteri ol ar constriction at an intermedi ate diameter.
7
The arteri ole,
therefore, has the potenti al for either further constriction or di lation. If the basal tone were not
present, the SNS coul d onl y effect vasoconstriction and not vasodi lation.
1
The SNS tone i n the
venules produces li ttl e resi stance to fl ow compared wi th the arteri oles and the arteri es. The
importance of SNS stimul ati on of vei ns i s to reduce or increase their capacity. By functi oning as a
reservoi r for approxi matel y 80% of the total blood volume, smal l changes in venous capaci tance
produce l arge changes in venous return and, thus, cardiac prel oad.
Lungs
The l ungs are i nnervated by both the SNS and PNS. Postgangl i oni c SNS fi bers from the upper
thoraci c gangli a (stell ate) pass to the l ungs to innervate the smooth muscl es of the bronchi and
pul monary blood vessel s. PNS innervati on of these structures i s from the vagus nerve.
SNS sti mul ati on produces bronchodil ati on and pul monary vasoconstri cti on.
8
Little el se has been
proven concl usi vely about the vasomotor control of the pul monary vessel s other than that they
adjust to accommodate the output of the ri ght ventri cl e. The effect of sti mulation of the
pul monary SNS nerves on pulmonary vascul ar resistance i s not great but may be i mportant i n
maintai ni ng hemodynami c stabi li ty duri ng stress and exerci se by bal anci ng ri ght and l eft
ventri cul ar output. Sti mul ati on of the vagus nerve produces al most no vasodil ati on of the
pul monary ci rculation. The phenomenon of hypoxic pulmonary vasoconstricti on appears to be an
important force i n regul ati on of pul monary bl ood fl ow. Hypoxi c pul monary vasoconstri cti on is a
l ocal phenomenon capabl e of provi di ng a faster adjustment to needs.
Both the SNS and the vagus nerve provide acti ve bronchomotor control . SNS stimul ati on causes
bronchodil ati on, whereas vagal stimul ati on produces constri cti on. PNS stimul ati on may al so
increase secreti ons of the bronchi al gl ands. Vagal receptor endi ngs i n the al veolar ducts al so pl ay
an important role i n the reflex regulation of the venti l ation cycl e.
9
The l ung has i mportant
nonventi l atory acti vi ty as wel l. It serves as a metabol ic organ that removes local medi ators such
as norepi nephri ne (NE) from the ci rcul ati on and converts others, such as angiotensin 1, to active
compounds.
10
(See Interaction with Other Regul atory Systems section.)

AUTONOMIC NERVOUS SYSTEM: NEUROTRANSMISSION
Transmi ssi on of exci tation across the termi nal juncti onal si tes (synapti c cl efts) of the peri pheral
ANS occurs through the medi ati on of li berated chemi cal s (Fi g. 12-5). Transmi tters i nteract wi th a
receptor on the end organ to evoke a bi ologi c response. The ANS can be pharmacologi cal ly
subdi vi ded by the neurotransmi tter secreted at the effector cel l . Pharmacol ogi c parl ance
desi gnates the SNS and PNS as adrenergi c and chol i nergic, respectivel y. The termi nals of the PNS
postgangl i onic fibers rel ease acetyl choli ne (ACh). Wi th the excepti on of sweat glands, NE i s
consi dered the principal neurotransmi tter rel eased at the termi nal s of the sympatheti c
postgangl i onic fibers (see Fi g. 12-3). Co-transmi ssi on of ATP, neuropepti de Y (NPY), and NE has
been demonstrated at vascul ar sympatheti c nerve termi nal s i n a number of di fferent ti ssues
incl udi ng muscl e, i ntesti ne, ki dney, and ski n (see SNS Neurotransmi ssi on section). The
pregangl ioni c neurons of both systems secrete ACh.
FIGURE 12-5. The anatomy and physi ol ogy of the termi nal postgangli oni c fibers of
sympatheti c and parasympatheti c fi bers are si mi lar.
The terminati ons of the postganglionic fibers of both ANS subdi vi si ons are anatomi cal l y and
physi ol ogi cal l y si mi lar. The termi nati ons are characteri zed by mul ti pl e branchi ngs call ed terminal
effector pl exuses, or reticulae. These fi l aments surround the elements of the effector unit li ke a
mesh stocking.
11
Thus, one SNS postgangli oni c neuron, for exampl e, can

innervate ~25,000 effector cell s (e.g., vascul ar smooth muscl e). The termi nal fi laments end in
presynaptic enl argements cal led vari cositi es. Each vari cosi ty contains vesicl es, ~500 in
di ameter, i n which the neurotransmi tters are stored (see Fi g. 12-5). The vari cosi ti es are also
heavi l y popul ated wi th mi tochondri a, whi ch rel ates to the i ncreased energy (adenosi ne
tri phosphate, ATP) requi rements of ACh and NE synthesi s. The rate of synthesi s depends on the
l evel of ANS acti vi ty and i s regul ated by l ocal feedback. The di stance between the vari cosi ty and
the effector cel l (synapti c or juncti onal cl eft) vari es from 100 in gangl ia and arteriol es to as
much as 20,000 in l arge arteri es. Thi s distance determi nes the amount of transmi tter required
to sti mul ate and the ti me i t takes to di ffuse to the effector cel l. The time for diffusi on i s di rectl y
proporti onal to the width of the synapti c gap. Depol arizati on rel eases the vesi cular contents into
the synapti c cleft by exocytosi s.
Parasympathetic Nervous System Neurotransmission
Synthesis
ACh is considered the pri mary neurotransmi tter of the PNS. ACh is formed in the presynapti c
termi nal by acetyl ati on of chol ine wi th acetyl coenzyme A. Thi s step i s catalyzed by chol i ne acetyl
transferase (Fi g. 12-6). ACh is then stored i n a concentrated form i n presynaptic vesi cles. A
conti nual rel ease of smal l amounts of ACh, cal l ed quanta, occurs during the resti ng state. Each
quantum resul ts in small changes in the el ectrical potential of the synapti c end pl ate wi thout
produci ng depol ari zati on. These are known as mi ni ature end-pl ate potential s. Arri val of an action
potential causes a synchronous rel ease of hundreds of quanta, resul ti ng in depolari zation of the
end pl ate. Rel ease of ACh from the vesi cl es i s dependent on i nflux of cal ci um (Ca2+) from the
intersti ti al space. Drugs that al ter Ca2+ binding or i nfl ux may decrease ACh rel ease and affect
end-organ functi on. ACh i s not reused l i ke NE; therefore, i t must be synthesi zed constantl y.
P.282
FIGURE 12-6. Synthesi s and metabol ism of acetylchol ine.
Metabolism
The ability of a receptor to modulate function of an effector organ i s dependent on rapi d recovery
to i ts basel i ne state after sti mul ati on. For thi s to occur, the neurotransmi tter must be qui ckl y
removed from the vi ci ni ty of the receptor. ACh removal occurs by rapi d hydrol ysi s by
acetylchol inesterase (see Fi g. 12-6). Thi s enzyme i s found in neurons, at the neuromuscul ar
juncti on, and i n vari ous other tissues of the body. A similar enzyme, pseudocholi nesterase or
pl asma chol i nesterase, i s also found throughout the body but onl y to a l imited extent i n nervous
ti ssue. It does not appear to be physi ologicall y important i n termi nation of the acti on of ACh. Both
acetylchol inesterase and pseudochol i nesterase hydrol yze ACh, as wel l as other esters (such as the
ester-type local anestheti cs), but they may be distingui shed by specifi c bi ochemical tests.
3

Sympathetic Nervous System Neurotransmission
Traditi onal l y, the catechol amines EPI and NE were considered the exclusi ve medi ators of
peri pheral SNS acti vi ty. Evidence accumulated over the past two decades, though, suggests rol es
for ATP as an addi ti onal sympatheti c neurotransmitter. NE i s rel eased from l ocali zed presynapti c
vesi cles of nearly al l postgangl ioni c sympatheti c nerves. Vascular SNS nerve terminal s, though,
al so rel ease ATP. Thus, ATP and NE are co-neurotransmitters. They are released directl y i nto the
si te where they act. Thei r postjunctional effects appear to be synergistic i n ti ssues studi ed to
date.
The SNS fi bers endi ng i n the adrenal medul l a are pregangl i onic, and ACh is the neurotransmi tter
(see Fi g. 12-3). It i nteracts wi th the chromaffi n cel ls i n the medull a, causi ng rel ease of EPI and
NE. The chromaffin cel l s take the place of the postgangl ioni c neurons. Sti mulati on of the
sympatheti c nerves to the adrenal medul la, however, causes the rel ease of large

quantiti es of a mixture of EPI and NE into the circul ati on to become neurotransmi tter hormones.
The greater porti on of thi s hormonal surge i s normal l y EPI. EPI and NE, when rel eased i nto the
ci rculati on, are classi fi ed as hormones i n that they are synthesi zed, stored, and rel eased from the
adrenal medul l a to act at distant si tes.
Hormonal EPI and NE have al most the same effects on effector cells as those caused by l ocal
di rect sympathetic stimul ati on; however, the hormonal effects, al though bri ef, l ast about 10 ti mes
as l ong as those caused by di rect sti mulation.
12
EPI has a greater metabol i c effect than NE. It can
increase the metabol i c rate of the body as much as 100%.
1
It al so i ncreases gl ycogenol ysi s in the
li ver and muscl e wi th gl ucose rel ease i nto the blood. These functions are al l necessary to prepare
the body for fight or fl i ght. Some of the overal l vascular tone resul ts from the basal resti ng
secretion of the adrenal medull a i n addi ti on to the tone that is mai ntai ned di rectl y through
stimul ati on from central vasomotor centers i n the medul l a.
Catecholamines: The First Messenger
The endogenous catecholami nes i n humans are dopami ne (DA), NE, and EPI. Dopamine i s a
neurotransmitter i n the CNS. It i s pri mari l y i nvol ved i n coordi nati ng motor activity in the brai n. It
is the precursor of NE. NE i s synthesized and stored in nerve endi ngs of postgangl i oni c SNS
neurons. It i s al so synthesized in the adrenal medul la and is the chemi cal precursor of EPI. Stored
EPI is l ocated chiefly i n chromaffi n cel ls of the adrenal medul l a. Ei ghty to 85% of the
catechol amine content of the adrenal medull a is EPI and 15 to 20% is NE. The brain contai ns both
noradrenergi c and dopami nergi c receptors, but ci rculating catecholami nes do not cross the blood-
brain barrier. The catechol ami nes present i n the brai n are synthesized there. Endogenous
catechol amines are uni que i n that several i ntermedi ates i n the synthesis functi on as
neurotransmitters.
A catechol ami ne i s any compound of a catechol nucl eus (a benzene ri ng wi th two adjacent
hydroxyl groups) and an amine-contai ning side chai n.
13
The chemical configurati on of si x of the
more common catecholami nes i n cl i ni cal use i s demonstrated i n Fi gure 12-7. A true catechol ami ne
must possess thi s basi c structure. Catechol amines are often referred to as adrenergi c drugs
P.283
because thei r effector actions are medi ated through receptors speci fi c for the SNS. Syntheti c
catechol amines can activate these same receptors because of their structural si mil ari ty. For
example, cl oni dine i s an -2 receptor agoni st that does not possess a catechol nucleus and even
has two ring systems that are apl anar to each other (Fi g. 12-8). However, cl oni dine enjoys a
remarkabl e spati al si mi l arity to NE that all ows it to activate the receptor.
14
Drugs that produce
sympatheti c-li ke effects but l ack the basi c catechol ami ne structure are defi ned as
sympathomimeti cs. All cl inicall y useful catecholami nes are sympathomimeti cs, but not all
sympathomimeti cs are catechol ami nes (Tabl e 12-4).
FIGURE 12-7. The chemical configurations of three endogenous catecholami nes are
compared with those of three syntheti c catecholami nes. Sympathomimeti c drugs di ffer in
thei r hemodynami c effects l argely because of differences in substituti on of the amine group
on the catechol nucl eus.
FIGURE 12-8. The spati al si mi l arity of cloni di ne and NE al l ows it to activate presynapti c -2
receptors i nhibi ting NE rel ease.
TABLE 12-4 Sympathomimetic Drugs
DRUG TRADE NAME
ADRENERGIC AMINES
Catecholamines
Epi nephri ne Adrenal i n
Norepi nephri ne Levophed
Dopamine
a
Inotropi n
Dobutamine Dobutrex
Dopexamine
Isoproterenol Isuprel
Noncatecholamines
The effects of endogenous or syntheti c catechol ami nes on adrenergi c receptors can be di rect or
indirect (see Tabl e 12-4). Indi rect-acti ng catechol ami nes (i.e., ephedri ne) have li ttl e i ntrinsi c
effect on adrenergic receptors but produce thei r effects by sti mul ating release of the stored
neurotransmitter from SNS nerve termi nal s. Some syntheti c and endogenous catechol ami nes
stimul ate adrenergi c receptor sites directl y, whereas others have a mi xed mode of acti on. The
acti ons of di rect-acti ng catechol ami nes are independent of endogenous NE stores; however, the
indirect-acti ng catechol ami nes are total l y dependent on adequate neuronal stores of endogenous
NE.

Metarami nol
a
,
b
Aramine
Mephentermine
b
Wyamine
Ephedrine
b
Ephedrine
Methoxami ne Vasoxyl
Phenylephri ne Neo-Synephri ne
Cloni di ne
NONADRENERGICS
Xanthi nes Ami nophyl l ine
Gl ucagon Gl ucagon
Digi tal i s Lanoxi n
Cal cium sal ts
Nal oxone Narcan
Amrinone Inocor
a
Direct-acti ng catechol ami ne with some indi rect acti on.
b
Pri maril y i ndirect-acti ng wi th some direct acti on. Adrenergic ami nes produce
sympathomimeti c effects via adrenergic receptors.
Nonadrenergi cs produce sympathomimeti c effects excl usi ve of the adrenergi c receptor.

Synthesis
The mai n si te of NE synthesi s is i n or near the postgangl ioni c nerve endi ngs. Some synthesis does
occur in vesi cl es near the cel l body that pass to the nerve endi ngs.
15
Phenylal ani ne or tyrosi ne is
taken up i nto the axoplasm of the nerve termi nal and synthesi zed into ei ther NE or EPI. Fi gure 12-
9 demonstrates thi s synthesis cascade. Tyrosi ne hydroxylase catal yzes the conversion of tyrosi ne
to dihydroxyphenyl al ani ne. This i s the rate-li mi ting step at which NE synthesi s is control l ed
through feedback inhi bi ti on.
16
Di hydroxyphenyl al ani ne and the subsequent compounds i n this
cascade are catechol ami nes.
Dopami ne synthesi s occurs i n the cytoplasm of the neuron. Dopami ne then enters the storage
vesi cles. Synthesis stops at this poi nt where dopamine is the neurotransmitter. The vesi cl es of
peri pheral postgangl ioni c neurons contain the enzyme dopami ne-b-hydroxyl ase, whi ch converts
dopami ne to NE. The adrenal medull a addi tional ly contains phenyl ethanol ami ne-N-
methyl transferase, whi ch converts NE to EPI. Thi s reacti on takes pl ace outside the medull ary
vesi cles, and the newl y formed EPI then enters the vesi cl e for storage (Fi g. 12-10). All the
endogenous catechol ami nes are stored in presynaptic vesi cles and rel eased on arrival of an action
potential . Exci tation-secretion coupl i ng i n sympatheti c neurons i s Ca2+-dependent.
P.284
FIGURE 12-9. Schemati c of the synthesis of catechol amines. The conversi on of tyrosi ne to
DOPA by tyrosi ne hydroxyl ase i s i nhi bi ted by i ncreased NE synthesi s. Epi nephri ne is shown i n
these steps but is pri mari ly synthesi zed i n the adrenal medul l a.
Regulation
Increased SNS nervous acti vi ty, as in congesti ve heart fai l ure (CHF) or chronic stress, sti mul ates
the synthesis of catechol amines.
17
Glucocorti coi ds from the adrenal cortex sti mul ate an i ncrease in
phenylethanol amine-N-methyl transferase that methyl ates NE to EPI.
The rel ease of NE i s dependent on depolari zation of the nerve and an i ncrease in cal cium ion
permeabil i ty.
17
Thi s rel ease i s inhi bi ted by col chi ci ne and prostagl andi n E2, suggesti ng a
contracti l e mechani sm. Blockade of prostaglandi n synthesi s enhances NE release. NE i nhibi ts its
own rel ease by sti mul ating presynapti c (prejuncti onal) -2 receptors. Phenoxybenzami ne

and phentol ami ne, -receptor antagonists, increase the rel ease of NE by blocki ng i nhi bitory
presynaptic -2 receptors (Fi g. 12-11). Other receptors may al so be i mportant in NE regulation.
(See Other Receptors section.)
FIGURE 12-10. Schemati c of the synthesis and disposi tion of NE i n adrenergi c
neurotransmission. (1) Synthesi s and storage i n neuronal vesi cles; (2) acti on potenti al
permi ts cal ci um entry with (3) exocytosis of NE i nto synapti c gap. (4) Released NE reacts
with receptor on effector cell . NE (5) may react wi th presynaptic -2 receptor to i nhi bi t
further NE rel ease or with presynaptic receptor to enhance reuptake of NE (6) (uptake 1).
Extraneuronal uptake (uptake 2) absorbs NE i nto effector cel l (7) with overfl ow occurri ng
systemi cal ly (8). MAO, monoami ne oxidase; COMT, catechol -O-methyl transferase; Tyr,
tyrosi ne; DOPA, di hydroxyphenyl alani ne; NE, norepi nephri ne.
P.285
Inactivation
The catecholami nes are removed from the synapti c cl eft by three mechani sms (see Fi g. 12-10).
These are reuptake i nto the presynaptic termi nals, extraneuronal uptake, and diffusi on.
Termi nation of NE at the effector site i s al most entirely by reuptake of NE i nto the terminal s of the
presynaptic neuron (uptake 1) for reuse. Uptake 1 is an active, energy-requi ring, temperature-
dependent process.
The reuptake of NE i n the presynaptic terminal s i s al so a stereospeci fi c process. Structurall y
si mi l ar compounds (guanethi di ne, metarami nol) may enter the vesi cles and displ ace the
neurotransmitter. Tri cycl i c anti depressants and cocai ne i nhi bit the reuptake of NE, resul ti ng in
hi gh synapti c NE concentrati ons and accentuated receptor response. In addi ti on, evi dence
suggests that NE reuptake i s medi ated by a presynapti c -adrenergi c mechani sm because -
bl ockade causes marked elevations of EPI and NE
18
(see Fi gs. 12-10 and 12-11), whereas a
bl ockade does not. Extraneuronal uptake (uptake 2) i s a mi nor pathway for i nacti vating NE. NE i s
taken up by effector cel l s and other extraneuronal tissues. The NE that is taken up by the
extraneuronal ti ssue is metabol i zed by monoamine oxi dase and by catechol -O-methyl transferase
to form vani l lylmandeli c aci d (Fi g. 12-12). The mi nute amount of catecholami ne that escapes
uptake 1 and uptake 2 di ffuses i nto the circul ati on (uptake 3), where it i s simil arl y metabol ized in
the l i ver and ki dney. The i mportance of uptake 1 and uptake 2 i s dimi ni shed when
sympathomimeti cs are given exogenousl y. EPI is i nacti vated by the same enzymes. Whereas
uptake 1 is the predomi nant pathway for inacti vati on of the endogenous catecholami nes, uptake 3
is the predominant pathway for catechol ami nes gi ven exogenousl y and is cl ini call y important. Thi s
accounts for the l onger duration of acti on by exogenous catechol ami nes than that noted at the
local synapse. The former i s sl ow (li ver metabol ism) and the l atter i s fast (uptake 1).
FIGURE 12-11. Thi s schemati c demonstrates just a few of the presynapti c adrenergi c
receptors thought to exi st. Agoni st and antagoni st drugs are cl i ni cal ly avail abl e for these
receptors (see Tabl e 12-5). The -2 receptors serve as a negative feedback mechani sm
whereby NE stimul ati on i nhibi ts its own rel ease. Presynapti c stimul ati on i ncreases NE
uptake, augmenti ng i ts avai l abi l ity. Presynaptic muscarinic (MUSC) receptors respond to ACh
diffusing from nearby cholinergi c termi nal s. They inhi bit NE rel ease and can be bl ocked by
atropi ne.
The fi nal metabol ic product of the catechol ami nes i s vani ll yl mandel i c aci d. Vani l lylmandeli c aci d
consti tutes the major metaboli te (80 to 90%) of NE found i n the uri ne. Less than 5% of rel eased
NE appears unchanged i n the urine. The metaboli c products excreted in the uri ne provi de a gross
estimate of SNS acti vi ty and can faci li tate the cl inical diagnosis of pheochromocytoma.
RECEPTORS
An agoni st i s a substance that i nteracts with a receptor to evoke a biol ogi c response. ACh, NE,
EPI, DA, and ATP are the major agonists of the ANS. An antagoni st i s a substance that i nterferes

with the evocation of a response at a receptor si te by an agoni st. Receptors are therefore
regarded as target si tes that when activated by an agoni st wi l l l ead to a response by the effector
cel l. Receptors are protein macromolecul es and are located in the pl asma membrane. Several
thousand receptors have been demonstrated in a single cel l. The enormi ty of thi s network i s
reali zed when it i s consi dered that ~25,000 singl e cel l s can be i nnervated by a single neuron.
19

Cholinergic Receptors
ACh is the neurotransmitter at three di sti nct classes of receptors. These receptors can be
di fferenti ated by their anatomi c l ocati on and thei r affi ni ty to bi nd vari ous agoni sts and
antagonists.
20
ACh medi ates the first messenger function of transmi tti ng i mpul ses i n the PNS,
the gangli a of the SNS, and the neuroeffector juncti on of stri ated, vol untary muscl e (see Fi g. 12-
3). The receptors are referred to as choli nocepti ve or chol i nergic receptors. The PNS is referred to
as the chol inergi c system.
Chol i nergi c receptors are further subdi vi ded i nto muscari ni c and ni cotini c receptors because
muscari ne and ni coti ne sti mulate them sel ecti vel y.
3
However, both muscari ni c and ni cotini c
receptors respond to ACh (see Choli nergi c Drugs section). Muscari ne activates chol i nergic
receptors at the postgangli oni c PNS juncti ons of cardiac and smooth muscl e throughout the body.
Muscari nic sti mulation is characterized by bradycardi a, decreased i notropism, bronchoconstricti on,
FIGURE 12-12. Catabol i sm of NE and EPI.
P.286
mi osi s, sal ivation, gastrointestinal (GI) hypermoti l ity, and i ncreased gastri c aci d secreti on (see
Tabl e 12-1). Muscarinic receptors can be bl ocked by atropi ne wi thout effect on ni cotinic receptors
(see Choli nergi c Drugs secti on).
Muscari nic receptors are known to exi st i n si tes other than PNS postgangl i oni c juncti ons. They are
found on the presynapti c membrane of sympathetic nerve terminal s i n the myocardium, coronary
vessel s, and peri pheral vascul ature (see Fi g. 12-11). These are referred to as adrenergic
muscari ni c receptors because of their l ocati on; however, they are sti mulated by ACh. Sti mulation
of these receptors i nhibi ts rel ease of NE i n a manner si mi l ar to -2 receptor sti mul ati on.
6

Muscari ni c bl ockade removes i nhi bi ti on of NE rel ease, augmenting SNS acti vi ty. Atropi ne, the
prototypical muscari ni c blocker, may produce sympathomimeti c acti vi ty in thi s manner as wel l as
vagal bl ockade. Neuromuscul ar blocki ng drugs that cause tachycardia are thought to have a
similar mechanism of action.
ACh acti ng on presynapti c adrenergic muscarinic receptors i s a potent i nhibi tor of NE rel ease.
18

The prejunctional muscari ni c receptor may pl ay an i mportant physi ol ogic rol e because several
autonomi cal l y i nnervated ti ssues (e.g., the heart) possess ANS pl exuses i n whi ch the SNS and PNS
nerve termi nal s are closel y associ ated.
3
In these pl exuses, ACh, rel eased from the nearby PNS
nerve termi nal s (vagus nerve), can inhi bit NE rel ease by activati on of presynaptic adrenergi c
muscari ni c receptors (see Fi g. 12-11).
Ni cotini c receptors are found at the synaptic juncti ons of both SNS and PNS gangl ia. Because both
juncti ons are chol i nergic, ACh or ACh-li ke substances such as ni cotine wi l l exci te postgangli oni c
fibers of both systems (see Fi g. 12-3). Low doses of ni cotine produce stimul ati on of ANS gangl ia,
whereas hi gh doses produce bl ockade. This dual i sm i s referred to as the ni cotinic effect (see
Gangl i onic Drugs secti on). Ni coti ni c sti mulation of the SNS gangl ia produces hypertensi on and
tachycardi a by causing the release of EPI and NE from the adrenal medull a. Adrenal hormone
rel ease i s mediated by ACh i n the chromaffin cell s, whi ch are anal ogous to postgangli oni c neurons
(see Fi g. 12-3). A further increase in nicoti ne concentration produces hypotensi on and
neuromuscul ar weakness as it becomes a gangl ioni c bl ocker. The chol i nergi c neuroeffector
juncti on of skeletal muscl e al so contains ni cotinic receptors, although they are not i denti cal to the
ni cotinic receptors i n ANS gangl i a.
Adrenergic Receptors
Von Eul er di fferenti ated the physi ol ogic effects of EPI and NE i n 1946.
14
The adrenergi c receptors
were termed adrenergi c or noradrenergi c, dependi ng on thei r responsiveness to EPI or NE. The
di ssimil ari ti es of these two drugs l ed Ahlqui st i n 1948 to propose two types of opposing adrenergic
receptors, termed al pha () and beta (). Thi s postul ation impli ed that sel ecti ve antagoni sm of
these receptors was possibl e. The receptors can be cl assified according to the order of potency by
whi ch they are affected by SNS agonists and antagoni sts. Receptors that respond wi th an order of
potency of NE EPI > isoproterenol are cal l ed receptors. Those respondi ng wi th an order of
potency of i soproterenol > EPI NE are cal l ed receptors (Tabl e 12-5). The devel opment of new
agoni sts and antagonists wi th rel ati vel y sel ective activity al l owed subdivisi on of the receptors
into
1
and
2
. receptors were subsequentl y di vi ded i nto
1
and
2
. The concept of rel ati ve
sel ecti ve acti vi ty ari ses from di fferenti al potenci es among ti ssue groups to the same drug, such
that two dose-response curves are obtained (Fi g. 12-13). The sympathomi metic adrenergi c drugs
in current use differ from one another i n thei r effects l argel y because of differences i n substi tuti on
on the ami ne group, whi ch i nfl uences the rel ati ve or effect (see Fig. 12-7).
13

TABLE 12-5 Adrenergic Receptors: Order of Potency of Agonists and Antagonists
RECEPTOR AGONISTS
a
ANTAGONISTS LOCATION ACTIO
Another major peri pheral adrenergi c receptor speci fi c for dopamine is termed the dopaminergi c
(DA) receptor. Further studi es have revealed not onl y subsets of the and receptors but al so
the DA receptor. These DA receptors have been i dentified in the CNS and in renal, mesenteric, and
coronary vessel s. The physi ol ogic importance of these receptors i s a matter of controversy
because there are no identi fi able peri pheral DA neurons. Dopami ne measured in the ci rcul ati on i s
assumed to result from spillover from the brain.
The functi on of dopami ne i n the CNS has l ong been known, but the peri pheral DA receptor has
been el ucidated only wi thi n the past 25 years. The presence of the peripheral DA receptor was
obscured because dopami ne does not affect the DA receptor exclusivel y. It al so sti mul ates and
receptors i n a dose-rel ated manner.
21
However, DA receptors functi on i ndependentl y of or
bl ockade and are modi fi ed by DA antagoni sts such as hal operi dol, droperi dol , and phenothi azines.
Thus, there i s a necessity for the addi tion of the DA receptor and i ts subsets (DA1 and DA2).
The anatomi c l ocati on and ami no acid structure of receptor bi ndi ng si tes have been made possi bl e
through radi ol i gand studies. The di stri buti on of adrenoreceptors i n organs and tissues i s not
uni form and thei r functi on di ffers not only by thei r l ocati on but al so i n thei r numbers and/or
di stri bution.
22
Adrenoceptors are found in two loci in the sympatheti c neuroeffector juncti on. They
are found in both the presynapti c (prejuncti onal ) and postsynapti c (postjuncti onal) si tes as well as
extrasynapti c si tes (Fi g. 12-14). Tabl e 12-6 is a review of the function and synaptic location of
some of the cl i ni cal ly i mportant si tes.
FIGURE 12-13. Rel ati ve dose-response rel ationship on target and other organs. Relative
sel ecti vi ty is i l lustrated by showing the relationshi p between two dose-response curves. The
curve on the l eft represents the desi red response of bronchodi lation using a rel ati vel y
sel ecti ve -2 agoni st. The unwanted effects on other organs that occur at hi gher doses are
represented by the curve on the ri ght. For exampl e, an i ncreased HR (-1 effect) may occur
with hi gher doses of a rel ati vel y sel ect -2 agoni st. The opti mal range is that concentrati on
of drug that wi l l gi ve the maximal desired response wi th mi nimal effects on other organs. The
si ze of the optimal range i s dependent on the therapeutic i ndex, or the distance between the
two curves. These are usuall y establ i shed i n vitro where drug concentrati on can be preci sely
control led. For many cardiovascular drugs, the opti mal range i s small , and wi de fl uctuati ons
in serum level of the drug are common; therefore, secondary or si de effects are often seen
duri ng drug therapy.
TABLE 12-6 Adrenergic Receptors
RECEPTOR SYNAPTIC SITE ANATOMIC SITE ACTION LV
FUNCTION
AND
STROKE
VOLUME
1
Postsynapti c Peri pheral
vascul ar smooth
muscle
Constriction Decreased
Renal vascul ar
smooth muscl e
Constriction
Coronary
arteries,
epi cardi al
Constriction
Myocardi um Positi ve i notropism
3040% of resti ng tone
Renal tubules Antidiuresis
2
Presynaptic Peri pheral
vascul ar smooth
muscle rel ease
Inhi bit NE
Secondary
vasodilation
Improved
Coronari es ?
CNS Inhi biti on of CNS activity
Sedati on
Decrease MAC
Postsynapti c Coronari es,
endocardi al
Constriction Decreased
CNS Inhi biti on of i nsul i n rel ease
Decreased bowel moti l ity
Inhi biti on of antidi uretic
hormone
Anal gesi a
Renal tubule
Promotes Na
2+
and H
2
O
excreti on
1
Postsynapti c
NE sensiti ve
Myocardi um Positi ve
i notropi sm and
chronotropi sm
Improved
Si noatri al (SA) node
Ventri cul ar conducti on
Ki dney Renin rel ease
Coronari es Rel axati on
2
Presynaptic Myocardi um Accelerates NE
rel ease
Improved
NE sensiti ve SA node
ventri cul ar
conducti on
vessel s
Opposi te action
to presynapti c
2
agoni sm

Constriction
Postsynapti c
(extrasynaptic)
(EPI sensi tive)
Myocardi um Positi ve i notropism and
chronotropi sm
Vascul ar smooth
muscle
Rel axati on Improved
Bronchial smooth
muscle
Rel axati on Improved
Renal vessels Rel axati on Improved
DA
1
Postsynapti c Bl ood vessel s
(renal,
mesentery,
Vasodi l ati on Improved
coronary)
Renal tubules Natri uresi s
Di uresi s
Juxtagl omerular
cel ls
Renin rel ease (modulates
di uresis)
Sympatheti c
gangli a
Mi nor i nhibi ti on
DA
2
Presynaptic Postgangl i onic
sympatheti c
nerves
Inhi bit NE
rel ease
Improved
Secondary vasodi l ati on
Postsynapti c Renal and
mesenteric
vascul ature
? Vasoconstriction
FIGURE 12-14. Loci of several known adrenergic receptors. The presynaptic -2 and DA
receptors serve as a negative feedback mechani sm, whereby sti mulation of NE i nhibi ts its
own rel ease. Presynaptic -2 sti mulation increases NE uptake, augmenting i ts avai labi li ty.
Prejuncti onal receptors are considered i nnervated in that they are in the i mmediate vi ci nity of the
neurotransmitter released by a sympathetic action potential . Postjuncti onal receptors are
consi dered to be innervated or noni nnervated dependi ng on thei r proxi mi ty to the synaptic cl eft.
23

Receptors l ocated directl y on postjunctional membranes are considered to be i nnervated. However,
most postsynaptic -2 and -2 receptors are extrasynapti c and considered noni nnervated even
though they are l ocated i n the vi ci nity of the postsynapti c membrane. These receptors are
infl uenced more by hormonal catecholamines (EPI) than by neurotransmi tter (NE).

Extrasynaptic receptors al so seem to be l ess infl uenced by factors causing the up or down
regul ati on of receptor numbers and sensiti vi ty. Thi s may explai n the cl i ni cal observati on of why
EPI may work where other agoni sts, whi ch work on synapti c receptors, may be ineffecti ve. The
agoni streceptor i nteraction of noni nnervated receptors i s of slower onset and longer durati on as
well.
-Adrenergic Receptors
Two cl asses of cl i ni cal l y i mportant receptors have been demonstrated, -1 and -2. Thi s
cl assi ficati on i s based on their response to the antagoni sts yohi mbi ne and prazosi n. Prazosin i s a
more potent antagoni st of -1 receptors, whereas -2 receptors are more sensi ti ve to yohi mbi ne.
The -1- adrenergi c receptors are found i n the smooth muscl e cel l s of the peri pheral

vascul ature of the coronary arteri es, skin, uterus, intestinal mucosa, and spl anchni c beds (see
Tabl e 12-5). The -1 receptors serve as postsynapti c activators of vascular and i ntesti nal smooth
muscle as wel l as of endocrine glands. Their acti vati on resul ts i n ei ther decreased or increased
tone, dependi ng on the effector organ. The response in resi stance and capaci tance vessel s is
constri cti on, whereas in the i ntesti nal tract i t is rel axation. There is now a l arge body of evi dence
documenting the presence of postjunctional -1 adrenoreceptors i n the mammal i an heart. -1
adrenoreceptors have been shown to have a positi ve inotropi c effect on cardiac tissues from most
mammal s studi ed, i ncl udi ng humans.
24
Experi mental work strongl y supports the concept that
enhanced myocardi al -1 responsiveness pl ays a pri mary rol e i n the genesi s of mal i gnant
arrhythmi as i nduced by catechol ami nes during myocardi al i schemi a and reperfusi on. Drugs
possessing potent -1 antagoni st acti vi ty such as prazosi n and phentol ami ne provi de si gni fi cant
anti arrhythmic acti vi ty. The cl i ni cal mechanism and significance of these fi ndi ngs are not yet
cl ear.
25
However, there i s no doubt that -1 adrenergic antagoni sts prevent catecholami ne-
i nduced ventri cul ar arrhythmi as.
26
In contrast, studi es of the effects of -antagonists in
experi mental and cl i ni cal myocardi al infarcti on have provi ded confl icting resul ts.
The di scovery of presynapti c -adrenoreceptors and thei r rol e in the modul ation of NE
transmi ssi on provi ded the stimul us for the subclassi fi cati on of receptors i nto -1 and -2
subtypes.
27
Presynapti c -1 receptors have not been i dentified and appear confined to the
postsynapti c membrane. -2 receptors are found on both presynapti c and postsynapti c membranes
of the adrenergic neuroeffector juncti on. Tabl e 12-6 revi ews these sites. Postsynapti c membranes
contai n a near equal mix of -1 and -2 receptors.
The -2 adrenoreceptors may be subdi vided even further i nto as many as four possible subtypes.
Many acti ons have been attri buted to the postsynapti c -2 receptor, incl uding arteri al and venous
vasoconstri cti on, pl atel et aggregation, inhi bi ti on of insul in release, inhi bi ti on of bowel moti l i ty,
stimul ati on of growth hormone rel ease, and inhi biti on of anti diuretic hormone rel ease.
-2 receptors can be found i n chol i nergic pathways as wel l as i n adrenergic pathways. They can
si gni fi cantl y modul ate parasympatheti c activity as wel l . Current research i mpl i es that -2
stimul ati on i n parasympatheti c pathways pl ays a rol e in the modul ati on of the baroreceptor refl ex
Postsynapti c -2 and -2 receptors are extrasynaptic and are consi dered noni nnervated
hormonal receptors.
P.287
P.288
(i ncreased sensi tivity),

vagal medi ati on of heart rate (bradycardi a), bronchoconstricti on, and sal ivati on (dry mouth).
However, chol i nergi c receptors can al so be found in adrenergi c pathways; thus, muscari ni c and
ni cotinic receptors have been found i n presynapti c and postsynapti c locati ons, where they in turn
modul ate sympathetic acti vi ty (see Fi g. 12-11). Maze specul ates that al though the functi onal rol e
of the postsynapti c -2 receptor in the CNS has not been wel l characteri zed, i t is probabl e that the
features that are so desirabl e to the anesthesi ol ogist, such as sedation, anxi ol ysi s, anal gesi a, and
hypnosi s, are medi ated through this si te.
Sti mul ati on of presynapti c -2 receptors medi ates i nhi bi ti on of NE rel ease i nto the synaptic cl eft,
servi ng as a negati ve feedback mechani sm.
28
The central effects are pri maril y rel ated to a
reduction in sympathetic outfl ow wi th a concomi tantl y enhanced parasympatheti c outfl ow (e.g.,
enhanced baroreceptor activity). This resul ts in a decreased systemic vascul ar resi stance,
decreased cardiac output (CO), decreased inotropi c state i n the myocardi um, and decreased HR.
The peri pheral presynapti c -2 effects are si mi l ar, and NE rel ease i s inhi bi ted i n postgangli oni c
neurons. However, sti mulation of postsynapti c -2 receptors, l i ke the -1 postsynapti c receptor,
affects vasoconstri cti on.

NE acts on both -1 and -2 receptors. Thus, NE not onl y activates smooth muscl e
vasoconstri cti on (postsynapti c -1 and -2 receptors) but al so sti mul ates presynaptic -2
receptors and i nhi bits i ts own rel ease. Sel ecti ve sti mulation of the presynapti c -2 receptor coul d
produce a benefi cial reducti on of peri pheral vascul ar resi stance. Unfortunatel y, most known
presynaptic -2 agoni sts also sti mul ate the postsynapti c -2 receptors, causing vasoconstriction.
Bl ockade of -2 presynapti c receptors, however, abl ates normal inhi bi ti on of NE, causi ng
vasoconstri cti on. Vasodi lation occurs wi th the bl ockade of postsynaptic -1 and -2 receptors.
Receptors in the Cardiovascular System. The presence of postsynapti c -1 and -2 receptors
in the mammalian myocardium and coronary arteri es as wel l as the peri pheral vasculature are
known.
25

Coronary Arteries. The presence of postsynapti c -1 and -2 receptors i n the coronary arteries
of humans has not been establ ished wi th certai nty, but other mammali an model s have
demonstrated thei r presence. Sympathetic nerves cause coronary vasoconstri cti on, which i s
mediated more by postsynapti c -2 than -1 receptors. The l arger epi cardi al arteri es possess
mainly -1 receptors, whereas -2 receptors and some -1 receptors are present i n the smal l
coronary artery resi stance vessel s.
29
Epi cardial vessel s contribute only 5% to the total resi stance
of the coronary ci rculation; therefore, -1 agoni sts such as phenylephri ne have l ittle infl uence on
coronary resi stance.
30

Myocardi al i schemi a has been shown to i ncrease -2 receptor density i n the coronary arteries.
Ischemi a has al so been shown to cause a refl ex i ncrease i n sympatheti c acti vi ty mediated by
mechani sms. Thi s cascade may further increase coronary constriction. Postsynapti c -1 receptors
do not rely on extracellular Ca2+ to constri ct the vessel , whereas the -2constri ctor response i s
hi ghl y dependent on extracel l ul ar i nflux and exqui sitely sensiti ve to calci um channel inhi bi tors.
31

Myocardium. The rol e of receptors i n mediating catechol ami ne-i nduced i notropi sm and
arrhythmogenesis is known. Studies have shown the presence of postsynapti c myocardi al -1
receptors, whi ch also exert a major, faci l atory, posi ti ve i notropic effect on the myocardium of
several species of mammal s i ncluding humans. Thei r contri buti on to mal i gnant reperfusi on
arrhythmogenesi s has al so been recognized.
Phenylephri ne, an -1 agoni st, can increase myocardi al contractil i ty two- to threefol d compared
with a si x- to sevenfold increase produced by i soproterenol , a pure agoni st.
32
Myocardi al
postsynapti c -1 receptors mediate perhaps as much as 30 to 50% of the basal inotropi c tone of
the normal heart. The i notropic response of the normal myocardi um is more sensiti ve to
agoni sts.
Postsynapti c myocardial -1 receptors pl ay a more prominent i notropi c rol e i n the fai l ing heart by
P.289
P.290
servi ng as reserve to the normal ly predomi nant -1 receptors. Al though the response to both -1
and -1 agoni sts i s reduced i n the fai li ng myocardium, the interacti on between the two receptors
i s more apparent. Chroni c heart fai l ure i s known to produce a reduced densi ty (down-regul ati on)
of myocardial -1 receptors as a resul t of hi gh level s of circul ati ng catechol ami nes. However,
there i s no evi dence of down-regul ati on of ei ther -1 or -2 receptors with fail ure.
33

The i ncrease in densi ty of myocardi al -1 adrenoreceptors shows a relative increase with fai l ure
and myocardi al ischemia.
33
Thus, enhanced myocardi al -1 receptor numbers, and sensi tivity, may
contri bute to posi ti ve i notropi sm seen duri ng i schemi a as wel l as to the mal i gnant arrhythmi as
that occur with reperfusion. Intracel l ul ar mobi li zation of cytosol i c Ca2+ by the activated -1
myocardi al receptors duri ng ischemia appears to contribute to these arrhythmias.
33
The -1
receptor al so i ncreases the sensi tivity of the contractil e el ements to Ca2+. Drugs possessing
potent -1 antagoni sm such as prazosin and phentol ami ne have been shown to possess si gni fi cant
anti arrhythmic acti vi ty, al though of l i mi ted useful ness because of hypotensi on. Enhanced -1
acti vi ty with myocardial i schemia may expl ai n why the anti arrhythmi c benefits of antagonists in
patients with acute myocardi al infarction are far from certain. The contribution of receptors to
positi ve i notropism and arrhythmogenesi s duri ng i schemi a and reperfusi on may be overshadowed
by the receptors during acute fai l ure and i schemi a.
Peripheral Vessels. Acti vati on of the presynaptic -2 vascul ar receptors produces vasodi lation,
whereas the postsynaptic -1 and -2 vascul ar receptors subserve vasoconstri cti on. Presynaptic
vascul ar -2 receptors i nhi bit NE rel ease. Thi s represents a negative feedback mechani sm by
whi ch NE inhi bi ts i ts own rel ease vi a the prejuncti onal receptor. Presynapti c -2 agoni sts, such as
cl oni dine, i nhi bi t NE release at the neurosympatheti c juncti on produci ng vasodi l atati on. The
effects of selective presynaptic -2 receptor agoni sts to amel i orate coronary vasoconstri cti on i n
humans are unclear. Exci tation of the i nhi bi tory presynaptic -2 receptors by endogenous or
synthetic catechol ami nes also inhi bi ts NE rel ease. However, most sympathomimeti cs are
nonselecti ve agoni sts that wi ll exci te equal l y presynaptic -2 vasodi l ators and vasoconstri cti ve
postsynapti c -1 and -2 receptors.
Postsynapti c -1 and -2 receptors coexist i n both the arterial and venous si des of the circul ati on
with the rel ati ve di stri bution of -2 receptors bei ng greater on the venous side.
34
Thi s may expl ai n
why pure -1 agoni sts, such as methoxamine, produce l i ttl e venoconstri cti on, whereas many
nonselecti ve agoni sts such as phenyl ephrine produce signi fi cant venoconstri cti on. NE i s the most
potent venoconstrictor of al l the catecholami nes. Cli nicall y, venoconstri cti on woul d have the effect
of prel oadi ng by shi fti ng venous capaci tance central ly, whereas sti mulati on of arterial postsynapti c
-1 and -2 receptors would effect afterl oadi ng by increasi ng arteri al resi stance.
Receptors in the Central Nervous System. Al l subtypes of the , , and DA receptors have
been found i n vari ous regi ons of the brai n and spinal cord. The functi onal role of the cerebral
and receptors suggests a cl ose associ ati on wi th bl ood pressure and HR control . Cerebral and
spi nal cord presynaptic -2 receptors are al so i nvol ved i n inhi bi ti on of presynapti c NE release.
Although the brai n contains adrenergic and dopami nergi c receptors, ci rcul ati ng catechol amines do
not cross the bl ood-brain barri er. The catechol amines in the brai n are synthesi zed there. Many
acti ons have been attri buted to the cerebral postsynapti c -2 receptor. Thi s i ncludes inhi biti on of
insuli n rel ease, i nhi biti on of bowel moti l ity, sti mulation of growth hormone release, and i nhibi tion
of anti di ureti c hormone rel ease. Central neuraxi s injecti on of -2 agoni sts, such as cl onidi ne, act
to produce anal gesi a, sedati on, and cardi ovascul ar depressi on. The increased duration of epidural
or i ntrathecal anesthesi a by the addi ti on of nonsel ecti ve agoni sts to the l ocal anestheti c may
al so produce addi tional anal gesia through this mechani sm.
Receptors in the Kidney. The kidney has an extensi ve and exclusi ve adrenergi c i nnervati on of
the afferent and efferent glomerul ar arteriol es, proxi mal and distal renal tubul es, ascendi ng l oop
of Henl e, and juxtagl omerul ar apparatus. The greatest density of innervati on i s in the thi ck
ascendi ng l oop of Henl e, fol l owed by the di stal convol uted tubul es and proxi mal tube. Both -1
and -2 subtypes are found in the kidney wi th the -2 receptor dominati ng. The -1 receptor is
predomi nant i n the renal vasculature and eli cits vasoconstriction, whi ch modul ates renal bl ood
flow. Tubular -1 receptors enhance sodi um and water resorpti on, l eadi ng to anti natri uresi s,
whereas tubular -2 receptors promote sodi um and water excreti on.

-Adrenergic Receptors
The -adrenergi c receptors, l i ke the receptor, have been di vi ded i nto subtypes. They are
desi gnated as the -1 and -2 subtypes. The -1 receptors predomi nate in the myocardi um, the
si noatrial node, and the ventri cul ar conducti on system. The -1 receptors al so medi ate the effects
of the catechol ami nes on the myocardium. These receptors are equal l y sensi tive to EPI and NE,
whi ch di sti ngui shes them from the -2 receptors. Effects of -1 sti mulation are outl i ned i n Tabl e
12-5. Tabl e 12-6 outl i nes thei r effects speci fi cal ly on the cardiovascular system.
The -2 receptors are located i n the smooth muscles of the bl ood vessels i n the ski n, muscle, and
mesentery, and i n bronchi al smooth muscl e. Sti mulation produces vasodil ati on and bronchi al
rel axation. The -2 receptors are more sensi ti ve to EPI than NE. The -1 receptors are suggested
to be innervated receptors respondi ng to neuronal ly rel eased NE, whereas -2 receptors are
normal receptors respondi ng pri mari l y to ci rculating EPI.
35

receptors are found i n both presynapti c and postsynaptic membranes of the adrenergi c
neuroeffector junction (see Tabl e 12-6). -1 receptors are di stri buted to postsynapti c si tes and
have not been i denti fi ed on the presynapti c membrane. Presynapti c receptors are mostl y of the
-2 subtype. The effects of acti vati on of the presynapti c -2 receptor are di ametri cal l y opposed to
those of the presynapti c -2 receptor. The presynapti c -2 receptor accel erates endogenous NE
rel ease, whereas blockade of this receptor wil l inhi bi t NE rel ease. Antagoni sm of the presynapti c
-2 receptors produces a physi ol ogical resul t si mi l ar to activati on of the presynapti c -2 receptor.
The postsynapti c -1 receptors are located on the synapti c membrane and are i nnervated
receptors respondi ng pri mari l y to neuronal NE. The postsynapti c -2 receptors, l i ke the
postsynapti c -2 receptor, are consi dered noninnervated, extrasynapti c, normal receptors
respondi ng pri mari l y to ci rcul ati ng EPI.
Receptors in the Cardiovascular System
Myocardium. Myocardi al receptors were ori ginal l y cl assified as -1 receptors. Those i n the
vascul ar and bronchi al smooth muscl e were cal led the -2 subtype. However, studies have
confi rmed the coexi stence of -1 and -2 receptors i n the myocardi um.
35
Both -1 and -2
receptors are functi onal l y coupled to adenyl cycl ase, suggesti ng a si mi lar i nvol vement i n the
regul ati on of i notropism and chronotropism.
Postsynapti c -1 receptors are di stri buted predominantl y to the myocardi um, the si noatrial node,
and the ventricul ar conducti on system. The -2 receptors have the same distri buti on but are
presynaptic. Activati on of the presynapti c -2 receptor accel erates the rel ease of NE into the
synapti c cl eft. The -2 receptor approximates 20 to 30% of the receptors i n the ventricul ar
myocardium and up to 40% of the receptors i n the atrium.
The i ncreased catechol ami ne l evel s associated wi th heart fai l ure lead to a proporti onall y greater
down-regul ati on of the -1 receptor densi ty wi th a rel ati ve spari ng of the -2 subtype and an
increase i n the -1 subtype. The -2 receptors increasi ngl y medi ate the i notropic response to
catechol amines during heart failure and are faci l i tated by the -1 receptor.
The effect of NE on inotropism i n the normal heart is medi ated entirel y through the postsynapti c
-1 receptor, whereas the inotropi c effects of EPI are medi ated through both the -1 and -2
myocardial receptors. The -2 receptors may al so medi ate the chronotropi c responses to EPI
because sel ecti ve -1 antagoni sts are less effective in suppressi ng i nduced tachycardi a than the
nonselecti ve -1 antagoni st propranol ol .
Peripheral Vessels. The postsynaptic vascul ar receptors are virtuall y al l of the -2 subtype.
The -2 receptors are located i n the smooth muscl e of the blood vessel s of the ski n, muscle,
mesentery, and bronchi . Sti mulation of the postsynapti c -2 receptor produces vasodi l ati on and
bronchi al relaxation. Modest vasoconstri cti on occurs when subjected to bl ockade because the
P.291
acti ons of the vascular postsynapti c -2 receptors no longer oppose the actions of the -1 and -2
postsynapti c receptors.
Receptor in the Kidney. The kidney contai ns both -1 and -1 receptors, with the -1 bei ng
predomi nant. Reni n rel ease from the juxtagl omerul ar apparatus i s enhanced by stimul ati on. -
bl ockers inhi bi t this response. The -1 receptor evokes reni n rel ease i n humans. Renal -2
receptors also appear to regulate renal bl ood fl ow at the vascul ar l evel . They have been i denti fied
pharmacol ogicall y and medi ate a vasodi l atory response.
Dopaminergic Receptors
Dopami ne, synthesized in 1910, was recogni zed i n 1959 not onl y as a vasopressor and the
precursor of NE and EPI, but also as an important central and peri pheral neurotransmitter.
Dopami ne receptors (DA) have been local i zed i n the CNS, on blood vessels, and on postgangl i oni c
sympatheti c nerves (see Tabl e 12-6). Two cl i ni cal ly i mportant types of DA receptors have been
recognized. These are the DA1 and DA2 receptors. The DA1 receptors are postsynapti c, whereas
the DA2 receptors are both presynapti c and postsynapti c. The presynapti c DA2 receptors, l ike the
presynaptic -2 receptor, inhibit NE rel ease and can produce vasodi latation.
36
The postsynaptic
DA2 receptor may subserve vasoconstriction si mi l ar to that of the postsynapti c -2 receptor.
37

Thi s effect is opposi te to that of the postsynapti c DA1 renal vascul ar receptor. Unpubl i shed data
suggest that dopami ne may be the i ntrinsi c regul ator of renal functi on.
38
The zona gl omerul ose of
the adrenal cortex al so contai ns DA2 receptors, whi ch i nhibi t rel ease of al dosterone.
Myocardium. Defi ni ng specific dopami nergi c receptors has been di ffi cul t because dopami ne al so
exerts effects on the and receptors.
39
DA receptors have not been descri bed i n the
myocardi um. Effects of dopami ne are those related to acti vati on of -1 receptors, whi ch promote
positi ve i notropism and chronotropi sm. -2 activation woul d produce some systemi c
vasodil atati on.
Peripheral Vessels. The greatest numbers of DA1-postsynapti c receptors are found on vascul ar
smooth muscl e cell s of the ki dney and mesentery, but are al so found i n the other systemic
arteries including coronary, cerebral, and cutaneous arteri es. The vascular receptors are, l i ke the
-2 receptors, l i nked to adenyl cycl ase and medi ate smooth muscl e rel axati on. Activati on of these
receptors produces vasodi l atation, increasi ng blood fl ow to these organs. Concurrent activati on of
vascul ar presynapti c DA2 receptors al so inhi bi ts NE rel ease at presynapti c -2 receptors, whi ch
may al so contri bute to peri pheral vasodi l atati on. Hi gher doses of dopami ne can medi ate
vasoconstriction vi a the postsynapti c -1 and -2 receptors. The constrictive effect i s relati vel y
weak i n the cardi ovascul ar system where the acti on of dopamine on adrenergi c receptors i s 1/35
and 1/50 as potent as that of EPI and NE, respectivel y.
40

Central Nervous System. DA receptors have been i denti fied in the hypothal amus where they are
invol ved in prol actin rel ease. They are al so found i n the basal gangl i a where they coordi nate
motor function.
39
Degenerati on of dopami nergi c neurons of the substanti a ni gra i s the source of
Parki nson' s di sease. Another central acti on of dopami ne i s to stimul ate the chemoreceptor trigger
zone of the medul l a, produci ng nausea and vomi ti ng. Dopami ne antagoni sts such as hal operidol
and droperi dol are cl i ni cal l y effective i n counteri ng thi s acti on.
Kidney and Mesentery. Apart from thei r effect on the vessel s of the kidney and mesentery, DA
receptors on the smooth muscl e of the esophagus, stomach, and smal l intestine enhance secreti on
producti on and reduce i ntesti nal moti l i ty.
40

Metocl oprami de, a dopami ne antagoni st, i s useful for aspi ration prophylaxis by promoti ng gastric
emptying.
The di stributi on of DA receptors i n the renal vascul ature i s wel l known, but DA receptors have
other functi ons wi thi n the ki dney. DA1 receptors are l ocated on renal tubules, whi ch i nhi bi t
sodium resorpti on with subsequent natri uresi s and di uresi s. The natriuresi s may be the result of a
combi ned renal vasodi latation, improved CO, and tubul ar acti on of the DA1 receptors.
Juxtagl omerular cel l s al so contai n DA1 receptors, which increase reni n rel ease when acti vated.
P.292
Thi s acti on modulates the diuresi s produced by DA1 activati on of the tubul es.
Dopami ne has uni que autonomi c effects by acti vating specific peri pheral dopami nergi c receptors,
whi ch promote natri uresis and reduce afterl oad vi a dil atati on of the renal and mesenteric arterial
beds. Peri pheral dopami nergi c acti vi ty serves as a natural antihypertensi ve mechani sm.
41
Its
acti ons are overshadowed by the opposite effect of its mai n bi ologi c partner, NE.
42
Pl asma NE
level s are known to i ncrease wi th agi ng, l ikel y the resul t of reduced cl earance. Peripheral
dopami nergic acti vi ty i s known to di mi ni sh. Subtl e changes i n the DANE bal ance wi th agi ng may
account for the dimini shed abi l ity of the aged kidney to excrete a sal t load. Thi s may al so
contri bute to the uniform fi ndi ng of increasi ng systol i c bl ood pressure i n soci eti es with hi gh sal t
consumpti on.
Other Receptors
Adenosine Receptors
Adenosi ne produces i nhi biti on of NE release. The effect of adenosi ne i s bl ocked by caffei ne and
other methyl xanthines. The physiol ogi c and pharmacol ogi c rol es of adenosi ne-mediated i nhi bi ti on
of NE rel ease are not cl earl y defined. The physiol ogi c functi on of these receptors may be the
reduction of sympatheti c tone under hypoxic condi ti ons when adenosi ne production is enhanced.
As a consequence of reduced NE release, cardiac work woul d be decreased and oxygen demand
reduced. Adenosi ne has been effecti vel y used to produce controll ed hypotensi on.
42

Serotonin
Serotoni n (5-hydroxytryptami ne) depresses the response of isol ated blood vessel s to SNS
stimul ati on and decreases rel ease of l abel ed NE i n these preparations. This i nhi bitory acti on of
serotonin i s antagoni zed by rai si ng the external cal cium i on concentrati on. Thus, serotonin may
inhi bit neuronal NE rel ease by a mechani sm that li mi ts the avai l abi l ity of cal ci um i ons at the nerve
termi nal.
Prostaglandin E2, Histamine, and Several Opioids
Prostagl andi n E2, hi stami ne, and several opioi ds have been reported to act on prejuncti onal
receptor si tes to inhi bi t NE rel ease i n certai n sympatheti cal l y i nnervated tissue. However, these
inhi bitory receptors are unli kel y to pl ay a physi ol ogi c rol e i n l i mi ting NE release because i nhibi tors
of cycl o-oxygenase, hi stami ne antagonists, and nal oxone produce no i ncrease i n NE rel ease.
Histamine acts i n a manner si mil ar to the neurotransmitters of the SNS. It has membrane
receptors speci fi c for hi stami ne, with the i ndi vi dual response bei ng determi ned by the type of cel l
bei ng sti mulated. Two receptors for hi stami ne have been determi ned. These have been desi gnated
H1 and H2, for whi ch it has been possi bl e to devel op speci fi c agoni sts and antagoni sts.
Sti mulation of the H1 receptors produces bronchoconstriction and i ntesti nal contraction. The major
role of the H2 receptors is related to acid producti on by the pari etal cel l s of the stomach;
however, hi stami ne i s present i n rel ati vel y hi gh concentrations i n the myocardi um and cardi ac
conducti ng ti ssue, where i t exerts posi ti ve inotropi c and chronotropi c effects whil e depressi ng
dromotropi sm. The posi ti ve i notropi c and chronotropi c effects of histamine are H2 receptor effects
that are not bl ocked by antagonism. These effects are blocked by H2 antagoni sts, such as
ci metidi ne, whi ch accounts for the occasional report of cardi ovascul ar col l apse fol lowi ng the use of
ci metidi ne.
43
The negati ve dromotropic effect and that of coronary spasm caused by histamine are
H1 receptor effects.
Adrenergic Receptor Numbers or Sensitivity
Receptors, once thought to be stati c enti ties, are now thought to be dynami cal l y regul ated by a
vari ety of condi tions and in a constant state of fl ux. Receptors are synthesi zed i n the sarcopl asmi c
reticul um (SR) of the parent cel l , where they may remai n extrasynapti c or external ize to the
synaptic membranes where they may cluster. Membrane receptors may be removed or internal ized
to i ntracel l ul ar si tes for either dehydrati on or recycl ing.
The number and sensi ti vi ty of adrenergi c receptors can be infl uenced by normal, geneti c, and
developmental factors. Changes in the number of receptors al ter the response to catechol ami nes.
Alteration i n the number, or density, of receptors i s referred to as either up-regul ati on or down-
regul ati on. As a rule, the number of receptors i s i nversel y proporti onal to the ambi ent
concentration of the catechol ami nes. Extended exposure of receptors to thei r agoni sts markedl y
reduces, but does not abl ate, the bi ologi c response to catechol ami nes.
44
For exampl e, i ncreased
adrenergi c acti vi ty occurs in response to reduced perfusion as a result of acute or chronic
myocardial dysfuncti on. Pl asma catechol amines are i ncreased. As a resul t, myocardi al postsynaptic
-1 receptors downregulate. Thi s is thought to expl ai n the di mi ni shed i notropic and chronotropic
response to -1 agoni sts and exercise i n pati ents wi th chronic heart fai l ure. However, cal cium-
i nduced i notropi sm i s not i mpai red because -2 receptor (extrasynapti c) numbers remai n
rel ati vely i ntact.
45
The -2 receptors may account for up to 40% of the i notropism of the fai li ng
heart compared wi th 20% i n the normal heart.
46
Tachyphyl axi s to i nfused catechol ami nes i s al so
thought to be the resul t of acute down-regul ati on of receptor numbers. There appears to be a
reduction in numbers or sensiti vi ty of receptors i n hypertensi ve patients who al so have el evated
pl asma catechol ami nes. Down-regul ati on i s the presumpti ve expl anati on for the lack of correlati on
between plasma catechol ami ne l evel s and the bl ood pressure el evati on in pati ents wi th
pheochromocytoma. Chronic use of agoni sts such as terbutali ne, i soproterenol, or EPI for the
treatment of asthma can result i n tachyphyl axis because of down-regul ati on. Even short-term use
(1 to 6 hours) of agoni sts may cause down-regul ati on of receptor numbers.
Down-regul ati on i s reversibl e on termi nati on of the agoni st. Chroni c treatment of animal s wi th
nonselecti ve -bl ockade causes a 100% i ncrease i n the number of receptors.
47
This accounts for
the propranol ol wi thdrawal syndrome i n whi ch the acute disconti nuati on of the antagonist l eaves
the receptors unopposed pl us an i ncreased number of receptors. Cl oni di ne wi thdrawal can be
expl ai ned by the same mechani sm.
48
Acute disconti nuati on of the -2- i nhi bi tory agoni st woul d
permi t a resumpti on of sti mulation of adrenoreceptors that up-regul ated duri ng the time NE
rel ease was i nhi bi ted.
Up- or down-regul ati on of receptor numbers may not al ter sensi tivity of the receptor. Li kewi se,
sensi ti vi ty may be i ncreased or decreased in the presence of normal numbers of receptors. The
pharmacol ogic factors affecti ng up- or down-regul ati on of the and receptors are si mi l ar.

AUTONOMIC NERVOUS SYSTEM REFLEXES AND INTERACTIONS
The ANS refl ex has been compared to the computer ci rcui t. Thi s control system, as in all refl ex
systems, has (1) sensors, (2) afferent pathways, (3) CNS i ntegration, and (4) efferent pathways
to the receptors and efferent organs. Fine adjustments are made at the l ocal l evel accordi ng to
posi ti ve and negati ve feedback mechani sms. The baroreceptor i s an example. The vari abl e to be
control led (bl ood pressure) is sensed (carotid si nus), integrated (medul l ary vasomotor center),
and adjusted through speci fi c effectorreceptor si tes. Drugs or di sease can interrupt this ci rcui t at
any point. -bl ockers may attenuate the effector response, whereas an agoni st such as cl onidi ne
may alter both the effector and the i ntegrator functi ons of bl ood pressure control (see
Antihypertensi ves section).
48

Baroreceptors
Several refl exes i n the cardi ovascul ar system help control arteri al blood pressure, CO, and HR.
Cardi ovascul ar ANS reflexes are an anachroni sm. The busi ness of ci rculation i s to provi de blood
flow. Yet the most i mportant control l ed vari abl e to whi ch the sensors are attuned is bl ood
pressure, a product of fl ow and resi stance.
Etienne Marey noted i n 1859 that the pulse rate i s i nversel y proporti onal to the bl ood pressure,
and thi s i s known as Marey' s l aw. Subsequentl y, Heri ng, Koch, and others demonstrated that the
al terati ons in HR evoked by changes i n bl ood pressure stretch are dependent on baroreceptors
located in the aortic arch and the caroti d si nuses. These pressure sensors react to al terations i n
P.293
stretch caused by bl ood pressure. Compli ance of the stretch receptors and their sensiti vi ty may be
al tered by caroti d si nus atherosclerosi s. Thus, carotid artery di sease may be one source of
hypertensi on rather than the resul t.
Impul ses from the caroti d si nus and aorti c arch reach the medull ary vasomotor center by the
gl ossopharyngeal and vagus nerves, respecti vel y. Increased sensory traffic from the
baroreceptors, caused by i ncreased bl ood pressure, i nhi bi ts SNS effector traffic. The rel ati ve
increase i n vagal tone produces vasodi lati on, sl owing of the HR, and a l oweri ng of bl ood pressure.
Real increases i n vagal tone occur when bl ood pressure exceeds normal l imi ts.
49

The arteri al baroreceptor reflex can best be demonstrated by the Val sal va maneuver (Fi g. 12-15).
The Valsalva maneuver rai ses the i ntrathoracic pressure by forced expi rati on against a cl osed
gl otti s. The arteri al blood pressure ri ses momentari ly as the intrathoraci c blood is forced i nto the
heart (prel oad). Sustai ned i ntrathoracic pressure di mi nishes venous return, reduces the CO, and
drops the blood pressure. Reflex vasoconstri cti on and tachycardi a ensue. Blood pressure returns
to normal with rel ease of the forced expirati on, but then briefly overshoots because of the
vasoconstri cti on and i ncreased venous return. A sl owi ng of the HR accompani es the overshoot i n
pressure, according to Marey's l aw.
The cardi ovascular responses to the Valsalva maneuver requi re an intact ANS ci rcui t from
peri pheral sensor to peri pheral adrenergi c receptors. The Val sal va maneuver has been used to
i denti fy pati ents at ri sk for anesthesi a because of ANS i nstabi l ity (see Fi g. 12-15). Thi s was once
a major concern i n pati ents recei vi ng drugs that depl eted catechol amines, such as reserpine.
Dysfuncti on of the SNS i s i mpl icated if exaggerated and prol onged hypotensi on devel ops duri ng
the forced expi rati on phase (50% from resting mean arteri al pressure).
4
In additi on, the overshoot
at the end of the Valsalva maneuver i s absent. Dysfuncti on of the PNS can be assumed if the HR
does not respond appropri atel y to the bl ood pressure changes. The Val sal va maneuver may sti l l be
a val i d cli ni cal preoperati ve test for detecti ng the autonomic dysautonomi a that accompani es
di abetes.
FIGURE 12-15. A. The normal blood pressure response to the Val sal va maneuver i s
demonstrated. Pulse rate moves i n a reci procal di rection according to Marey's l aw of the
heart. B. An abnormal Val sal va response i s shown i n a pati ent wi th C5 quadri pl egi a.
Venous baroreceptors may be more domi nant in the moment-to-moment regulation of CO.
Baroreceptors i n the ri ght atri um and great vei ns produce an i ncrease i n HR when stretched by
increased right atri al pressure.
50
Reduced venous pressure decreases HR. Unl i ke the arteri al
baroreceptors, venous sensors are not thought to al ter vascular tone; however, venoconstriction is
postulated to occur when atrial pressures decl ine. Stretch of the venous receptors produces
changes i n HR opposi te to those produced when the arterial pressure sensors are sti mulated. The
arterial and venous pressure receptors are separatel y monitori ng two of the four major
determi nants of CO: afterl oad and prel oad, respectivel y. Venous baroreceptors sampl e prel oad by
stretch of the atri um. Arteri al baroreceptors survey resi stance, or afterl oad, as refl ected i n the
mean arteri al pressure. Afterl oad and prel oad produce opposi te effects on CO; thus, one shoul d
not be surprised that the venous and arteri al baroreceptors produce effects opposite those of a
si mi l ar stretch sti mulus, pressure.
Bai nbri dge descri bed the venous baroreceptor reflex and demonstrated that i t can be abol i shed by
vagal resecti on. Numerous i nvesti gators have confi rmed the accel erati on of the HR i n response to
vol ume. However, the magni tude and di recti on of the HR response are dependent on the prevail i ng
HR at the time of sti mulation. The denervated, transplanted mammali an heart al so accelerates in
response to volume l oadi ng. HR, l ike CO, can apparentl y be adjusted to the quanti ty of bl ood
enteri ng the heart.
51

The Bai nbridge refl ex relates to the characteristic but paradoxi cal sl owi ng of the heart seen wi th
spi nal anesthesi a. Bl ockade of the SNS l evel s of T1-4 abl ates the efferent l i mb of the cardi ac
accel erator nerves. This source of cardiac decel eration is obvi ous, as the vagus nerve i s
unopposed. However, bradycardi a duri ng spinal anesthesi a i s more related to the devel opment of
arterial hypotensi on than to the hei ght of the bl ock. The pri mary defect i n the devel opment of
spi nal hypotension is a decrease in venous return. Theoreti cal l y, the arteri al

hypotensi on should refl exl y produce a tachycardi a through the arterial baroreceptors. Instead,
bradycardia i s more common. Greene suggests that in the unmedi cated person, the venous
baroreceptors are domi nant over the arteri al . A reduced venous pressure, therefore, slows HR.
52

In contrast, humoral ly medi ated tachycardi a is the usual response to hypotensi on or acidosis from
other causes.
Denervated Heart
Refl ex modul ati on of the adrenergi c agoni sts i s best seen i n the denervated transpl ant heart,
whi ch retai ns the reci pi ent's i nnervated sinoatri al node and the donor' s denervated si noatri al
node.
53
Tabl e 12-7 i s a summary of drug effects on the transpl anted heart. NE si mul taneousl y
acti vates and receptors of the i ntact heart and vessel s. NE i nfusi on i n the transpl anted heart
produces a sl owing of the reci pient' s atri al rate through vagal feedback as the bl ood pressure
ri ses. In the unmodul ated donor heart, atri al rate i ncreases. Methoxamine-induced hypertension
and ni tri te-i nduced hypotension fail to induce decel erati on and accelerati on of the donor atri al
rate. The baroreceptors are therefore not operant in the transpl anted heart. Isoproterenol , a pure
agoni st, i ncreases the di scharge rate of both the reci pi ent and donor node by di rect acti on, wi th
the donor rate near doubli ng that of the recipi ent node. Atropi ne accel erates the reci pient' s atrial
rate, whereas no effect i s seen on the donor rate, which now controls HR. Hypersensi tivity to
cardi ac sti mul ati on i n denervated dog hearts has been demonstrated. Pati ents who have
undergone chemi cal sympathectomy wi th bretyl i um or guanethi di ne are known to be hyperreacti ve
to the usual doses of catechol amines.
P.294
TABLE 12-7 Drug Effects on the Denervated Heart
DRUG SINUS RATE ATRIOVENTRICULAR
CONDUCTION
VELOCITY
INTRAVENTRICULAR
CONDUCTION
VELOCITY
BLO
PRES
DONOR RECIPIENT
-bl ockade produces comparabl e sl owi ng of the sinoatri al node of both reci pi ent and donor. The
exercise capabi li ty of the denervated heart is conspi cuousl y reduced by -bl ockade, presumabl y
because of i ts reli ance on ci rculating catecholami nes. Propranolol has al so been demonstrated to
reduce the response to chronotropic effects of NE and isoproterenol in the transpl anted heart.
The CO of the transpl anted heart varies appropri ately wi th changes i n prel oad and afterl oad.
Interaction of Autonomic Nervous System Receptors
Strong i nteracti ons have been noted between SNS and PNS nerves i n organs that recei ve dual,
antagonistic i nnervati on. Release of NE at the presynaptic termi nal is modi fi ed by the PNS. For
example, vagal i nhibi tion of left ventri cul ar contracti li ty i s accentuated as the l evel of SNS acti vi ty
is rai sed. Thi s interaction is termed accentuated antagonism and is mediated by a combi nation
of presynaptic and postsynapti c mechani sms. The coronary arteri es present an example of this
phenomenon and deserve special attention. The concept of accentuated antagoni sm has yet to be
cl earl y defi ned because i t i s unusual for hi gh SNS and PNS activity to coexi st, except duri ng
anesthesia. The importance of accentuated antagonism in the i ntact, consci ous human has yet to
be demonstrated; however, i t may expl ain the clinical observation that angi na and myocardi al
infarcti on owi ng to coronary spasm i n humans are not often rel ated to cardi ac work, as i s angi na
caused by scl eroti c coronary di sease. Attacks of angina usual ly occur at rest, often waking the
patient from sl eep. Thi s diurnal vari ation al so corresponds to the greatest acti vi ty of the PNS
system. The mechani sm by which coronary arterial spasm occurs remains unknown, but thi s
conti nues to be an exci ti ng area of investi gati on.
The myocardi um and coronary vessel s are abundantl y suppl i ed wi th adrenergic and chol i nergi c
fi bers. Strong acti vi ty of both and receptors has been demonstrated i n the coronary vascul ar
bed. Selective sti mul ati on of both the -1 and postsynapti c -2 receptors i ncreases coronary
vascul ar resi stance, whereas sel ecti ve bl ockade eli mi nates this effect. Therefore, both -1 and
-1 adrenoreceptors are present on coronary arteri es and accessi ble to NE from sympatheti c
nerves.
54

The close anatomi c proxi mi ty of the postgangl i oni c vagal and SNS nerve endi ngs i n coronary
arteries provides the morphologi c basi s for strong interacti on. SNS and PNS nerve

termi nals are found in such cl ose proximity that transmitters from one can easi l y reach the other
and affect transmitter rel ease. In addi tion, the presynapti c adrenergi c termi nal s of the
myocardium and coronary vessels, l i ke all bl ood vessel s examined, contai n muscarini c receptors.
18

Recent observati ons confi rm that muscari ni c agents and vagal sti mul ati on, acti ng on the
presynaptic, SNS muscari ni c receptor, i nhi bi t the rel ease of NE in a manner si mi l ar to that of the
presynaptic -2 and DA2 receptors (see Fi g. 12-11). Conversel y, bl ockade of the muscari ni c
receptors wi th atropi ne markedl y augments the posi tive i notropi c responses to catechol ami nes.
3

Suppressi on of NE rel ease expl ai ns, i n part, vagal -i nduced attenuation of the i notropi c response to
strong SNS sti mulation (accentuated antagoni sm) and onl y a weak negati ve i notropic effect of
vagal sti mulation when there is l ow background SNS acti vi ty. This may also explain why vagal
acti vi ty reduces the vulnerabil i ty of the myocardi um to fi bri l lation duri ng i nfusi ons of NE.
ACh may cause coronary spasm during periods of hi gh SNS tone.
6
Inhi bi ti on of NE rel ease by
presynaptic adrenergi c muscari ni c receptors of the smooth muscle of coronary vessel s woul d
lessen the coronary relaxation normal ly produced by NE on the -1 receptor (see Fi g. 12-11). In
anesthetized dogs, the rate of NE outfl ow i nto the coronary si nus bl ood, evoked by cardi ac SNS
sti mul ati on, i s markedl y di mi nished by simul taneous vagal efferent sti mulation.
55
Thi s acti on i s
known to be prevented by atropine, whi ch al so causes coronary vasodi l ation. Methachol ine, a
muscari ni c parasympathomimeti c agent, has been reported to cause coronary vasoconstri cti on.
56

However, it simul taneousl y reduces ventri cular irritabi l i ty by reducing NE rel ease i n myocardi al
fi bers.
3

Interaction with Other Regulatory Systems
The ANS i s integrall y rel ated to several endocri ne systems that ul timately summate to control
P.295
bl ood pressure and regul ate homeostasi s. These include the reni nangiotensi n system, anti di ureti c
hormone, glucocorti coi ds, and insul in.
Anti di ureti c hormone or vasopressi n i s formed i n the hypothal amus and rel eased from nerve
endi ngs i n the posteri or pi tui tary gl and. It causes vasoconstri cti on and increased resorpti on of
water in the di stal col lecting ducts of the ki dney. It therefore affects not onl y central bl ood
vol ume but al so plasma osmol ali ty. The pri mary regul ator of anti diuretic hormone rel ease i s
pl asma osmol al i ty; however, several other sti muli may outweigh thi s control i n stressful
si tuati ons. Release is al so tri ggered by decreased central bl ood volume via l ow-pressure atri al
receptors and hypotensi on via the caroti d baroreceptors. Stress, pain, hypoxia, anesthesia, and
surgery also sti mulate rel ease of anti diuretic hormone. Infusi on of catecholami nes may al ter i ts
rel ease, but these effects appear to be medi ated by the caroti d baroreceptors. ANS drugs that
induce hypotension or decrease cardi ac fil l i ng may induce release of antidi ureti c hormone and thus
affect pl asma osmolal ity.
Both and receptors have been found i n the endocrine pancreas and modul ate i nsuli n rel ease
(see Tabl e 12-5). stimul ati on increases i nsul i n rel ease, whereas stimul ati on decreases it. The
overal l i mportance of thi s i nteraction is not enti rel y cl ear, but decreased tolerance to gl ucose and
potassium has been noted in subjects taki ng -bl ocki ng drugs.
57

The reni nangiotensi n system is a complex endocri ne system that modul ates both blood pressure
and water-el ectrol yte homeostasis (Fi g. 12-16). Renin i s a proteolyti c enzyme contai ned wi thin the
cel ls of the juxtaglomerul ar apparatus of the renal cortex. When released, it acts on pl asma
angi otensi nogen to form angi otensi n I. Angi otensi n I i s then converted to angi otensi n II by
converting enzyme i n the l ung. Angi otensi n II i s a powerful direct arteri al vasoconstri ctor. It al so
acts on the adrenal cortex to release al dosterone and on the adrenal medul la to rel ease EPI. In
addi ti on to its di rect effects on vascul ar smooth muscl e, angi otensi n II augments NE rel ease vi a
presynaptic receptors, thus enhanci ng peri pheral SNS tone. A group of drugs cal l ed angi otensi n-
converting enzyme (ACE) inhi bi tors act by interfering with the formation or function of angiotensi n
II. These drugs have been found useful in the treatment of essential and renovascul ar
hypertensi on and of congesti ve heart fai lure. Captopri l , enalapril , and li sinopri l inhi bit the action
of converting enzyme, thus preventi ng the conversion of angiotensi n I to angiotensin II.
58
They
have suppl anted di ureti cs and -bl ockers as fi rst-li ne agents i n the treatment of hypertension.
Renin i s rel eased i n response to hyponatremi a, decreased renal perfusi on pressure, and ANS
FIGURE 12-16. The i nteracti ons of the reni nangiotensi n and SNS i n regul ati ng homeostasi s
are shown schemati cal ly along wi th the physi ologi c vari abl es that modulate their functi on.
Arrows with a plus si gn (+) represent sti mul ati on, and those wi th a mi nus sign (-) represent
inhi biti on.
stimul ati on via receptors on juxtaglomerul ar cell s. Changes in sympathetic tone may thus alter
reni n rel ease and affect homeostasis i n a vari ety

of ways. The ANS i s also i ntimatel y related to adrenocortical functi on. As outli ned earli er,
gl ucocorti coi d release modul ates phenyl ethanol ami ne-N-methyl transferase formati on and thus
synthesis of EPI. Gl ucocorticoids are al so i mportant i n regul ati ng the response of peri pheral
ti ssues to changes i n SNS tone. Thus, the ANS i s i nti matel y related to other homeostati c
mechanisms.
CLINICAL AUTONOMIC NERVOUS SYSTEM PHARMACOLOGY
The cli nical appl icati on of ANS pharmacol ogy i s based on knowl edge of ANS anatomy,
physi ol ogy, and mol ecul ar pharmacol ogy. Drugs that modi fy ANS acti vi ty can be cl assi fi ed by
thei r site of acti on, mechanism of action, or pathology for which they are most commonly used.
Antihypertensi ve drugs are an exampl e of the third category. Thi s cl assi fi cation i s a matter of
degree because considerabl e functional overl ap occurs. An example of cl assi fi cation by site relates
to the gangl i onic agonists or bl ocki ng agents. ANS drugs can be further categorized as those that
act at the prejuncti onal membrane and those acti ng postjuncti onall y. They can then be more
speci fi cal l y cl assi fi ed by the predomi nant receptor or receptors on whi ch they act.
Mode of Action
ANS drugs may be broadl y classi fi ed by mode of acti on accordi ng to their mimeti c or l yti c acti ons.
Thi s may also be termed agoni st or antagoni st. A sympathomimeti c, such as ephedri ne, mimics
SNS sympatheti c acti vity by sti mulation of adrenergi c receptor sites both di rectl y and i ndi rectl y.
Sympatholyti c drugs cause di ssolution of SNS activity at these same receptor si tes. receptor
bl ockers are examples of sympathol yti c drugs. The terms parasympathomi meti c and
parasympatholytic are self-explanatory and may be further di vi ded by their site of acti on on the
muscari ni c or ni coti ni c receptors.
Several modes of ANS drug acti on become evident when one foll ows the cascade of
neurotransmission. The mode i s rel ated to site. Drugs that act on prejunctional membranes may
therefore (1) interfere wi th transmi tter synthesi s (-methyl paratyrosine), (2) i nterfere wi th
transmi tter storage (reserpine), (3) i nterfere wi th transmitter release (cl onidi ne), (4) sti mulate
transmi tter rel ease (ephedri ne), or (5) i nterfere wi th reuptake of transmi tter (cocaine). Drugs
may also modi fy metabol i sm of the neurotransmi tter in the synapti c cl eft (anti choli nesterase).
Drugs acti ng at postjuncti onal si tes may directl y stimul ate postjuncti onal receptors and interfere
with transmi tter agoni st at the postjunctional receptor.
The ul timate response of an effector organ to an agoni st or antagoni st depends on (1) the drug,
(2) i ts pl asma concentration, (3) the number of receptors i n the effector organ, (4) bi ndi ng by the
receptor, (5) the concurrent activiti es of other drugs and hormones, (6) the cel l ul ar metabol i c
status, and (7) refl ex adjustments by the organism. Thi s i s the source of confli cti ng resul ts for
drugs used in di ffering cli ni cal ci rcumstances.
Ganglionic Drugs
SNS and PNS gangl ia are pharmacol ogicall y si mi l ar i n that transmi ssi on through these ANS gangl i a
is affected by ACh (see Fi g. 12-3). Most gangli oni c agoni sts and antagonists are not sel ecti ve and
affect SNS and PNS gangl i a equal ly. Thi s nonselective property creates many undesi rabl e and
unpredictabl e si de effects, whi ch have li mi ted the cl i ni cal useful ness of this category of drugs.
Agonists
There are essenti al l y no cl ini cal ly useful gangl i oni c agoni sts. Ni coti ne i s the prototypi cal gangl i onic
agoni st. In low doses, it stimul ates ANS gangli a and the neuromuscul ar junction of stri ated
muscl e. Hi gh doses produce gangli oni c and neuromuscular blockade. Low-dose sti mulation and
hi gh-dose bl ockade are referred to as ni cotini c effects i n descri bing any drug wi th si mil ar effects.
P.296
Most gangli oni c agoni sts and antagonists produce thei r effects through thei r ni cotinic effects. The
protean si de effects of ni coti nic sti mulation render i t useful onl y as an i nvesti gati ve tool.
Despi te its l ack of cl ini cal usefulness, nicoti ne is wi del y used i n the form of tobacco. The novi ce
tobacco user can often descri be the overl ap of SNS and PNS si de effects of nicoti ni c sti mul ati on,
whi ch appear as nausea and vomi ti ng, tachycardi a, bradycardi a, diarrhea, and someti mes fainti ng
as a resul t of hi gh-dose gangl i oni c bl ockade.
3

Antagonists
Drugs that i nterfere wi th neurotransmission at ANS gangl i a are known as gangli oni c blocki ng
agents. Nicoti ne, in high doses, i s the prototypi cal gangl ioni c bl ocki ng agent al so; however, earl y
stimul atory ni cotini c acti vi ty can be bl ocked at the gangl i a and muscl e end pl ates wi th other
gangli oni c blockers and muscle rel axants, respecti vel y, wi thout blocking muscari ni c effects.
Gangl i onic bl ockers produce thei r ni cotini c effects by competi ng, mi mi cki ng, or i nterferi ng wi th
ACh metaboli sm. Hexamethoni um, tri methaphan, and pentol i ni um produce a selecti ve
nondepol ari zi ng bl ockade of neurotransmi ssi on at ANS gangli a wi thout produci ng nicoti ni c
neuromuscul ar blockade. They compete wi th ACh i n the gangl ia wi thout sti mul ati ng the receptors.
The i ntroduction of drugs that produce vasodil ati on di rectly or by action on the SNS vasomotor
center has made the gangl i onic bl ockers obsol ete. d-Tubocurare (dTC) produces a competi ti ve
nondepol ari zi ng bl ock of both motor end pl ates and ANS gangl i a. The acti on of motor paral ysis
predomi nates, but the concomi tant gangl i onic bl ockade at hi gher doses expl ai ns part of the
hypotensi ve effect often seen wi th the use of dTC for muscl e rel axati on. Hi stami ne rel ease is the
major hypotensi ve factor that i s common to dTC and other gangl i oni c blockers. Antichol inesterase
drugs may produce nicoti ni c type gangl ioni c blockade by competi ti on wi th ACh as wel l as by
persi stent depol ari zati on via accumul ated ACh.
Tri methaphan i s the onl y gangli oni c blocker avai labl e in the Uni ted States. Tri methaphan produces
bl ockade by competi ti on with ACh for receptors, thus stabi li zing the postsynaptic membrane.
However, side effects and rapi d onset tachyphyl axi s have markedl y reduced i ts use i n
anesthesia.
59
The pati ent' s pupi l s become fi xed and di l ated duri ng admi ni strati on, which obscures
eye si gns, an i mportant consi derati on for neurosurgery. In this regard, i t i s di sti nctl y i nferi or to
ni troprusside. The major advantage of tri methaphan i s i ts short durati on of acti on, whi ch i s the
resul t of pseudochol inesterase hydrolysi s.
Cholinergic Drugs
Chol i nergi c drugs may be cl assi fi ed by the fol lowi ng outl ine, whi ch foll ows physi ol ogic response
and si te of acti on.
I. Chol i nergi c drugs: agoni sts
3

A. Ni cotini c

1. ANS gangl i oni c transmi ssi on
2. Neuromuscul ar transmission
B. Muscarinic
1. Direct acti ng
2. Indirect acti ng
II. Choli nol ytic agents: antagonists
A. Ni cotini c
1. ANS gangl i oni c transmi ssi on
P.297
2. Neuromuscul ar transmission
B. Muscarinic
Muscarinic Agonists
The choli nomimeti c muscari ni c drugs act at si tes i n the body where ACh is the neurotransmi tter of
the nerve i mpulse. These drugs may be di vi ded i nto three groups, the fi rst two of whi ch are direct
muscari ni c agoni sts.
60
The thi rd group acts i ndirectl y. These groups are chol i ne esters (ACh,
methachol i ne, carbamyl choli ne, bethanechol ), alkal oi ds (pi l ocarpi ne, muscari ne, arecol i ne), and
anti choli nesterases (physosti gmi ne, neosti gmi ne, pyri dosti gmi ne, edrophonium, echothi ophate).
Direct Cholinomimetics. ACh has vi rtual ly no therapeuti c appl i cations because of its di ffuse
acti on and rapi d hydrol ysi s by chol inesterase (see Fi g. 12-6). One may encounter the use of
topical ACh (1%) drops duri ng cataract extracti on when a rapi d mi osi s i s desi red. Systemic effects
are not usual ly seen because of the rapi di ty of ACh hydrol ysi s.
Other choli ne esters have been synthesi zed, mostly deri vati ves of ACh, which possess more
sel ecti ve muscari ni c acti vi ty than ACh. They di ffer from ACh in bei ng more resi stant to inactivati on
by choli nesterase and thus having a more prolonged and useful acti on. They also differ from ACh
in thei r relative muscari ni c and nicoti ni c acti vi ti es. The best studi ed of these drugs are
methachol i ne, bethanechol, and carbamyl choli ne.
3
The chemical structures of ACh and these
chol i ne esters are shown i n Fi gure 12-17. Thei r pharmacol ogic actions are compared with those of
ACh in Tabl e 12-8. These are not i mportant drugs in anesthesi ology but anesthesi ol ogi sts may
encounter pati ents who are recei vi ng them. They may be useful i n the postoperati ve peri od to
al leviate cardiac tachydysrhythmi as, uri nary retenti on, and i leus.
TABLE 12-8 Comparative Muscarinic Actions of Direct Cholinomimetic Agents
SYSTEMIC
ACETYL-
CHOLINE
METHA-
CHOLINE
CARBAMYL-
CHOLINE
BETHANECHOL PILOCARPINE
Esterase
Hydrolysis
+++ + 0 0 0
Eye (Topical)
Iris ++ ++ +++ +++ +++
Cil i ary ++ ++ +++ +++ ++
Heart
Rate --- --- -- -- ?
Contracti li ty -- -- -- --
Conducti on -- --- -- --
Smooth
Muscle

Vascul ar -- --- -- --
Bronchi al ++ ++ + + ++
Gastroi ntesti nal
moti li ty
++ ++ +++ +++ ++
Gastroi ntesti nal
sphincters
-- -- --- --- ++
Bi l i ary ++ ++ +++ +++ ++
Bl adder
Detrusor ++ ++ +++ +++ ++
Sphincter -- -- --- --- --
Exocrine
Glands

Respi ratory +++ ++ +++ ++ ++++
Sal i vary ++ ++ ++ ++ +++++
Pharyngeal ++ ++ ++ ++ ++++
Lacri mal ++ ++ ++ ++ ++++
Sweat ++ ++ ++ ++ +++++
Gastroi ntesti nal
acid and
secretions
++ ++ ++ ++ ++++
Nicotinic +++ + +++ +++
ACh is a quaternary ammonium compound that i nteracts with postsynapti c receptors, causi ng
conformati onal membrane changes. Thi s results in increased permeabil i ty to smal l ions and, thus,
depol arizati on. Al l the receptors transl ate the reversi bl e bi ndi ng of ACh i nto openi ngs of di screte
channel s in exci table membranes, al l owing Na+ and K+ i ons to flow al ong thei r electrochemi cal
gradients. Structureacti vi ty relationshi ps point to the presence of two important binding sites on
the receptor, an esteractic si te that binds the ester end of the molecul e and an i onic si te that
bi nds the quaternary amine portion (see Fi g. 12-6). Subtle changes i n the structure of the
compound can markedly al ter the responses among di fferent ti ssue groups. The degree of
muscari ni c activity fal l s if the acetyl group is repl aced, but this confers a resistance to enzymatic
hydrol ysi s. Carbamyl chol i ne i s synthesi zed by repl aci ng the acetyl group wi th carbamyl (see Fi g.
Actions
+, sti mul ati on; --, inhi biti on.
FIGURE 12-17. Chemical structures of di rect-acti ng chol i nomi meti c esters and al kal oi ds.
12-17). It possesses both muscari ni c and nicoti ni c acti ons but i s vi rtual ly resi stant to esterase
hydrol ysi s (see Tabl e 12-8). Bethanechol i s also resi stant to hydrol ysis but possesses mainly
muscari ni c activity. -methyl substituti on produces methachol i ne, whi ch i s l ess resi stant to
hydrol ysi s but i s pri mari l y a muscari ni c agoni st.
Methachol i ne sl ows the heart and di l ates peri pheral blood vessel s. It i s used to termi nate
supraventricul ar tachydysrhythmi as, especi all y paroxysmal tachycardi a, when other measures
have fai led. It also increases intestinal tone. Methachol i ne should not be gi ven to patients with
asthma. Hypertensi ve patients may al so develop marked hypotensi on. Si de effects are those of
PNS sti mul ati on such as nausea, vomiti ng, and fl ushed sweati ng. Overdose i s treated with
atropi ne.
Bethanechol i s rel ati vel y sel ecti ve for the gastroi ntestinal and urinary tracts. In usual doses i t
does not sl ow the heart or l ower the blood pressure, as does methachol i ne. Bethanecol is of val ue
in treati ng postoperative abdominal di stenti on (nonobstructi ve paral ytic i l eus), gastri c atony
fol l owing bil ateral vagotomy, congeni tal megacol on, nonobstructive urinary retention, and some
cases of neurogeni c bl adder. It i s not a parenteral drug. Precauti ons are as for methacholi ne.
Direct-acti ng chol i nomi meti c al kaloi ds incl ude muscari ne, pil ocarpi ne, and arecol i ne. They act at
the same si tes as ACh, and thei r effects are similar to those of ACh as descri bed in Tabl e 12-8.
There are no uses for these drugs i n anesthesi ol ogy. Pi locarpine i s the onl y drug of thi s group
used therapeuticall y in the Uni ted States. Its sole use i s for the treatment of glaucoma, for whi ch
it i s the standard. It i s used as a topi cal mi oti c drug i n ophthal mologi c practi ce to reduce
intraocul ar pressure i n glaucoma.
Common si de effects of chol i nomi metic al kal oids are those of intense PNS sti mulati on, whi ch
incl ude gastrointestinal crampi ng, hypotension, diaphoresi s, sal ivati on, di arrhea, and bl adder
pai n.
3
Muscarinic agoni sts are parti cularly dangerous i n pati ents wi th myastheni a gravi s (who are
recei vi ng antichol inesterases), bulbar pal sy, cardi ac di sease, asthma, pepti c ul cer, progressi ve
muscul ar atrophy, or mechani cal i ntesti nal obstructi on or uri nary retenti on.
61

Indirect Cholinomimetics. The indi rect-acti ng chol i nomi meti c drugs are of greater i mportance to
the anesthesi ol ogi st than are the direct-acting drugs. These drugs produce chol i nomi meti c effects
indirectl y as a resul t of i nhi bi ti on or inactivati on of the enzyme acetylchol inesterase, which
normal ly destroys ACh by hydrol ysis. They are referred to as chol i nesterase i nhi bitors or
anti choli nesterases. Tabl e 12-9 li sts therapeutic choli nesterase inhi bitors and thei r major
indicati ons. Most of these drugs i nhi bi t both acetylchol inesterase and pseudochol inesterase.
Inhi biti on of acetyl choli nesterase

permi ts the accumul ati on of ACh transmi tter in the synapse, resul ti ng in i ntense PNS activity
si mi l ar to that of the di rect chol i nomi meti c agents. The action of ACh is therefore potenti ated and
prol onged. Thei r effects can be predi cted from a knowl edge of ANS pharmacol ogy previ ousl y
presented. Some of the acetyl choli nesterase drugs (i .e., edrophonium) may al so sti mulate
chol i nergi c receptors by di rect action. The accumulation of ACh by the anti chol inesterases
potential ly can produce all of the foll owing: (1) sti mulation of muscari ni c receptors at ANS effect
organs, (2) sti mul ati on foll owed by depressi on of all ANS gangl i a and skel etal muscl e (nicoti ni c),
and (3) sti mul ati on wi th l ater depressi on of chol i nergi c receptor sites in the CNS. Al l of these
effects may be seen wi th l ethal doses of anti choli nesterase drugs, but therapeuti c doses only
produce the fi rst two.
P.298
TABLE 12-9 Cholinesterase Inhibitors
DRUG TRADE
NAME
ROUTE DURATION INDICATIONS
Reversible
Physostigmi ne Eserine Topi cal 612 hr Gl aucoma
Pyri dosti gmi ne Mestinon Oral ,
iv, i m
4 hr Myastheni a gravi s
Regonol Reversal of
neuromuscul ar bl ockade
Neosti gmi ne Prosti gmi n Oral , i v 46 hr Myastheni a gravi s
Reversal of
Edrophonium Tensi l on iv 12 hr Reversal of
Enl on Diagnosis of myasthenia
gravi s
Demecari um Humorsol Topi cal 35 days Gl aucoma
Ambenoni um Mytel ase Oral 4 hr Myastheni a gravi s
Nonreversible
Echothiophate Phosphol i ne Topi cal 314 days Gl aucoma
Isofluorophate Topi cal 37 days Gl aucoma research
Mal athi on Topi cal Insecti ci derel ati vely
safe for mammal s
because of rapi d hepati c
metabolism
Parathi on Topi cal Insecti ci dehi ghl y toxic
to hi gher ani mal s;
frequent accidental
poi soni ng
Sari n (GB) Nerve gas Topi cal and gas
Acti ons of therapeutic si gni fi cance of the anti choli nesterase drugs to the anesthesiol ogi st concern
the eye, the i ntesti ne, and the neuromuscular juncti on. The effects of anti chol i nesterases are
useful i n the treatment of myastheni a gravi s, gl aucoma, and atony of the gastrointestinal and
uri nary tracts. Anti chol i nesterase drugs are used routi nel y i n anesthesia to reverse
nondepol ari zi ng neuromuscul ar bl ock.
The most promi nent pharmacol ogic effects of the antichol inesterase drugs are muscari ni c. Thei r
most useful actions are thei r ni coti ni c effects.
3
Muscarinic acti vi ty i s evoked by lower
concentrations of ACh than are necessary to produce the desi red ni coti ni c effect. For exampl e, the
anti choli nesterase neostigmine reverses neuromuscul ar blockade by i ncreasing ACh concentrati on
at the muscl e end plate, a ni coti ni c receptor. Nicoti ni c reversal of neuromuscul ar bl ockade can
usuall y be produced safel y onl y when the pati ent has been protected by atropi ne or other
muscari ni c blockers. This prevents the untoward muscari ni c effects of bradycardia, hypotension,
bronchospasm, or intestinal spasm. Conversely, neuromuscular paralysi s may be produced or
increased i f excessi ve anti choli nesterase i s used. Excess accumul ation of ACh at the motor end
pl ates produces a depol ari zi ng block si mil ar to that produced by succinyl chol i ne or ni cotine.
Reversal of neuromuscular bl ockade i n pati ents who have had bowel anastomosi s was at one time
a major controversy. Some thought that the muscari ni c effects of anti choli nesterase drugs
(hypermoti li ty) increased the ri sk of anastomoti c l eakage
62
whereas others found no associ ati on
between their use and subsequent breakdown.
63
National experience has favored the l atter
opi ni on.
Cli nicall y, anti choli nesterase drugs may be di vi ded i nto two types: the reversi bl e and
nonreversibl e chol inesterase inhi bi tors.
60
Reversi ble chol inesterase i nhi bi tors del ay the hydrolysi s
of ACh from 1 to 8 hours. Nonreversi ble drugs are so named because their i nhibi tory effects may
last from days to weeks. The differences i n durati on of vari ous antichol i nesterases apparentl y
depend on whether they inhi bi t the ani onic or esterati c site of acetyl choli nesterase. Therefore, the
anti choli nesterase drugs have al so been pharmacol ogi cal l y

subdi vi ded. Drugs that i nhi bi t the ani oni c si te are cal l ed competi ti ve inhi bitors. Their acti on i s a
resul t of competi ti on between the anti chol i nesterase and ACh for the ani oni c si te. These drugs
tend to be short acti ng. Edrophoni um i s an exampl e of thi s type. Drugs that inhi bit the esteratic
si te are cal l ed aci d-transferring i nhibi tors. These drugs incl ude the longer- acting neosti gmi ne,
pyri dosti gmi ne, and physosti gmi ne. Thus, the differences i n the mechani sm of i nhi biti on produced
by prostheti c i nhibi tors (edrophonium) and aci d-transferring i nhibi tors (neosti gmine) account for
the longer durati on of acti on associ ated with the l atter agents.
Most of the reversibl e chol inesterase inhi bi tors are quaternary ammoni um compounds and do not
cross the bl ood-brai n barri er. Physosti gmi ne is a terti ary ami ne that readil y passes i nto the CNS
(Fi g. 12-18). It produces central muscari ni c sti mulation and, thus, is not used to reverse
neuromuscul ar bl ockade but can be used to treat atropi ne poi soni ng. Conversel y, atropi ne i s used
Tabun Nerve gas Topi cal and gas No i ndi cations for the
use of nerve gas
Soman Nerve gas Topi cal and gas
Note: Atropi ne should al ways be gi ven pri or to or wi th i v chol inesterase inhi bi tors and
when onl y ni cotini c effects are desi red; muscari ni c effects are dangerous when
excessive.
P.299
to treat physosti gmi ne poi soni ng. Physosti gmi ne has al so been found to be a specific anti dote i n
the treatment of postoperative deli rium (see Central Anti chol i nergic Syndrome section).
3

The i rreversi ble chol i nesterase i nhibi tors are mostl y organo-phosphate compounds. In addi ti on,
the organophosphate compounds are hi ghl y l i pi d sol ubl e; they readi l y pass i nto the CNS and are
rapidl y absorbed through the ski n. They are used as the active i ngredi ent i n potent i nsecti ci des
and chemi cal warfare agents known as nerve gases. Tabl e 12-9 li sts some of these agents. The
only therapeutic drug of this group is echothi ophate, whi ch i s avai labl e i n the form of topical
drops for the treatment of glaucoma. Its pri mary advantage i s i ts prol onged durati on of acti on.
Topi cal absorpti on i s vari abl e but considerabl e. Echothi ophate can remai n effecti ve for 2 or 3
weeks foll owing cessati on of therapy.
64
A history of use of echothi ophate i s i mportant in avoi di ng
prolonged acti on of succinyl choli ne, whi ch requi res pseudochol i nesterase for i ts hydrolysi s.
Organophosphate poi soning mani fests al l the signs and symptoms of excess ACh.
65
The anti dote
cartri dges di spensed to troops to counter the effects of anti chol i nesterase nerve gases contai n
only atropi ne, whi ch would effecti vel y counter

the muscari ni c effects of the gas; however, atropi ne does li ttl e to counter the high-dose ni coti ni c
muscle paral ysi s or the central ventil ati on depressi on that contri butes to death from nerve gases.
Treatment requires hi gh doses of atropi ne, 35 to 70 mg/kg IV every 3 to 10 mi nutes until
muscari ni c symptoms abate. Lower doses at less frequent i nterval s may be requi red for several
FIGURE 12-18. Structural formulas of cli ni cal l y useful reversibl e anti chol i nesterase drugs.
Physostigmi ne i s a terti ary amine and crosses the bl ood-brai n barri er. It is useful i n treati ng
the central anti choli nergic syndrome.
P.300
days. Central venti latory depressi on and nicoti ni c paralysi s or weakness requi re respi ratory
support and speci fi c therapy of the chol i nesterase l esion. Prali doxi me has been reported to
reacti vate chol i nesterase acti vi ty by hydrol ysi s of the phosphate enzyme complex. It i s
parti cul arl y effective wi th parathi on poi soni ng and is the onl y chol i nesterase reacti vator avai l abl e
in the Uni ted States.
60

Muscarinic Antagonists
Muscari nic antagoni st refers to a speci fi c drug action for whi ch the term anti choli nergic is wi del y
used. Any drug that interferes wi th the action of ACh as a transmi tter can be considered an
anti choli nergic agent. The term anti choli nergi c refers to a broader cl assi fi cation that woul d i ncl ude
the ni cotini c antagonists.
Atropinic Drugs. Atropi ne, scopol ami ne, and glycopyrrolate are the most commonly used
muscari ni c antagoni sts used i n anesthesi a (Fi g. 12-19).
The acti ons of these drugs i ncl ude i nhi biti on of sal i vary, bronchi al, pancreati c, and gastroi ntesti nal
secretions to antagoni ze the muscari ni c side effects of antichol inesterases during reversal of
muscle rel axants. Atropi ne is useful in i ncreasing CO wi th si nus bradycardi a as a resul t of vagal
stimul ati on i f hypoxi a is rul ed out. It has many uses outside of anesthesi a for the treatment of
renal col i c, gastrointestinal spasm, gastri c secreti on, and asthma. Hi stori cal l y, atropine was
introduced to anesthesi a practi ce to prevent excessi ve secretions duri ng ether anesthesi a and to
FIGURE 12-19. Structural formulas of the cli nicall y useful antimuscari ni c drugs.
prevent vagal bradycardia duri ng the administrati on of chloroform.
66
Atropine and scopolami ne
al so possess anti emeti c action. Atropine, however, reduces the opening pressure of the l ower
esophageal sphi ncter, which theoreti cal l y i ncreases the ri sk of passi ve regurgi tati on. Atropinic
drugs al so produce di l ati on of the pupil (mydri asi s) and paralysi s of accommodati on (cycl opl egi a).
Antimuscarini c agents do not inhi bi t transmissi on equall y, and there are marked vari ati ons in
sensi ti vi ty at di fferent muscari ni c si tes owi ng to di fferences in penetration and affi ni ti es of the
vari ous receptors. Di fferences i n rel ati ve potency between the di fferent anti muscari ni cs are
outl i ned i n Tabl e 12-10. Glycopyrrol ate produces l ess tachycardi a than atropine and i s a more
potent antisi al ogogue.
The antimuscarini c effects of the atropinic drugs are the resul t of competi ti ve i nhi biti on of ACh at
the receptors of organs i nnervated by chol i nergi c postgangl i oni c nerves. The antagoni sm can be
overcome by suffici ent concentrati ons of chol i nomi metic drugs or anti choli nesterases that increase
ACh level s at the receptor si te. Thi s expl ai ns most of the therapeuti c actions of atropi ni c drugs;
however, they are nei ther purel y anti muscari ni c nor purely antagoni st.
3

The bel ladonna alkal oids (atropi ne and scopol ami ne) al so block ACh transmi ssi on to sweat gl ands,
whi ch, al though they are chol inergi c, are innervated by the SNS. Antimuscarinic agents produce
anti ni coti ni c actions at hi gher doses and resul t i n i mportant actions on CNS transmi ssi on that are
pharmacol ogicall y si mi l ar to the postgangli oni c chol i nergi c function.

Atropi ne and scopol ami ne are terti ary amines (see Fi g. 12-19) and easi ly penetrate the blood-
brain barrier and placenta. Gl ycopyrrolate is a quaternary ami ne that, l i ke the reversi bl e
anti choli nesterase drugs, does not easil y penetrate these barri ers. Glycopyrrolate, a synthetic
TABLE 12-10 Comparison of Antimuscarinic Drugs
DURATION
CNS
GI
TONE
GASTRIC
ACID
AIRWAY
SECRETIONS
a
HEART
RATE IV IM
Atropine 15
30
mi n
2
4
hr
++ -- +++
c
Scopol ami ne 30
60
mi n
4
6
hr
+++
b
---- 0
c
Glycopyrrolate 24
hr
6
8
hr
0 --- --- --- +0
a
Secreti ons may be reduced by inspissati on.
b
CNS effect often manifest as sedati on before sti mul ati on.
c
May decel erate ini ti all y.
P.301
anti muscari ni c, has gained popul ari ty because i t avoi ds the central effects of the other two drugs.
Atropi ne and scopol ami ne have notabl e CNS effects that are dissimil ar. Scopol ami ne di ffers from
atropi ne mainl y i n its central depressant effects, whi ch produce sedation, amnesia, and euphoria.
Such properties are widel y used for premedi cation for cardi ac pati ents in combinati on wi th
morphine and a major tranquilizer. Atropi ne, as a premedi cant, has sli ght effects on the CNS,
incl udi ng mi l d sti mulation. Hi gher doses such as those gi ven for reversal of muscl e rel axants (1 to
2 mg) may produce restlessness, disori entati on, hal l ucinati ons, and del iri um (see Central
Antichol inergi c Syndrome secti on). Excessi ve sti mul ati on may be fol l owed by depression and
paral ysi s of respirati on. Occasi onall y, scopolami ne i n low doses may cause restl essness and
del i ri um. This syndrome i s more frequentl y seen i n the el derl y and pati ents experi enci ng pai n, for
example, in obstetri c pati ents.
Atropi ne and scopol ami ne are noted to produce a paradoxi cal bradycardi a when gi ven i n l ow
doses. Scopol ami ne (0.1 to 0.2 mg) usual l y causes more sl owing than atropine but al so produces
less cardi ac accelerati on at higher doses. The usual intramuscul ar premedi cant doses of
scopol amine causes ei ther a decrease or no change i n HR. The paradoxi cal bradycardi a was once
thought to be caused by an earl y central i nhibi tion of the medull ary cardioi nhi bi tory center.
However, this phenomenon occurs i n ani mals that have had total vagotomy. Atropine may al so
produce sympathomi metic effects by blocking presynaptic muscari ni c receptors found on
adrenergi c nerve terminal s.
6
ACh sti mulation of these receptors i nhibi ts NE rel ease, and bl ockade
by atropi ne rel eases this i nhi biti on (see Chol i nergi c Receptors Secti on).
Atropi ni c drugs are wi del y used in ophthalmol ogy as mydri atics and cycl oplegi cs. Atropi ne is
contrai ndi cated i n pati ents wi th narrow-angle gl aucoma. Pupi l l ary di l ati on thi ckens the peri pheral
part of the i ri s, whi ch narrows the i ri docorneal angl e. Drai nage of aqueous humor is i mpai red, and
intraocul ar pressure i ncreases. Doses of atropi ne used for premedi cati on have li ttl e effect i n this
regard, whereas equal doses of scopol ami ne cause mydri asi s. Prudence woul d di ctate avoidance of
ei ther agent in pati ents wi th narrow-angle gl aucoma. The need for anti muscari ni c premedicati on i s
questi onabl e in thi s situation.
Atropi ne i s best avoi ded where tachycardia woul d be harmful , as may occur i n thyrotoxi cosi s,
pheochromocytoma, or obstructive coronary artery disease. Atropi ne should be avoi ded i n
hyperpyrexi al pati ents because i t inhi bi ts sweati ng.
Central Anticholinergic Syndrome. The bel l adonna al kaloi ds have l ong been known to produce
undesi rable si de effects rangi ng from stupor (scopol amine) to deli rium (atropi ne). Thi s syndrome
has otherwi se been cal led postoperati ve deli rium and atropi ne toxi ci ty. The central anti choli nergic
syndrome appears to involve the muscari ni c receptor.
3
Bi ochemical studi es have demonstrated
abundant muscari ni c ACh receptors in the brai n that can be affected by any drug possessi ng
anti muscari ni c acti vi ty and capabl e of crossi ng the bl ood-brai n barri er. Hundreds of drugs exi st
that meet these cri teri a with whi ch this syndrome has been associ ated. Tabl e 12-11 li sts some of
those drugs.
3

TABLE 12-11 Antimuscarinic Compounds Associated with Central Anticholinergic
Syndrome
Belladonna Alkaloids
Atropi ne sul fate
Scopol ami ne hydrobromide
Synthetic and Natural Tertiary Amine Compounds
Dicycl omine (Bentyl )anti spasmodic wi th l ocal anesthetic acti vi ty
Thi phenami l (Troci nate)anti spasmodic with local anestheti c activity
Procai ne
Cocaine
Cyclopentol ate (Cycl ogyl ) mydri ati c
Hi gh doses of atropi ni c al kal oi ds rapi dl y produce dryness of the mouth, blurred vi sion wi th
photophobia (mydri asi s), hot and dry skin (fl ushed), and fever. Mental symptoms range from
sedati on, stupor, and coma to anxi ety, restl essness, di sori entation, hal luci nations, and deli rium.
Convulsi ons and venti latory arrest may occur i f l ethal poi soni ng has occurred. Although an
al armi ng reacti on may occur, fatal iti es are rare. Intoxication is usually short l i ved and fol l owed by
amnesia. These reactions can be controll ed by the intravenous (i v) injecti on of physostigmine.
Physostigmi ne i s an anti chol inesterase that, by vi rtue of being a terti ary ami ne, readi l y passes
into the CNS to counter anti muscari ni c acti vi ty. It should be given slowl y in 1-mg doses, not
exceedi ng 3 mg, to avoi d produci ng peri pheral chol i nergi c acti vi ty. Neosti gmi ne, pyri dosti gmi ne,
Quaternary Derivatives of Belladonna Alkaloids
Methscopol amine bromi de (Pami ne)anti spasmodic
Homatropi ne methyl bromi desedati ve, anti spasmodi c
Homatropi ne hydrobromi deophthal mi c sol utionmydriatic
Synthetic Quaternary Compounds
Methanthel i ne bromi de (Banthi ne)
Propantheli ne bromi de (Pro-Banthi ne)
Antihistamines
Chl orphenirami ne (Ornade)
Di phenhydrami ne (Benadryl )
Plants
Deadl y ni ghtshade (atropine)
Bi ttersweet
Potato leaves and sprouts
Ji mson or loco weed
Coca pl ant (cocai ne)
Over-the-Counter
Asthma-Doratropi ne-li ke
Compozscopol amine sedation
Sleep Ezescopol amine sedation
Sominexscopol amine sedation
Antiparkinson Drugs
Benztropi ne (Cogenti n)
Tri hexpheni dyl (Artane)
Bi peri den (Aki neton)
Ethopropazine (Parsidol)
Procycl i dine (Kemadri n)
Antipsychotic Drugs
Chl orpromazi ne (Thorazi ne)
Thi oriazi ne (Mel laril )
Hal operi dol (Hal dol )
Droperi dol (Inapsi ne)
Promethazi ne (Phenegran)
Tricyclic Antidepressants
Ami tri ptyl i ne (Elavi l )
Imiprami ne (Tofrani l)
Desi prami ne (Norpramine, Pertofrane)
Synthetic Opioids
Meperi di ne
Methadone
Note: Trade names are gi ven in parentheses.
and edrophoni um are not effective because they cannot pass i nto the CNS. Li kewi se, atropi ne is an
effecti ve anti dote for physostigmi ne overdose. The durati on of physosti gmi ne acti on may be
shorter than that of the offendi ng anti muscari ni c agent and requi re repeated i njecti on i f symptoms
recur. Physosti gmi ne appears safe when used withi n dose recommendati ons and when i ndi cati ons
are establi shed. Central disori entati on al one does not establi sh a di agnosi s. Peri pheral si gns of
anti muscari ni c acti vi ty shoul d be present i n addi ti on to a central anti chol i nergic syndrome.
Physostigmi ne has been reported to reverse the CNS effects of many of the drugs l isted in Tabl e
12-11, i ncluding anti histamines, tricycl i c anti depressants, and tranqui li zers. Reversal of the
sedati ve effects of opioi ds and benzodi azepi nes has al so been reported.
67
However,
anti choli nesterase agents potenti ate chol i nergic synapti c transmi ssi on and i ncrease neuronal
activity, even if no receptor antagoni st i s present. Thus, arousal may not be a functi on
independent of i ts choli nesterase activity, and cl aims that physosti gmi ne i s a nonspeci fi c CNS
stimul ant may not be warranted and coul d, i n fact, be dangerous.
3

Hemodynamics
Unti l recently, sympathomi metics were the most common means of treati ng the hypotension
associated wi th shock. A vasopressor is a drug that i s used to el evate arterial bl ood pressure
above the exi sti ng l evel because the pressure is too l ow. However, el evati on of arteri al blood
pressure al one has repeatedl y been demonstrated to be an i nsuffi ci ent goal i n the treatment of
shock.
68
The goal , i nstead, is to reestabl i sh bl ood fl ow to vital organs. Al though bl ood pressure
has been the historical gol d standard for esti mating perfusion, there i s no correlati on between
bl ood pressure and fl ow (Fi g. 12-20).
69
In physiologi c as wel l as constructed systems, fl ow tends
to be l east when pressure i s hi ghest. Flow used i n thi s context refers to CO.
Oxygen transport i s the product of the arterial oxygen content (DO
2
) and CO:
DO
2
= Cao
2
CO
Therefore, there i s a close correl ation between oxygen transport and CO. Unfortunatel y, oxygen
transport i s not i dentical to cel l ul ar oxygen suppl y, whi ch can be i nadequate despi te normal or
el evated oxygen transport. Cel lular oxygen supply can be i nadequate because of mal distri buti on of
bl ood fl ow to vital organs or from the i nabi li ty of the cel l to use oxygen.
69
Improvi ng cel l ul ar
oxygen uti l izati on remai ns eni gmati c, but the catechol ami nes can be of some assistance in the
redi stri buti on of fl ow.
The physi ol ogi c equati on that expresses how fl ow (CO) i s generated states that CO is the product
of the HR and stroke volume (SV):
CO = HR SV
However, SV i s determi ned by three factors: (1) the contractil e or inotropi c state of the
myocardium, (2) prel oad, or end-di astoli c myocardi al fi ber l ength, and (3) afterl oad, or

resistance to ejecti on. The physi ol ogic determi nants of CO can therefore be expressed as:
CO = HR (inotropism:prel oad:afterl oad)
Synchrony of AV contraction is an addi tional determi nant when dysrhythmi as devel op. Thi s
equati on i s il l ustrated i n Fi gure 12-21 to emphasi ze that the bi ol ogic mechanisms that produce
and regulate fl ow are i nterdependent. Terms such as inotropism, preload, and afterload
FIGURE 12-20. Correlati on between mean arterial pressure (MAP) and O
2
del i very (DO
2
)
duri ng the peri operati ve peri od i n pati ents undergoi ng aorta bi femoral bypass grafti ng.
(Repri nted with permi ssi on from Rei nhart K: Principl es and Practi ce of Svo
2
Moni tori ng, p
121. London, Intensive Care World, Ki ng and Worth, Publi shers, vol 5, no 4, Dec 1988.)
P.302
cannot be defi ned i ndependentl y or i sol ated i n the cli nical setti ng. We can now measure, cal culate,
and mani pul ate each of the l i nks in the chai n of events that determi ne flow. Note that bl ood
pressure i s not among the determinants of fl ow. It i s the product and not the cause. Most
catechol amines affect one or more of these factors vi a the receptors and may cause changes i n
bl ood pressure by al teri ng fl ow, vascul ar tone, or both. A measured bl ood pressure does not
di sti ngui sh changes i n flow, resistance, inotropi sm, or HR; therefore, bl ood pressure and oxygen
transport do not correl ate.
Heart Rate
HR becomes an i mportant support of CO when SV i s decreased. A change i n ei ther HR or SV
invari abl y causes an alteration of the other by reflex activity. Tachycardi as can reduce SV by not
al lowi ng suffi cient diastoli c ventricul ar fil l ing time. Coronary bl ood fl ow to the ventricl es and
especi al l y the subendocardi um occurs pri mari l y duri ng di astole. The subepi cardial muscl e is
perfused duri ng systole as wel l as di astol e. However, subendocardi al bl ood fl ow i s total l y
dependent on di astol i c perfusi on ti me, di astol i c pressure, and mi croci rculatory tone.
70

Diastoli c perfusi on ti me becomes even more criti cal wi th ventricul ar hypertrophy. Increases in HR
wil l not onl y shorten the percent diastol ic perfusi on time for the endocardi um but al so i ncrease
oxygen demand.
71
Increased HR, al one, has been shown to i ncrease the severi ty of i schemi a and
the incidence of reperfusion arrhythmias. Animal studi es have shown that myocardi al bl ood flow
and contractil e functi on decrease wi th i ncreased inotropi c activity and tachycardi a. Thi s does not
occur when i ncreased inotropi sm i s not accompani ed by tachycardi a.
Diastoli c perfusi on ti me has a curvil i near relationshi p with HR, increasi ng rapidl y as rates fall
bel ow 75 beats/mi n (Fi g. 12-22). Once HR goes above 90 beats/mi n i n the adult, there i s l i ttl e
further decrease i n percent di astole. There is an exponential i ncrease in percent di astol e bel ow
rates of 70 beats/mi n.
70
Wide swi ngs i n percent di astol i c ti me are of li ttl e consequence i n the
patient wi th normal coronary function but can be cri ti cal i n those wi th obstructive coronary artery
di sease.
FIGURE 12-21. The four pri ncipal factors determi ni ng CO are demonstrated. Synchrony of
AV contraction is an addi tional factor becomi ng i mportant wi th the development of cardi ac
dysrhythmi as. (Repri nted with permi ssi on from Lawson NW, Wall fi sch HK: Cardi ovascul ar
pharmacol ogy: A new l ook at the pressors. In Stoel ti ng RK, Barash PG, Gal l agher TJ (eds):
Advances i n Anesthesi a, p 195, Chi cago, Year Book Publ i shers, 1986.)
Two factors actuall y determi ne the duration of systole: HR and electromechani cal systol e (QS2).
HR and QS2 have an inverse relationship (Fi g. 12-23).
70
Percent di astol i c perfusi on time i s
calculated as the cardi ac cycl e (R-R) minus QS2. A decrease i n HR and/or shorteni ng i n QS2 wi ll
resul t in prol ongati on of the total diastol ic peri od and vi ce versa. HR i s the more

i mportant factor because smal l changes in the HR can produce si gni fi cant changes in percent
di astole as a resul t of the curvil i near rel ati onship between HR and di astoli c perfusion ti me.
Changes i n HR al one produce movement al ong that curve, whereas changes i n QS2 resul t i n shi fts
of the curve. Dopami ne and dobutami ne (DBT) affect diastol ic perfusi on ti me by al teri ng HR and
QS2. DBT has been shown to increase percent diastole without si gnifi cantly al teri ng HR. The
increase i n diastoli c perfusion ti me is because of a shorteni ng of QS2. Isoproterenol reduces
percent di astol e because i t reduces QS2 proportional to the increase i n HR. -bl ockers,
parti cul arl y atenol ol, wi ll si gni fi cantl y decrease HR and i ncrease percent di astol e because i t has
li ttl e effect on QS2 i n the usual l y cli nical dose range. The benefici al effects of -bl ockers on
myocardial oxygen del i very and consumpti on can be rel ated to a reduced HR al one, al though
hi gher doses may reduce i notropi sm as wel l. Diastol ic perfusi on pressure may al so i ncrease wi th
-bl ockade because of an unopposed rel ati ve i ncrease i n vascul ar tone.
FIGURE 12-22. Smal l changes i n HR produce l arge changes i n percent di astol e especial ly at
low HRs because of the curvi li near rel ati onshi p between rate and di astol i c ti me. Shorteni ng of
el ectromechani cal systole (QS
2
) produces an upward shi ft of the curve. Shortening of QS
2
or
a decrease in HR, or both, wi l l increase percent diastol ic perfusi on time. Cardi oacti ve drugs
may affect di astol i c perfusi on ti me through ei ther or both mechani sms.
70

P.303
Preload
Prel oad i s cl i ni cal ly synonymous wi th the vol ume of venous return to the heart, which establ i shes
CO by the purported Frank-Starl i ng mechani sm. Prel oad has repeatedl y been demonstrated to be
of paramount i mportance in supporting cardiovascular functi on i n the normal heart. It can be
i ncreased by addi ng volume to the circul ati on or by acute venous constri cti on. The catechol ami nes
can be sel ected for their effect on preload by ei ther increasi ng (-1, -2) or decreasi ng (-2, DA1,
DA2) venous tone.
72
Posi ti ve or negati ve prel oading can be a major unrecogni zed benefi t of some
sympathomimeti c agents. Al though venoconstriction produces li ttl e i ncrease i n total vascul ar
resistance (afterl oad), mi ni mal venoconstri cti on i s capabl e of produci ng l arge shi fts of bl ood
vol ume i nto the central ci rculati on because the capacitance vessel s contain 60 to 80% of the total
bl ood vol ume, an effect that has l argely been i gnored. The central distri buti ve effect of a
catechol amine may be as i mportant as its inotropi c action in i ncreasing the CO i n the hypovol emi c
patient. Likewi se, a central distri buti on of capacitance blood may be undesi rable if the heart i s
fai l ing, even though that agent may possess inotropi c properties.
Afterload
Afterl oad i s a measure of i mpedance to ventri cul ar ejecti on and is the domi nant factor in
determi ni ng CO when inotropi sm i s i mpaired. In the absence of outl et obstructi on, the cl i ni cal
correlate of afterload to the left ventricl e is the systemi c vascul ar resistance refl ected by the
mean arteri al pressure. Afterl oad i s the onl y factor of the four major determinants of CO that, if
increased, wi l l reduce flow. Ohm' s law states that blood fl ow through any organ is di rectly rel ated
to the bl ood pressure gradi ent across that organ but i s inversel y proporti onal to the resi stance
(afterl oad).
FIGURE 12-23. Nomogram for the rel ati onshi p between el ectromechani cal systol e (QS
2
),
heart rate (HR), and percent di astol e. The percent di astol e can be obtained from QS
2
and
HR.
70
(Reprinted from Boudoul as H, Rittgers SE, Lewi s RP, Lei er CV, Wei ssl er AM: Changes i n
di astoli c time wi th various pharmacol ogi c agents. Circul ati on 60:164, 1979.)
Inotropism
Inotropi sm i s defi ned as the force and velocity of ventri cular contracti on when prel oad and
afterl oad are hel d constant. Vasoacti ve drugs can be descri bed as havi ng either a posi ti ve or
negati ve i notropic effect. Inotropic agents, such as DA and DBT, represent therapeutic agents that
al together increase myocardi al contractil i ty. As yet, there are no cl inicall y feasi ble means to
di rectl y measure i notropi sm at the bedsi de. We can defi ne fai l ure of i notropi sm better than we can
define what i t is. The myocardium permi ts CO to be regul ated at any level bel ow i ts i notropic
state.

Several direct i ndi cators of cardi ac i notropism appear useful i n li eu of direct force velocity
measurements. Pump functi on can be esti mated cl i ni cal l y by work-pressure curves usi ng the
Frank-Starl i ng mechani sm. When inotropi sm i s normal , CO i s more dependent on extracardi ac
factors such as prel oad and afterl oad (see Fi g. 12-21).
Lusitropism
Lusitropi sm i s a factor determi ning CO that i s not depi cted i n Fi gure 12-21. Lusi tropi sm descri bes
abnormali ties of myocardi al relaxati on, or diastol e, as opposed to probl ems of inotropi sm. Some
vasodil ators such as nitrogl yceri n and some sympathomimeti c inodi l ators are thought to improve
cardi ac functi on by promoti ng diastoli c rel axati on and thus ventricul ar fil l ing (prel oadi ng) and
coronary perfusion. Lusi tropi c dysfuncti on may pl ay a l arger role i n chronic heart fai l ure than
earli er appreci ated because lusitropi c dysfuncti on i s now known to pl ay a large role i n many
myocardial disease processes and may, i n fact, precede i notropic dysfunction. Decreased
lusi tropism is characteri sti c of the agi ng myocardi um.
Fi gure 12-21 del i beratel y emphasi zes prel oad and afterl oad as bal ancing forces i n produci ng CO.
They are antagoni sti c and assume di fferi ng degrees of domi nance dependi ng on whether the
myocardium i s healthy or fai l ing. Prel oad is the domi nant regul ator of CO in the normal
cardi ovascul ar system. Afterload dominates fl ow regulation when the myocardi um is fai l ing. Fi gure
12-24 compares the contrasti ng effects of prel oad and afterload on the CO of both the heal thy and
fai l ing myocardi um. Acute increases (in afterl oad) in the heal thy pati ent are tol erated, up to a
fourfol d i ncrease. In contrast, even small i ncreases in afterl oad produce l arge reducti ons in CO
when the myocardi um i s depressed by di sease or anesthesi a. The use of vasodi l ators for afterl oad
reduction in the pati ent with a fai l ing myocardi um i s based on thi s concept.
P.304
The weak l i nks i n the chain of cardi ovascul ar events that produce blood fl ow and oxygen transport
can now be selectivel y detected and mani pul ated rather than just the mi ndl ess i ncrease i n bl ood
pressure. The term vasopressor, once synonymous with vasoconstri cti on, has now become a
generi c term for several speci es of vasoactive drugs that, by whatever means, i ncrease CO that
may or may not increase blood pressure. Thei r uses i n anesthesi a i ncl ude (1) mai ntenance or
organ perfusion, (2) treatment of all ergic reactions, (3) prol ongation of the acti on of l ocal
anesthetics, and (4) for cardi opul monary resuscitati on.
Low-Output Syndrome
Patients with the l ow CO syndrome have abnormal i ti es of ei ther the heart, bl ood vol ume, or bl ood
flow distri bution. Those remai ni ng in thi s state for more than 1 hour usual ly have dysfuncti on of
al l three components. Modern hemodynami c moni tori ng has pinpoi nted hypovol emi a, rel ati ve or
absol ute, as the most common cause of the low-output syndrome, regardl ess of the eti ol ogy.
Initi al treatment wi th adrenergi c ami nes i n thi s setting i s li kel y to del ay volume repleti on and
potentiate the shock state. The proper hemodynami c management of septic shock, the most
commonly seen di stri buti ve abnormali ty, remai ns controversi al , but volume repleti on i s the
pri mary consi deration. Likewi se, the ini ti al treatment of cardi ac dysfuncti on i s optimum volume
repl acement because hypovol emi a i s a frequent accompani ment of impai red myocardi al
performance. Ventri cul ar performance may be i mproved solel y on the basi s of increased preload.
The treatment of cardi ogeni c shock i s an exampl e of the l ow-fl ow state that requi res mul ti pl e
autonomi c interventi ons common to other forms of the l ow-output syndrome. An acute reducti on
of left ventri cul ar contractil i ty (i notropism) produces a cascade of events that worsen i n cycl ic
fashi on (Fi g. 12-25). One coul d draw thi s cascade begi nni ng wi th any one of the five determinants
of CO. Loss of contracti li ty produces a reducti on i n CO, i ncreased left ventri cul ar end-di astoli c
pressure, and a host of compensatory refl exes. These compensatory mechani sms incl ude increased
sympatheti c activity that augments contracti l ity and rate. Chroni c dysfuncti on produces a third
compensatory mechanism, hypertrophy.
FIGURE 12-24. The contrasti ng effects of preload and afterl oad on CO. Increasi ng prel oad
increases output in the normal myocardi um, but to a l esser degree i n the fai li ng myocardi um.
Increased afterl oad i s usual ly tol erated by the normal myocardi um, but even small i ncreases
produce l arge reducti ons in output i n the fai li ng myocardium.
FIGURE 12-25. Reversal of heart fail ure by interventi on () with the i deal posi tive inotropi c

The attri butes of the i deal i notropi c drug are l isted in Tabl e 12-12. The i notropic agent needed for
the pati ent i l l ustrated i n Fi gure 12-25 woul d be rapi d acti ng and short l i ved and woul d not
increase HR, prel oad (unless hypovol emi c), afterl oad, or i nfarct si ze. Because the i deal i notropic
drug is not avail able, the peri pheral si de effects of any i notropi c agent become criti cal to sel ection
because all are mul tireceptor agoni sts.
Myocardi al fai l ure exi sts when the heart cannot pump enough bl ood to meet metabol i c needs. The
cl i ni cal mani festations of heart fai l ure resul t from peri pheral circul atory derangements that are
the resul t of the heart' s forward output laggi ng behind the i nput. Venous pressure i ncreases and
produces congestion. There are marked pathophysiologi c differences between chroni c heart fail ure
and acute fai l ure from infarction. Pati ents with chroni c heart fai l ure have retenti on of sodium and
water and are typi cal l y hypervol emi c, whereas pati ents wi th acute heart fail ure are ei ther
normovol emi c or, commonl y, hypovol emi c. Cardi omegal y i s a common compensatory feature of
chroni c heart fail ure (late) but is absent wi th acute heart fai lure. Circul ati ng catechol ami nes and
myocardial catechol ami ne content are decreased i n chronic fail ure but markedl y el evated in the
acute i nfarct. Thus, the response to inotropi c drugs in chronic heart fail ure i s infl uenced not onl y
by the l ack of myocardi al catecholami ne stores but al so by down-regul ati on of receptors. The CO
in chronic fai lure is borderli ne to decreased, whereas i t is usual l y normal or el evated with acute
fai l ure as a resul t of compensatory mechanisms.
Acute fai l ure i s the most common compl i cati on of infarcti on, occurri ng in 40 to 50% of patients,
whi ch refl ects a 20 to 25% i nvol vement of the myocardi um. In contrast to the pati ent wi th chroni c
heart fail ure, thi s dysfuncti on i s usual ly transient, lasti ng between 48 to 72 hours. Drugs with a
predomi nant i notropi c acti on are used al one or i n combi nation to acutel y i mprove cardiac
contracti l ity. Therefore, one has to be concerned that myocardi al damage i s not extended duri ng
thi s transi ent peri od by i nappropriate i notropi c or chronotropic support. Thi s is not as major a
concern i n the pati ent wi th hypertrophy, in whom i ncreased inotropi sm may actual l y reduce
oxygen consumpti on by reducing ventri cular mass.
Tabl e 12-13 presents one approach to the management of cardiogeni c shock l i sted i n order of
rel ati ve i mportance. The use of sympathomi metic support i s pl aced i n proper perspecti ve. It
agent depicted. (Reprinted wi th permission from Evans DB, Wei shaar RE, Kapl an HR:
Strategy for the di scovery and devel opment of a posi ti ve i notropi c agent. Pharmacol Ther
16:303, 1982.)
P.305
TABLE 12-12 Characteristics of the Ideal Positive Inotropic Agent
Enhances contracti le state by i ncreasi ng vel ocity and force of myocardi al fi ber shorteni ng
Lacks tol erance
Does not produce vasoconstriction
No cardi ac dysrhythmi as
Does not affect heart rate
Controll abi l i tyimmedi ate onset and termi nation of action
El evates perfusion pressure by rai si ng cardiac output rather than systemic vascul ar
resistance
Redi stri butes bl ood flow to vital organs
Di rect-acti ngnot dependent on rel ease of endogenous ami nes
Compati bl e with other vasoacti ve drugs
Effective orally or parenteral ly
emphasizes the essenti al rol e that invasi ve hemodynamic monitori ng and volume management
pl ay in confi rming a di agnosi s of cardi ogeni c fai l ure. Al though vol ume

expansion and reduction of afterl oad may i mprove CO, other pharmacologi c interventi ons may stil l
be necessary to opti mi ze CO and i ts di stri bution. Invasi ve moni tori ng is a prerequi si te for the
rati onal use of the vasoacti ve drugs to (1) establ ish that a sympathomi meti c is necessary, (2)
sel ect drugs for the hemodynami c condi tion, (3) fol low resul tant hemodynami c changes because
many of the benefi cial effects of the catechol ami nes are hi dden to the cl ini cal eye, and (4) avoi d
compl i cati ons of pressor therapy that are vi si bl e to al l.
Adrenergic DrugsSelection
The selecti on of vasoactive drugs requi res a knowl edge of both the hemodynami c di sturbance and
pharmacol ogy of the avai labl e drugs. The catechol ami nes and sympathomi meti c drugs continue to
be the pharmacologi c mainstay of cardi ovascul ar support for the l ow-flow state. Sustained i nterest
in the catechol ami nes i s rel ated to their predi ctabl e pharmacodynami cs and favorabl e
pharmacokineti c profi l es. Their effects are l inearl y related to pl asma level s, whi ch are di rectly
rel ated to the rate of infusi on. There are few cl i ni cal surpri ses within any given dose range and
the pharmacoki netics of catechol ami nes all ow rapi d titration to the effect. The hal f-li fe of most i s
short, rangi ng from 2 to 3 mi nutes. Undesi rabl e si de-effects di ssi pate wi thi n mi nutes of l oweri ng
or stopping the i nfusion. Sympathomi meti cs, as a group, produce a wi de range of hemodynami c
effects and can be used in combinati on to achi eve a yet wider spectrum of effects. As a result, one
need become fami l i ar wi th onl y a few agents to manage most cl i ni cal situations.
Tabl e 12-14 is a summary of the hemodynami c effects of some of the currently popul ar and once
popul ar sympathomimeti c drugs. Many of the hemodynamic effects are dose rel ated. The dose
ranges are l i sted and a standard i nfusi on rate ci ted. Standard rates of infusi on are si mpl y
gui del i nes, and the actual dose admi ni stered shoul d be determi ned by pati ent response.
P.306
TABLE 12-13 Management of Low Output Syndrome Caused by Myocardial Dysfunction
1. Assure adequate ventil ati on and oxygenati on
2. Rel i eve pai n and symptoms of recurrent i schemia
3. Insti tute hemodynamic monitori ng (pul monary artery, pulmonary capi l l ary wedge,
and arteri al pressures; uri ne output; cardi ac output)
4. Optimize l eft ventri cul ar fil l ing pressure
5. Correct metabol ic abnormal i ti es
6. Control dysrhythmi as (#2 priority if life threatening)
7. Pharmacol ogic support
a. Vasodi l ators
b. Inotropi c drugs
c. Diureticschroni c heart fai lure
8. Rule out correctable causes of shock (septal or l eft ventricl e rupture, mi tral
regurgi tati on, acute aneurysm)
9. Mechani cal support of ci rculation
10. Surgical correcti on i f possi ble
Note: Hemodynami c moni toring i s essenti al i n confirmi ng a diagnosis, opti mizing fi l li ng
pressures and cardi ac output, sel ecti ng pharmacol ogic support, and avoi di ng
compl i cati ons. Adjustment of l eft ventri cular fi ll i ng pressure may requi re addi tional
vol ume or a relative volume reducti on with vasodi lators. The di agnosti c criteri a for
cardi ogeni c shock are not met unti l step 4 i s accompli shed.
The goal for managi ng the l ow-output or hi gh-output shock syndrome is to establi sh and maintai n
adequate ti ssue perfusion. Aggressive fl ui d therapy wi ll suffi ce i n most i nstances.
Sympathomi metics are not a substi tute for volume. However, once i ntravascul ar vol ume is
optimized, a vasoacti ve drug may be requi red to sustain CO. The term inodi l ator has entered our
lexi con duri ng the earl y 1990s to suppl ant the more archaic term vasopressor. This neol ogi sm
refl ects a change i n phi losophy i n managing l ow-flow states, particularl y those characteri zed by
heart fail ure. The new synthetic sympathomi meti cs have been chemi cal l y engi neered to obtai n
i notropi sm and vasodi l ati on rather than for pressor effects. The potenti al for benefi t or harm can
best be understood i n terms of receptor characteristics. For exampl e, acti vation of the inotropi c -
1 and -2 receptors resul ts in posi ti ve inotropi sm and chronotropi sm. Sel ecti ve stimul ati on of the
vascul ar -2 receptors causes vasodil atati on. Left ventricul ar outfl ow may improve as a functi on of
decreased afterl oad reducti on and i notropi sm. However, chronotropi sm may not be a desi rabl e
feature i n a pati ent wi th mitral stenosi s or coronary artery di sease.
Catecholamine ReceptorEffector Coupling
The net physi ol ogi c effect of a sympathomimeti c i s usuall y defined as the al gebrai c sum of i ts
rel ati ve acti ons on the , , and DA receptors.
73
Most adrenergic drugs acti vate or block these
receptors to varyi ng degrees. Each catecholami ne has a distincti ve effect, quali tati vel y and
of 0.2
mg/mL
solution)
c. 0.15
g/kg/mi n
to
Thi rd-
degree
heart bl ock
desi red
effect
d. 0.015
g/kg/mi n
+++++ +++++
+++++ +++++
a
a. Mi xture
b. Concentration g/mL
c. Dose range g/kg/mi n
d. Standard rate infusion
b
Rule of six.
c
Dopami ne and dobutami ne empl oy the same doses. Dosage of either may qui ckl y be cal cul ated by mu
D5%W. The number of drops del i vered through a cal i brated infusor (60 drops = 1 mL) i s the number o
= 420; 420 mg/100 mL = 4,200 g/kg or 70 g gtt; 5 g/kg/mi n = 5 gtt/min. N/R, not recommended;
rate; VR, venous return (preload); TPR, peri pheral resi stance (afterl oad); RBF, renal bl ood fl ow.
Repri nted wi th permi ssion from Lawson NW, Wal l fi sch HK: Cardiovascular pharmacol ogy: A new l ook a
(eds): Advances in Anesthesi a, p 195. Chi cago, Year Book Medi cal Publ i shers, 1986.
quantitati vel y, on the myocardium and peri pheral vascul ature. Tabl e 12-15 demonstrates the
rel ati ve potency of the adrenergic ami nes on the vari ous myocardi al and vascul ar receptors. Thi s
rel ati ve potency i s al so dose rel ated, addi ng yet another vari abl e. The use of pluses (+) or zeros
(0) i s the cl assi cal method by whi ch the rel ati ve sensi tiviti es of catechol ami ne-receptor coupl ing
are demonstrated. The use of the (+) is al so symbol i c of the apparent summati on effect of the
catechol amines on the receptors. The summation effect further i mpli es a fi ni te number of
adrenergi c receptor sites to whi ch adrenergi c agoni sts can compete.
TABLE 12-15 Actions of Adrenergic Agonists
SYMPATHO-
MIMETICS
RECEPTORS DOSE
DEPENDENCE
(, , or DA)
1

2

1

2
DA
1
DA
2
Methoxami ne +++++ ?
a
0 0 0 0 V
o
Phenylephri ne +++++ ? 0 0 ++ P
v
Norepi nephri ne +++++ +++++ +++ 0 0 +++

p
s
Metarami nol +++++ ? +++ 0 0 +++ R
Epi nephri ne +++++ +++ ++++ ++ 0 ++++
Ephedrine ++ ? +++ ++ 0 ++ D
i
Mephentermine 0 to
++
? ++++ +? 0 ++ C
s
Dopamine + to
+++++
? ++++ ++ +++ ? +++++
Dobutamine 0 to + ? ++++ ++ 0 ++ I
g
c
Dopexamine 0 0 + ++++ + ++
Prenal terol + ++++ ++ +
For many years, the emphasi s on catecholami nes was focused al most entirel y on thei r actions on
the myocardium and on arteri olar resi stance vessel s. Changes i n venous resi stance contri bute
li ttl e to total vascul ar resi stance and bl ood pressure. However, small changes i n venous
capaci tance resul t i n l arge changes i n venous return because 60 to 70% of the ci rcul ati ng bl ood
vol ume i s the venous ci rcul ati on.
50
The effect of the sympathomimetic ami nes on the venous
ci rcul ati on appears to be di stri buti ve i n that acute venular constri cti on i ncreases the central bl ood
vol ume (prel oad), whereas di l atati on decreases venous return by the promoti on of peri pheral
pooli ng.
74
The distributive effect of a catecholamine may be as i mportant as its i notropi c acti on
and more important than i ts arteri olar effect.
10
Further defi ni ti on shoul d el uci date some of the
compl ex and confusing data i n the li terature generated when cli ni cal observations are l i mi ted
solel y to adrenergi c effects on the myocardi um and arteri ol ar vascul ature.
Intravenous and i ntra-arterial i nfusi ons of EPI i n humans have been shown to cause marked
constri cti on of the vei ns. Arteri olar vasoconstri cti on may or may not precede venoconstri cti on;
however, SV does not i ncrease until the onset of venoconstri cti on. The initi al i ncrease i n CO seen
wi th the i nfusi on of EPI i s more an effect of increased preload than an arteriol ar or di rect cardiac
effect. NE produces a si mi l ar effect, but the onset of venoconstri cti on i s sl ower.
A differenti al abi l ity of the amines to constrict vei ns has been noted in ani mals.
75
The data are
expressed as the average percentage contribution of venous resi stance to total change

in vascular resistance (Tabl e 12-16). Methoxami ne and NE are consi dered equi potent -1
arteriol ar vasoconstrictors; however, these effects differ dramati cal l y from thei r effects on
venoconstri cti on. The lack of venoconstri ctor response to methoxami ne has been demonstrated in
humans.
Isoproterenol 0 0 +++++ +++++ 0 0
a
The cli nical si gni fi cance of the effects of agoni sm and antagonism is not yet known.
P.307
P.308
TABLE 12-16 Average Percentages of Contributions of Increments in Venous
Resistance to Increments in Total Resistance (VR/TR 100)
Agent VR/TR 100
Norepi nephri ne 13.8
Tyrami ne 8.0
A si mil ar study in humans found si mi lar resul ts.
76
Tabl e 12-17 demonstrates rel ati ve potenci es of
several catecholamines on resi stance versus capaci tance vessel s. These data represent only the
rel ati ve potenci es of the ami nes wi thi n either resi stance or capaci tance vessels and are not a
compari son of potency ratios between the two. Neverthel ess, the data poi nt out the marked
di fferences between the agents. NE i s the most potent ami ne with respect to arteriol ar and venous
constri cti on. Metaraminol i s 1.5 times more potent than phenyl ephrine i n constri cti ng resistance
vessel s; however, phenyl ephri ne i s 1.5 times more effecti ve i n constri cti ng capaci tance vessel s
than metarami nol. NE proved to be 12 ti mes more potent than metarami nol in constri cti ng
resistance vessel s and 24 ti mes more effective in constricting capacitance vessel s.
Metarami nol 7.2
Ephedrine 3.3
Mephentermine 1.9
Phenylephri ne 1.8
Methoxami ne 1.4
After Zi mmerman BG, Abboud FN, Eckstei n JW: Comparison of the effects of
sympathomimeti c ami nes upon venous and total vascul ar resi stance i n the foreleg of the
dog. J Pharmacol Exp Ther 139:290, 1963, wi th permission.
TABLE 12-17 Relative Potencies of Several Sympathomimetic Amines in Humans with
Respect to Constrictor Effects on Resistance Vessels and Capacitance Vessels
RESISTANCE VESSELS CAPACITANCE VESSELS
DRUG RELATIVE
POTENCY
DRUG RELATIVE
POTENCY
Norepi nephri ne 1.0000 Norepi nephri ne 1.0000
Metarami nol 0.0874 Phenylephri ne 0.0570
Phenylephri ne 0.0684 Metarami nol 0.0419
Tyrami ne 0.0148 Methoxami ne 0.0068
Mephentermine 0.0049 Ephedrine 0.0025
Brown et al
77
reported the responses of resistance and capaci tance vessels to catechol ami nes i n
humans on cardiopul monary bypass. Thi s i s a uni que method of exami ni ng hemodynami c drug
response because fl ow rate (CO) is fixed, excluding the myocardi al effects of the drugs. Changes
in resi stance or capacitance are refl ected as ei ther changes in pressure or changes i n reservoi r
vol ume, respecti vel y. The agoni st phenyl ephri ne produced a marked decrease in venous
capaci tance (venoconstriction). Arteri ol ar resi stance i ncreased al so, but to a lesser degree,
confi rmi ng the study by Schmi d et al .
76
Dopami ne produces si gni fi cant venoconstri cti on at doses
that have no di rect arteriol ar or cardi ac effect, confi rmi ng studi es of dopami ne in ani mals (Fi g.
12-26).
77

Tabl e 12-18 is a summary of the avail able data on the relative potenci es of the ami nes on the
receptors of the resistance and capaci tance vessels. Scant data permi t inaccuraci es, but the tabl e
i s deri ved from sources that demonstrate remarkabl e consi stency. It i s offered as a cli ni cal guide
to drug selection. The peripheral receptors of both resi stance and capaci tance vessels subserve
vasoconstri cti on, but wi th di vergent effects on afterl oad and preload; therefore, the -1 receptors
Ephedrine 0.0020 Tyrami ne 0.0023
Methoxami ne 0.0018 Mephentermine 0.0023
After Schmi d PG, Eckstei n JW, Abboud FM: Comparison of the effects of several
sympathomimeti c ami nes on resi stance and capacitance vessel s in the forearm of man.
Circul ati on 34:III209, 1966, with permission.
FIGURE 12-26. The spectrum of dose-rel ated adrenergi c acti vi ty of dopami ne i s
demonstrated. Progressi ve rates of i nfusi on produce dopami nergi c (DA), , then acti vi ty.
Infusi on rates of greater than 15 g/kg/mi n produce a predomi nant effect, like that of NE.
Earl y -1 venoconstri cti on may be an i mportant redi stri buti ve feature of i nfused dopami ne.
have been subdi vi ded i nto -1 arteri al (-1a) and -1 venous (-1v). Note that methoxami ne and
phenylephri ne, both pure drugs, are equi potent arteri al vasoconstri ctors. Phenyl ephri ne,
however, is a potent venous constri ctor, but methoxami ne has vi rtuall y no effect on the
capaci tance vessels. Dopami ne has potent venoconstrictor (-1v) effect at doses at which few -
1a or -1 effects are noted.
TABLE 12-18 Comparison of Relative
1
Catecholamine Responses on Peripheral
Resistance and Capacitance Vessels
a

VASOCONSTRICTION
1
ARTERIAL
(
1a
)

1
VENOUS
(
1v
)
Norepi nephri ne +++++ Norepi nephri ne +++++
Metarami nol +++++ Phenylephri ne +++++
Phenylephri ne ++++ Metarami nol ++++
Methoxami ne ++++ Dopamine +++
Epi nephri ne 0/++++
b
Epi nephri ne 0/++++
b
Dopamine 0/++++
c
Ephedrine +++
Ephedrine ++ Mephentermine +?
Mephentermine ++ Methoxami ne 0/+?
Dobutamine +/0 Dobutamine ?
Isoproterenol 0 Isoproterenol 0
a
Drugs are li sted in descendi ng order of potency wi thi n each vascular region.
b
Dose-dependent; effects of epinephrine predomi nate at l ow doses.
c
Dose-dependent; DA and effects predomi nate at l ow doses.
Repri nted wi th permi ssi on from Lawson NW, Wal l fi sch HK: Cardiovascular pharmacol ogy:
A new look at the pressors. In Stoel ti ng RK, Barash PG, Gal l agher TJ (eds): Advances
in Anesthesia, p 195. Chi cago, Year Book Medi cal Publ i shers, 1986.
Adverse Effects
The major adverse effects of the sympathomimeti c ami nes are related to excessi ve or acti vi ty.
The potenti al for harm can be understood i n terms of receptor characteri sti cs. Excessi ve -1
acti vi ty may i ncrease contractil i ty but i ncrease HR and myocardi al oxygen consumpti on beyond
supply. Severe dysrhythmi as are a frequent companion of excess -1 activity as a resul t of
increased conduction velocity, automatici ty, and i schemi a. The -2 activity has the potenti al to
increase CO by

reduci ng resi stance (afterl oad) whi l e reduci ng blood pressure. An excessi ve decrease i n di astoli c
pressure, however, reduces obstructi ve coronary perfusion and may further aggravate myocardi al
ischemi a. The -1 and -2 effects of adrenergi c agoni sts are more useful cli ni cal l y than -1 effects
and can be used for l onger peri ods of time. Unfortunately, it is diffi cul t to separate the i notropic,
dromotropi c, and chronotropic effects i n the cl ini cal setting. The characteri sti cs of the i deal
positi ve i notropic agent are l i sted i n Tabl e 12-12 for comparison wi th each drug as i t is di scussed.
Drugs with promi nent -1 agoni st effects may produce an i ncrease i n bl ood pressure but reduce
total fl ow because of increases i n arteriol ar resi stance (afterload). A more promi nent -1 venous
constri cti on may improve CO by i ncreasi ng prel oad or preci pi tate fai l ure i f preload exceeds the
contracti l e li mits of the myocardi um (see Fi g. 12-24).
In general , the effects of the sympathomimetics are of benefit onl y when used for specific
indicati ons and for the bri efest possi bl e ti me. Other measures are usual l y more effecti ve i n
i mprovi ng fl ow and are i ndi cated before a pressor shoul d be used. The onl y ti me an adrenergi c
amine shoul d be used as a pressor or i n a pressor dose range wi thout consi derati on of flow i s
when arteri al perfusi on pressure must be increased i mmediately to prevent i mminent death or
morbidity.
78
Cardi opul monary resuscitati on i s the pri mary exampl e where a pressor effect i s
necessary to create di astoli c coronary perfusion duri ng closed- or open-heart massage. Any drug
wi th strong agoni st properti es seems equall y effecti ve i n thi s regard. EPI, wi th i ts added
properties, has been the fi rst-li ne agent for thi s si tuati on. Vasopressi n has been added to thi s fi rst
li ne. Drugs that vasodi l ate, such as i soproterenol , have li ttl e use i n this setting even if they
possess i notropi c properti es. Another si tuati on i n whi ch a vasoconstri ctor may be justi fi ed as a
temporary measure i s acute hypotensi on when cerebral , coronary, or extracorporeal bypass
perfusi on pressure i s the pri me consi derati on.
The prol onged use of adrenergi c agoni sts with strong properties commonl y resul ts i n
tachyphyl axi s. This phenomenon i s probabl y caused by increasi ng plasma volume l oss through
ischemi c capi ll ari es and down-regul ati on of the adrenergi c receptors. Precapi l lary sphi ncters are
under l ocal myogeni c control and rel ax when hypoxic and acidotic, despi te strong stimul ati on.
Postcapil l ary sphi ncters are more functional i n an hypoxi c and acidoti c mi l i eu but are under
stronger central neurogeni c control . Continued postcapi l l ary tone i n the face of precapi ll ary
rel axation increases hydrostati c pressure wi th a net l oss of i ntravascular volume. These events are
just a few of the explanations for the once mysteri ous so-call ed l evophed shock, in whi ch pati ents
were unable to be weaned from NE infusions.
79

Adrenergie Agonists , DA
Methoxamine and Phenylephrine. Methoxamine i s the prototype pure vasoconstri ctor.
Phenylephri ne produces simi l ar acti ons, but there are important cl i ni cal differences. Methoxami ne
possesses onl y -1 properti es and produces almost no venoconstri cti on. Its onl y pharmacol ogi c
effects are to increase arterial resi stance, i ncrease afterl oad, and reduce fl ow, even though blood
pressure i s el evated. Few cl ini cal uses for methoxamine remai n. It has been useful for treating
paroxysmal atri al tachycardi as. A si ngl e i v dose of methoxami ne can break a paroxysmal atri al
tachycardi a refl exl y through baroreceptor stretch, obvi ati ng the need for use of di gi tal i s or
countershock. Caroti d massage produces si mi l ar results by a si mi lar mechani sm.

Phenylephri ne, al so considered a pure drug, increases venous constri cti on and arterial
P.309
P.310
constri cti on i n a dose-rel ated manner. Constriction of capaci tances vessel s precede arteri olar
constri cti on. Venous constriction may be i ts most redeeming feature when compared wi th the
purel y arteriol ar effect of methoxami ne. One cannot di scount the possi bil i ty of an i notropi c effect
now that -1 receptors are known to exi st in the myocardi um that improve i notropism. Acutely,
venoconstri cti on favors venous return (prel oad), even though arteri al resi stance (afterload) al so
increases. The net effect may result i n an i ncrease in pressure and CO. Phenylephri ne, li ke
methoxamine, does not change CO in normal indi vi dual s but can cause a decreased output i n
patients with ischemi c heart di sease.
80
Phenylephri ne has conti nued to be favored in operati ng
rooms to bri efl y increase bl ood pressure duri ng cardi opul monary bypass as wel l as during
intracranial and peripheral vascul ar procedures. It does not produce dysrhythmias. Phenyl ephrine
is also useful in reversing right-to-left shunt in tetral ogy of Fall ot when pati ents are havi ng
spel ls duri ng anesthesi a.
81
The arteri al vasoconstri ctors may reduce the si ze of an i schemic
injury when used i n conjuncti on with intra-aorti c bal l oon pumpi ng or nitrogl yceri n.
82

Norepinephrine. NE i s the natural l y occurri ng medi ator of the SNS and the i mmedi ate precursor
of EPI. It produces direct-acti ng hemodynami c effects on the and receptors i n a dose-rel ated
manner when gi ven by i nfusi on. NE produces i ncreased CO and bl ood pressure when gi ven i n l ow
doses (see Tabl e 12-14). Hi gher doses reduce fl ow because arteriol ar constriction supersedes
the effects. Refl ex baroreceptor bradycardi as may occur vi a active stimul ati on.
Increased pl asma l evel s of the endogenous catecholami nes NE and EPI are the sympatheti c mi li eu
(stress) i n whi ch exogenous sympathomi meti cs are ordi nari l y gi ven. NE i s the catechol ami ne
standard agai nst whi ch other catechol ami nes are compared. Intravenous NE has recei ved an
unseeml y reputati on over the years that i s not merited. Studi es i ndi cate that NE was bei ng used i n
doses that are orders of magni tude greater than that necessary to obtain i ts best response i n
produci ng CO rather than produci ng a bl ood pressure. They do not correl ate (see Fi g 12-20).
Compli cati ons such as renal fail ure and ti ssue necrosi s are routine and can be expected when NE
i s used. If NE i s used si mpl y to ti trate to bl ood pressure rather than measured fl ow, the amount of
NE i nfused i s 5 to 10 ti mes more than necessary to obtain the best oxygen del i very and oxygen
consumpti on.
3
Al though NE is l ess commonly used i n the cri ti cal ly i ll patient than other
catechol amines, a resurgence of i nterest in thi s agent i s noted. It has remai ned cl i ni cal l y useful
because i ts effects are predi ctabl e, prompt, and potent.
Objecti ons to the use of NE for the treatment of cardi ogenic shock are based on two
consi derati ons: (1) vasoconstriction increases the pressure work of the l eft ventri cl e, wi th an
adverse effect on the oxygen economy of the ischemi c pump and (2) these drugs cause further
vasoconstri cti on and organ ischemia i n a syndrome i n which intense constri cti on may al ready have
occurred.
16
The use of NE requi res the use of invasi ve moni tori ng; otherwise, compl icati ons are to
be expected. It is not usual ly necessary to el evate the systol i c blood pressure above 90 to 100
mm Hg. At this l evel of i nfusion, the CO wi l l normal l y be i ncreased as a effect without excessi ve
peri pheral vasoconstriction. NE is al so a potent venoconstri ctor, whi ch wil l alter interpretati on of
venous fi ll i ng pressures as a gui de to adequate vol ume repl etion.
Other undesi rabl e effects associated wi th NE i ncl ude renal arteri ol ar constri cti on and oli guri a. In
addi ti on, prol onged therapy may produce a reduction in pl asma vol ume as a resul t of fl ui d
transudati on. Indeed, i n some instances, cardiogeni c shock requiring conti nuous NE i nfusi ons has
been reversed by fluid infusi ons.
16

Norepi nephri ne should only be admi ni stered in a centrall y placed iv to avoid ti ssue necrosis from
extravasati on. It can be used for i ts i ntropi c effect at l ow doses and titrated to effect while
moni tori ng cardiac output. Monitori ng of blood pressure al one or ti trati ng to a predetermi ned
effect i s often detri mental to cardiac output. Bl ood pressure i ncreases are usual ly a resul t of
increases i n SVR and can dimini sh forward fl ow and contri bute to cardiac fail ure. Even moderate
doses of norepi nephri ne may have a detri mental effect on end-organ perfusion, whi ch has gi ven
the drug an i l l -gotten reputation when used to ti trate to pressure rather than flow. However, i n
those cli ni cal condi tions characteri zed by a low perfusi on pressure and hi gh fl ow (vasodi l atati on)
and mal distri bution of fl ow (sepsis), norepi nephri ne has been shown to i mprove renal
P.311
and spl anchni c bl ood flow by i ncreasing pressure provi ded the pati ent has been vol ume
resusci tated.
Epinephrine. EPI i s the prototypi cal endogenous catechol ami ne. It i s synthesized, stored, and
rel eased from the adrenal medull a and i s the key hormonal el ement i n the fight-or-flight response.
It i s the most widel y used catechol ami ne i n medi ci ne. It i s used to treat asthma, anaphyl axi s,
cardi ac arrest, and bl eedi ng and to prol ong Regi onal Anesthesi a. The cardi ovascul ar effects of EPI,
when given systemi cal ly, resul t from its di rect sti mulati on of both and receptors. This i s dose
dependent and i s outl i ned i n Tabl e 12-14.
The effect of EPI on the peri pheral vascul ature i s mi xed. It has predomi nantl y -stimul ati ng
effects i n some beds (ski n, mucosa, and ki dney) and -stimul ati ng actions in others (skeletal
muscle). These effects are also dose dependent. At therapeutic doses, -adrenergi c effects
predomi nate i n the peri pheral vessel s, and total resi stance may be reduced. Constri cti on,
however, is mai ntained i n the renal and cutaneous areas because of i ts domi nant effect in these
areas. An i ncrease i n CO wi th EPI may be a resul t of a redi stri buti on of bl ood to l ow resi stance
vessel s in the muscl e, but wi th further reduction in fl ow to vital organs. Cardi ac dysrhythmi as are
a promi nent hazard, and the strong chronotropic effects of EPI have li mi ted its use i n the
treatment of cardi ogeni c shock.
Epi nephri ne i s commonl y used i n the peri operati ve period i n anesthesi a. It i s often used to
produce a bl oodl ess fi el d i n denti stry, otol aryngol ogy, and skin grafti ng ei ther topi cal ly or i n local
and fi el d bl ocks. Anesthesi ologi sts often use i t to prol ong regi onal anesthesi a. The addi ti on of
epi nephri ne to arthroscopi c i nfusi ons to attai n a bl oodl ess fi el d i s another area of increased
epi nephri ne usage with the devel opment of these techni ques. These i nfusi ons are usual l y safe i n
maintai ni ng a dry operative fi eld because the sol uti ons are very di l ute at around 1:3,000,000.
However, the large volumes infused, the unpredi ctable absorpti on of the epi nephri ne, especi al l y i n
denuded cancel lous bone, offers the opportuni ty of exposure of the pati ent to an excessi ve amount
of epi nephri ne over a short period of ti me despite the dil uti on.
83
The unexpected compl i cations are
those of epi nephri ne overdose, that i s, acute heart fai lure, pul monary edema, or cardiac
arrhythmi as and arrest i n the otherwi se young and heal thy pati ent. Impendi ng probl ems duri ng
the infusi on of i ntra-arti cul ar fl uids wi l l be noted by an increasi ng bl ood pressure exceedi ng that
attri butabl e to surgi cal pain or hypertension that i s poorl y responsi ve to deepeni ng of anesthesia.
Absent a pul satil e flow or vasoconstri cti on oxi metry may become dysfunctional . The pati ent wi l l
appear pal e and cyanoti c. Unless alert, one may uni ntenti onal l y treat an unexpected acute heart
fai l ure or cardi ac arrest with the very agent that caused the probl em. The outcome i s uni versall y
poor. Vasodi l ators and -blockers may save the day instead.
Intravenous and l ocall y infi ltrated adrenergi c agents shoul d be used cauti ously duri ng i nhalati on
anesthesia, especi all y wi th hal othane. The foll owing schedul e has been found to be rel ati vel y safe
duri ng i nhal ati on anesthesi a.
84
(1) EPI concentrations no greater than 1:100,0001:200,000
(1:200,000 = 5 g/mL). (2) Adul t dose should be no greater than 10 mL of 1:100,000 or 20 mL of
1:200,000 wi thin 10 minutes. (3) Total should not exceed 30 mL of 1:100,000 (60 mL of
1:200,000) withi n 1 hour.
The dose of submuscosall y injected EPI necessary to produce ventricul ar cardi ac dysrhythmi a in
50% of patients anesthetized wi th a 1.25 MAC of a volatil e anestheti c was 10.9, 10.9, and 6.7
g/kg during admi ni strati on of hal othane, enfl urane, and i sofl urane, respectively.
85
No data are
currently avai l abl e for sevofl urane or desflurane. The i nci dence of cardiac dysrhythmia i s
el i mi nated when thi s dose i s hal ved i n patients anestheti zed with halothane or isofl urane. In
contrast with adults, chi l dren seem to tolerate hi gher doses of subcutaneous EPI without
developing cardi ac dysrhythmi a.
86

Ephedrine. Ephedri ne i s the most commonly used noncatechol amine sympathomi metic agent. It is
used extensivel y for treating hypotension fol l owing spinal or epidural anesthesi a. Ephedri ne
stimul ates both and receptors by di rect and i ndi rect actions. It i s predomi nantl y an i ndirect-
acti ng pressor, produci ng its effects by causi ng NE release.
16
Tachyphyl axi s devel ops rapi dl y and
i s probabl y rel ated to the depl eti on of NE stores wi th repeated i njecti on. The cardiovascular
effects of ephedrine (see Tabl e 12-14) are nearl y i denti cal to those of EPI but less potent. Its
effects are sustai ned about 10 times longer than those of EPI.
Ephedrine remai ns the pressor of choice i n obstetri cs because uteri ne blood fl ow improves l inearly
wi th bl ood pressure.
52
Thi s effect is probabl y not rel ated to i ts arteri ol ar vasoconstri cti on but
rather to i ts venoconstri ctive acti on. Ephedri ne is a weak, indirect-acti ng sympathomi meti c agent
that produces venoconstriction to a greater degree than arteri olar constri cti on (see Tabl e 12-18),
at the doses ordi nari l y used.
87
Thi s may be i ts most i mportant and unappreci ated effect. It causes
a redi stri buti on of bl ood central l y, i mproves venous return (prel oad), increases CO, and restores
uteri ne perfusi on. The mi ld acti on restores HR si mul taneousl y wi th i mproved venous return. An
i ncreased bl ood pressure i s noted as a resul t rather than a cause of these events. Mi l d -1
arteriol ar constriction does occur, but the net effect of improving venous return and HR is
increased CO (Fi g. 12-27). Uteri ne bl ood fl ow i s spared. Thi s response, however, depends on the
patient' s state of hydrati on.
Neosynephri ne i s an attracti ve al ternate vasopressor for obstetrics for si mi l ar reasons. It produces
strong -1 venoconstri cti on and vol ume redi stri bution at infusion rates at which -1a or effects
are mi ni mal (see Tabl e 12-15). Alternati vel y, the pri mary di sadvantage of the venoconstriction of
low doses of dopami ne i s i ts l ack of immedi ate avai l abi l ity as an i v push drug. It requi res more
careful ti tration than ephedri ne. The prophyl actic admi nistrati on of pressors before spinal
bl ockade in obstetri cs can produce mi sl eading cli ni cal estimates of volume status because of i ts
effects on venous return and arteri al pressure.
88

Isoproterenol. Isoproterenol is a potent bal anced -1 and -2 receptor agoni st wi th no
vasoconstri ctor effects. It increases HR and contractil i ty whi l e decreasi ng systemi c vascular
resistance. Although i t can increase CO, it i s not useful i n shock because i t redi stributes bl ood to
nonessenti al areas by i ts preferential effect on the cutaneous and muscul ar vessel s.
89
As a result,
i t produces vari abl e and unpredi ctable results on CO and bl ood pressure. Isoproterenol i s a potent
dysrhythmogeni c drug and extends myocardi al ischemi c areas. Deleteri ous effects on an evol vi ng
cardi ac ischemi c process i ncl ude cardi ac dysrhythmi as, tachycardi a, and reduced diastol ic
FIGURE 12-27. Stroke vol ume (SV), end-di astol i c vol ume (EDV), and systemic vascul ar
resistance (SVR) (1) before regi onal bl ock, (2) duri ng hypotensi on, and (3) after therapy
with ephedri ne or phenyl ephrine. The increase i n stroke vol ume was rel ated entirel y to an
increased venous return secondary to venoconstriction i n these awake, heal thy pati ents. The
afterl oad effects of phenyl ephrine at hi gher doses predomi nate i n patients wi th heart disease
or myocardi al depressi on and reduce CO. (Repri nted with permi ssi on from Ramanthan S,
Grant G: Vasopressor therapy for hypotension due to epidural anesthesi a for cesarean
secti on. Acta Anaesthesi ol Scand 32:4, 1988.)
P.312
coronary perfusion pressure and time. Increased myocardi al oxygen demand makes i t an
unattractive drug for pati ents i n cardiogeni c shock.
Isoproterenol i s hel pful in managi ng cardi ac fai l ure associ ated wi th bradycardi a, asthma, and cor
pul monale. It i s al so a useful chemi cal pacemaker i n thi rd-degree heart bl ock unti l an arti fi ci al
pacemaker can be inserted or the cause can be removed. Isoproterenol mi ght be useful i n treating
both i di opathi c and secondary pul monary hypertensi on.
15, 16
It has also been reported as useful i n
i mprovi ng the forward fl ow i n patients wi th regurgi tant aortic val vular disease, but i t should not
be used i f there is an accompanyi ng stenosi s.
82

Dobutamine. Dobutamine is a syntheti c catechol ami ne modi fi ed from the cl assic i nodi lator
isoproterenol . Isoproterenol was, in turn, synthesized from dopami ne. Vari ations and si mi l ari ti es
in structure can be seen in Fi gure 12-7.
DBT has cl ear advantages over i soproterenol and dopami ne i n many cl i ni cal si tuati ons. It acts
di rectl y on -1 receptors but exerts much weaker -2 sti mulati on than isoproterenol. It does not
cause NE rel ease or sti mul ate DA receptors. DBT, unli ke i soproterenol or DPX, possesses weak -1
agoni sm, whi ch can be unmasked by -bl ockade as a prompt and dramati c i ncrease in bl ood
pressure.
90
Ordi nari l y, changes i n arteri al bl ood pressure do not occur because the mi ld -1
acti vi ty i s countered by the -2 activity. DBT produces strong i notropism but wi th weak
chronotropi c or vascul ar effects. Increases i n CO are pri maril y through i ncreased inotropi sm and
secondari l y by reduced afterl oad.
DBT i ncreases automati city of the SA node and increases conducti on through the AV nodes and
ventri cles. DBT produces l ess i ncrease in HR per unit gain in CO than dopami ne, but i t i s not
devoi d of chronotropi c activity. Troubl esome tachycardi as can occur i n sensiti ve i ndi vi duals and
cauti on shoul d be exerci sed in pati ents wi th establ ished atri al fibri ll ati on or recurrent
tachycardi as. Early studies found DBT preferabl e to dopami ne, EPI, or isoproterenol because of i ts
reduced chronotropi c effects.
91
DBT i ncreases HR more than EPI for a gi ven i ncrease i n CO.
92

DBT may decrease di astol i c coronary fi l li ng pressure because of i ts vasodi lation i n contrast to the
constri cti on produced by dopami ne.
71
These studies suggest that dobutami ne produces an overal l
favorabl e metabol i c cl i mate i n the i schemi c myocardium despi te an increase i n inotropi sm.
Improvement i s rate l i mi ted. Dobutami ne has been used effecti vel y to i mprove coronary fl ow to
di fferenti ate, by echocardi ography, responsive or unresponsive areas of dyskinesi a i n patients
following myocardial infarction.
93

Dobutami ne is highly control l abl e wi th a hal f-li fe of 2 mi nutes. Tachyphyl axi s is rare but may be
noted i f gi ven over 72 hours. The net hemodynamic effects of DBT include an i ncrease in CO, a
decrease i n l eft ventricul ar fil l ing pressure, and a decrease in systemic vascul ar resi stance wi thout
a si gni fi cant i ncrease i n chronotropi sm at l ower doses.
94
It has been proven to be as effecti ve as
combi ned dopami ne and ni troprussi de i n treating heart fai l ure wi th i nfarcti on. It i s even more
effecti ve when summated wi th the dopami nergi c properti es of DA. In contrast to dopami ne, DBT
seems to inhi bi t hypoxi c pul monary vasoconstriction. Like i ts parent compound i soproterenol , DBT
may prove to be useful i n managi ng ri ght ventricul ar heart fail ure.
Dopami ne offers some advantages over many sympathomi meti cs i n treati ng the low-output
syndrome.
95
It i s a dose-rel ated agonist to al l three types of adrenoceptors, and the desi red acti on
can be sel ected by changi ng the i nfusi on rate. The DA receptors are most sensi tive foll owed by the
, and then receptors. Dopami ne dosage regimens have been traditi onal l y, and arbitraril y,
di vi ded i nto l ow, medi um, and high doses according to its dose-receptor sensi ti vi ty (see Tabl e 12-
14). Renal and mesenteri c vascul ar di l atati on and tubul ar cell natri uresi s are medi ated through
the DA receptors at l ow-dose i nfusion rates of 0.5 to 2.0 g/kg/mi n. Thi s i s often referred to as
renal dose dopami ne because of the purported enhanced renal blood fl ow and di uresi s. However,
the concept of renal dose DA may be more i magi ned than real. The di uresi s may al so be
attri buted, i n part, to i nhi bi ti on of al dosterone secreti on seen with l ow-dose DA admi ni strati on.
96

A general i mprovement i n CO from afterl oad reducti on al so contributes to i mprovements i n renal
bl ood fl ow. These effects have been well demonstrated in pati ents wi th heart fai l ure. However, the
protecti ve effects of DA on the devel opment of renal fai l ure in the cri ti cal l y i l l or i njured pati ent,
al though an attracti ve pri ncipl e, i s much less certai n. Preventi on of renal fai l ure by prophyl acti c
renal dose DA (wi th or wi thout furosemi de) i n the cri ti cal l y i l l
97
or traumati zed pati ent has not
been concl usi vel y demonstrated, and no l onger tenabl e. Thi s may be rel ated to the adrenergi c
mi li eu into whi ch the DA is given. The vasoconstrictive effects of DA are expected to occur onl y at
rel ati vely hi gh doses. However, even rel ati vel y l ow doses of DA can cause renal vasoconstri cti on
when added i nto pre-exi sting hi gh pl asma l evel s of endogenous catechol ami nes commonl y seen i n
the cri ti cal l y i l l or acutel y i njured pati ent or those al ready recei vi ng i ntravenous
sympathomimeti cs.
The hemodynami c effects of l ow-dose DA are pri mari l y related to vasodi latation by acti vati on of
the DA1 and DA2 receptors. Acti vati on of presynaptic DA2 adrenoceptors add to the vasodi l ati ng
effect of the DA1 receptors by i nhi bi ti ng presynapti c NE rel ease i n the renal and mesenteri c
vessel s. The reducti on of total systemi c vascular resistance woul d be si gnifi cant when one
consi ders that 25% of the CO goes to the ki dneys al one (Fi g. 12-28). A reduced di astol i c bl ood
pressure i s often noted with a sl i ght reflex i ncrease i n HR. Increasi ng the i nfusi on rate of DA to 2
to 5 g/kg/mi n begi ns to acti vate receptors increasi ng the CO by increasi ng chronotropi sm and
contracti l ity with earl y venoconstri cti on (prel oad) and systemi c vasodi latation (afterl oad
reduction). Bl ood pressure may not increase despite si gni fi cant i ncreases in CO. This dose range
woul d appear opti mal for managi ng congesti ve heart and l ung fai lure because i t combi nes
i notropi sm and afterl oad reducti on wi th possibl e di uresi s. Further i ncreases in dose acti vate
receptors, whi ch wi ll i ncrease vascular resi stance and bl ood pressure, but further i mprovements in
CO may be attenuated. Infusi on rates of greater than 10 g/kg/mi n produce intense a acti vi ty,
which may override any benefici al DA or vasodil ati on effect on total fl ow. Hi gh-dose dopami ne
behaves much like NE and, in fact, causes NE rel ease at thi s dose range.
98

Despi te the apparent dose-response di vi sions of DA, a wi de vari abi l i ty of indi vi dual responses has
been noted. The -adrenergi c effects can be seen in some i ndi vi duals i n doses as l ow as 5
g/kg/mi n, whereas doses as high as 20 g/kg/mi n may be required to obtain this effect in
shocked pati ents.
98
Thi s wi de vari ati on i n dose response has l ed to a reexami nation of DA as a
FIGURE 12-28. Dobutamine produces a net reducti on i n vascul ar resi stance. Its weak
vasoconstri cti ve effects are balanced by a direct -2 vasodil ati on with li ttl e change i n
vascul ar tone. However, further refl ex arterial vasodi l ation occurs wi th i ncreased CO. Low-
dose dopami ne di l ates renal and mesentri c arteri al beds, whi ch reduces afterl oad but
increases resi stance at i ncreasing doses as a resul t of its predomi nant effect.
pri mary adrenergic for pati ents in cardi ogeni c shock or fail ure. Increased venous return may not
be desi rabl e i n thi s si tuati on, but dopami ne' s hemodynami c versati l ity conti nues to be useful in
cardi ogeni c shock when

combi ned with other complementary catechol ami nes such as dobutamine (Fi g. 12-29) (see
combi nations). The venoconstri cti on, or distri butive effects, of dopami ne are useful i n surgi cal
patients i n whom third-space edema and sepsi s are the most common abnormal i ti es. Dopamine
increases mean pul monary arteri al pressure and i s not recommended for sol e support i n pati ents
with ri ght heart fail ure, adul t respi ratory di stress syndrome, or pul monary hypertensi on.
Combination Therapy
Dopami ne and DBT are two of the most popul ar i nodi lators in use today. A compari son of these
two drugs wi l l underscore the i mportance of the extracardiac si de effects in selecting a drug ei ther
for use al one or i n combi nation.
99
Thi s comparison i s particul arl y appropri ate because dopami ne
and DBT are consi dered equipotent inotropi c agents and are effecti ve i n the same dose range of 2
to 15 g/kg/mi n. Thei r differences can be compared at l ow (0.5 to 4 g/kg/mi n), medi um (5 to 9
g/kg/mi n), and hi gh (10 to 15 g/kg/mi n) doses. Thi s compari son wi l l il l ustrate the divergent
effects of two drugs on prel oad and afterl oad whi l e shari ng the property of i notropi sm. Al though
they share several cl inical indicati ons, these drugs are pharmacologi cal ly distinct and not
interchangeabl e. Their di vergent properties, however, make them parti cularly valuabl e when used
in combinati on.
100

DBT i s a direct-acti ng catechol ami ne that produces a posi ti ve inotropi c -1 effect but with minimal
changes i n -2 HR or vascul ar resi stance (-2, -1 counteraction). Thus, DBT may not al ter bl ood
pressure even though CO is markedly improved. Dopami ne may do both. Low-dose dopami ne can
produce hemodynami c changes si mi l ar to those of DBT (i notropi sm and mesenteri c vasodi latation)
(see Fi g. 12-28). Dopami ne produces an increase i n bl ood pressure at hi gher doses rel ated to its
di rect and i ndi rect -1 activation. Thi s increased afterl oad with dopami ne may attenuate any
P.313
FIGURE 12-29. A decrease i n venous capaci tance has been demonstrated as an earl y effect
of dopami ne. An i ncrease i n pul monary capi l lary wedge pressure may be noted. Dobutami ne
may decrease pul monary capi l l ary wedge pressure by i ncreased i notropi sm as wel l as
vasodilation with mi nimal effect on venous capaci tance. (Redrawn wi th permi ssi on of El i Li ll y
Co., Indi anapoli s, Indi ana.)
further i ncrease i n CO comparabl e to that of an equal dose of DBT. DBT does not have any
cl i ni cal ly important venoconstri ctor activi ty i n contrast to dopamine i n whi ch an increase in
ventri cul ar fi l l ing pressure can be noted at l ow doses. Thi s contrasti ng effect on prel oad i s seen i n
Fi gure 12-29. The cardi ac response to all vasodi l ators i s dependent on the preexi sti ng prel oad
status. Pati ents who have acute fai lure with normal or only sli ghtl y el evated end-di astoli c vol umes
may not respond to afterload reducti on wi th an increase i n CO. Bal anced vasodil ators such as
ni troprusside or venodi lators such as the ni trates may actuall y reduce CO i n these patients.
Patients with dil ated l eft ventricl es and elevated fi ll i ng pressures usual l y have impressi ve
improvement in CO with afterload reducti on. This underscores the i mportance of moni tored volume
l oadi ng before proceedi ng apace wi th vasoacti ve drugs (see Tabl e 12-13). It i s possibl e, and
indeed li kel y, that a portion of the reduced effecti veness of l ong-term vasodi l ator therapy results
from inadequate prel oad, whi ch in some ci rcumstances can actual ly be a consequence of
successful drug therapy. Cli nical studi es suggest that DBT i s l ess l i kel y to increase HR than
dopami ne for a gi ven dose, a major concern i n the patient with coronary artery disease. DBT i s a
coronary artery dil ator, whereas dopami ne i s not. A dopamine-induced tachycardi a, however, may
be of less concern i n the septi c pati ent who commonly has a maldi stri bution of volume, l ow
vascul ar resi stance, a preexi sti ng refractory tachycardi a, but a previ ousl y heal thy heart. The
empiri c preference of dopamine i n surgi cal units and DBT i n coronary units has been observed and
i s perhaps wel l founded. The surgi cal patient i s more li kel y to have di stri buti ve defects and fl ui d
shifts from major trauma and surgery. The hemodynami cs of the septic pati ent are characteri zed
by l ow vascular resistance, hypotension, hi gh CO, and some degree of myocardi al depressi on. The
mesenteri c di stri buti on, i notropi c, and pressor effects of dopamine woul d seem i deal for this
condi ti on. However, a shift of bl ood vol ume to the central ci rcul ati on, tachycardi a, or an
unpredictabl e i ncrease i n afterl oad may not be appropri ate for the pati ent in congesti ve heart
fai l ure or an acute i nfarct. DBT, wi th i ts dose-rel ated i notropi sm, afterl oad reduction, and rel ati ve
lack of chronotropism, woul d seem more appropri ate for these ci rcumstances.
Dobutami ne does not cause NE rel ease or stimulate DA receptors. Dopami ne does both, but the
effect i s dose rel ated.

Dopami ne offers possi bl e advantages over many sympathomi metics in managi ng the low-output
syndrome wi th ol i guria. Thi s effect is ablated at higher doses. DBT does not sel ecti vel y i ncrease
renal bl ood fl ow but does i mprove renal blood fl ow secondari ly wi th i mproved CO and weak -2
vasodi l ati on. Much of the reduced afterl oad observed wi th the use of DBT may be rel ated more to
a reduced sympathetic tone wi th i mproved fl ow than that of active vasodi latation. DBT bel ongs on
the opposite end of the spectrum from amri none. DBT i s a potent i notropi c agent but a weak
vasodil ator, whereas amri none i s a potent vasodi lator but weak inotrope.
Dopami ne and DBT al so have contrasti ng effects on the pul monary vascul ature. Dopami ne has
been noted to i ncrease pul monary artery pressure and does not i nhi bit the pul monary hypoxi c
response. It i s not recommended for pati ents in ri ght heart fail ure. DBT does vasodi l ate the
pul monary vascul ature and i s hel pful i n treati ng ri ght heart fai l ure and cor pul monal e.
17
The
adrenergi c effects of combi ned sympathomimeti cs, li ke the sol o drugs, al so appear to be addi ti ve
and competi ti ve for receptor sites. Many combi nati ons of adrenergi c drugs have been descri bed as
havi ng a synergi sti c effect. Synergism is the joi nt acti on of agents such that thei r combi ned effect
is greater than the algebrai c sum of their i ndi vi dual effects. Thi s synergi sm may be a cli nical
interpretati on of a summated receptor effect that appears synergistic. For example, infusi ons of
the combi nation of dopami ne and DBT have been noted to produce a greater i mprovement in CO,
at l ower doses, than can be achieved by ei ther drug al one. Each drug, al though equi potent
inotropi c agents, di lates di fferent vascul ar beds. Therefore, the summati on of afterl oad reduction
by both drugs coul d produce a greater i mprovement i n CO than could be achi eved by ei ther drug
al one, even at the same l evel of inotropi sm. Summation is more consi stent wi th current receptor
pharmacol ogy and can be used to advantage in avoi di ng unwanted si de effects of one drug whi l e
suppl ementi ng i ts desi red attri butes wi th another. The summation pri nci ple obvi ates the necessity
of knowi ng a l arge number of drugs. One need only become fami li ar with a few agents to manage
most cli nical si tuati ons.
P.314
Because of summation, many combi nations of vasoacti ve drugs have been found useful in making
fine hemodynami c adjustments in the cri ticall y il l . The avai lable sympathomimeti c agents provide
a wide range of hemodynami c effects, parti cul arly when combi ned wi th vasodil ators. For example,
if a larger posi ti ve i notropi c acti on and less vasoconstri cti on are desi red, DBT coul d be added to
dopami ne. Al so, ni troprussi de coul d be added to dopami ne or combi ned wi th any other appropri ate
inodi l ator.
101
Combi nati ons are al so useful in redistri buting the CO to vi tal organs. This i s why the
combi nati on of DBT and dopami ne has been hel pful . Dopami ne coul d distri bute the CO to the renal
and mesenteri c vascul ar bed, whereas DBT could provi de additi onal afterl oad reducti on by openi ng
up the vascul ar beds of ski n and muscl e (Fi g. 12-30).
102
NE has been successful ly used i n
combi nation with dopami ne to i ncrease vascul ar resistance i n septi c pati ents whi l e distri buti ng a
greater portion of the CO to the renal and mesenteri c bed.
103

The studied use of adrenergic combi nati ons i n patients with cardi ac fail ure has been proposed
because pathophysiology cannot be approached wi th the attitude that agoni sm i s al l good and a
agoni sm i s al l bad. The objecti ve i s to increase coronary perfusi on and CO whil e decreasi ng
afterl oad. Thi s is the effect achi eved by the intra-aorti c bal loon pump. No si ngle vasoacti ve agent
can achi eve thi s, but these conditi ons can be approached wi th combinati on therapy. Because of
receptor summation during combinati on therapy, standard rates of i nfusi on (as outl i ned i n Tabl e
12-14) no longer apply. Invasive hemodynamic moni tori ng is mandatory for success; otherwise,
iatrogeni c di sasters can be expected. Other conditi ons necessary for success with vasoactive drugs
al so requi re that the fai l ing myocardi um or vasculature must have functi onal reserve, the reserve
can be sti mul ated, and perfusi on can be mai ntai ned.
104, 105

Fenoldopam
Fenol dopam, a benzazepi ne derivati ve, i s a sel ecti ve DA1 agoni st wi th no or receptor activity
compared to dopami ne (see Tabl e 12-15).
98, 106
Oral bi oavai l abi l ity i s poor, but i t i s an effecti ve
anti hypertensive when gi ven iv. Intravenous fenoldopam has di rect natri ureti c and di ureti c
properties that promote natri uresi s, diuresi s, and an i ncrease i n creatinine clearance. It offers
advantages i n the acute resol uti on of severe hypertensi on compared to sodi um ni troprussi de,
parti cul arl y i f the patient has preexi sti ng renal impai rment.
107
Aronson et al reported a
comparative study usi ng SNP and fenol dopam i n dogs under general anesthesi a. A 30% reducti on
FIGURE 12-30. Combi ni ng l ow doses of dopami ne and dobutami ne may produce
improvements i n CO that are greater than can be achi eved with ei ther drug al one. This
appears to be cl i ni cal synergism. However, the vasodi l ati on of di fferent vascul ar beds l i kel y
produces a summed reduction of afterload at the same l evel of i notropi sm that onl y appears
to be synergi sti c. The second law of thermodynamics remai ns i ntact.
in mean arterial pressure was produced by ei ther fenol dopam or SNP. Fenoldopam mai ntai ned
renal bl ood fl ow whil e SNP showed a reducti on.
106, 108
Preservation or augmentation of renal bl ood
fl ow duri ng bl ood pressure reducti on presents a potential for use duri ng several situations i n the
peri operative peri od. Fenol dopam has an el imi nati on hal f-li fe of 5 mi nutes. Thi s property mi ght
well l end itsel f in produci ng hypotensi ve anesthesi a whi l e preservi ng renal function.
108

Human studies have demonstrated that fenol dopam i s a potent di rect renal vasodi l ator. Left
ventri cul ar function has been noted to i mprove with afterload reducti on. The study by Kien and
col l eagues suggests that the i mprovement in renal functi on i s a di rect vasodi l ator effect of the
drug.
108
Intravenous fenol dopam may prove to be ideal for treati ng condi ti ons i n whi ch renal
vasoconstri cti on i s an expected compl i cati on. Exampl es are cycl ospori ne-induced renal
vasoconstri cti on, radi ographi c dye toxi ci ty, and human ki dney reci pi ents.
109, 110, 111

The onset of acti on with intravenous fenol dopam i s about 5 minutes, reachi ng a steady state i n
about 20 mi nutes. The drug i s rapi dl y metabol i zed i n the l i ver and excreted in the uri ne. The
el i mi nation half-li fe i s about 5 mi nutes. There has been no evi dence of tol erance i n reduci ng bl ood
pressure for up to 24 hours. No rebound on wi thdrawal has been noted.
The most common adverse effects of fenoldopam are rel ated to vasodi lation, whi ch i ncl ude
hypotensi on, flushi ng, di zziness, headache, and increases i n heart rate, nausea, and hypokal emi a.
It shoul d be used cauti ousl y in pati ents wi th gl aucoma as i t can increase i ntraocul ar pressure. No
si gni fi cant drug interacti ons have been reported. Concomitant use wi th -bl ockers wi l l reduce the
effective dose of fenoldopam.
Fenol dopam is di l uted in normal sal ine or 5% dextrose and i s gi ven by continuous i nfusion wi thout
a bol us dose. The effecti ve dosage range i s 0.1 to 1.6 g/kg/mi n. A refl ex tachycardia may be
produced. The dosage i s titrated upward every 15 minutes according to patient response. Any
change in i nfusion rate should be detectabl e wi thi n 15 mi nutes.
Clonidine
Cloni di ne i s a centrall y acting sel ecti ve parti al -2 adrenergic agonist (220:1 -2 to -1). It i s an
anti hypertensi ve drug by i ts abi l ity to decrease central sympatheti c outfl ow. Sti mulati on of -2
receptors i n the vasomotor centers of the medul la obl ongata i s thought to produce thi s effect.
112

It i s not cl ear whether these are pre- or postsynapti c receptors. However, the end resul t i s
decreased SNS tone and enhanced vagal tone. Peri pherall y there i s decreased pl asma reni n
acti vi ty as wel l as decreased EPI and NE l evel s. Thi s drug has been proven to be effective in the
treatment of severe hypertension and renin-dependent hypertensive disease.
Cloni di ne i s not avai l abl e for i ntravenous use. The usual dai ly adult oral dose i s 0.2 to 0.3 mg. A
transdermal cl oni di ne patch is avai lable for use on a weekl y basi s for surgi cal pati ents unabl e to
take oral medi cation.
Cloni di ne i s cli nical l y useful i n anesthesiol ogy in other ways. It has been found to produce dose-
dependent analgesia when introduced into the epidural or subarachnoi d space i n doses of 150 to
450 gs.
113
The addi ti on of 75 to 150 g of cl oni di ne to subarachnoid tetracai ne or bupi vi cai ne can
prolong the durati on of sensory and motor bl ockade of the l ocal anestheti cs. Unl ike the opioi ds,
cl oni di ne does not depress respi rati on or cause pruri tis, nausea, vomiti ng, or delayed gastric
emptying.
114
Clonidine and morphi ne do not produce cross-tolerance. Hypotensi on, sedati on, and
xerostomi a may fol low the neuraxi al use of cloni di ne.
115, 116

Oral cl onidi ne (5 g/kg) when used as a premedi cant enhances the postoperati ve anal gesi a
provi ded by i ntrathecal morphine wi thout adding to the si de effects of the morphine.
117
Other
addi ti onal benefi ts noted from a cloni di ne premedi cati on i nclude (1) bl unted refl ex tachycardi a for
intubati on, (2) reducti on of vasomotor l iabi li ty, (3) decreased pl asma catechol amines, and (4)
dramati c decreases i n MAC for inhaled gases or i njected drugs.
Other uses of cloni di ne have been i n the diagnosis of pheochromocytoma, treatment of opi oi d
withdrawal, and shi veri ng.
118
Cl onidi ne, 0.3 mg oral l y, wil l decrease the plasma concentrati on of
P.315
catechol amines in normal patients but not in the presence of a pheochromocytoma. Thi s refl ects
the abi l ity of cl oni dine to suppress rel ease of catechol amines from nerve endi ngs but not from the
pheochromocytoma. Its useful ness in suppressi ng opi oi d wi thdrawal i s li kewi se attri buted to i ts
abi li ty to repl ace the opi oi d-mediated i nhi bi ti on with -2mediated i nhi bi ti on of CNS sympatheti c
outfl ow. It may li kewise be useful for ni coti ne wi thdrawal.
Cloni di ne i s rapi dl y absorbed by mouth and reaches peak pl asma l evel s wi thi n 60 to 90 mi nutes.
The el iminati on hal f-li fe i s between 9 to 12 hours. It i s equal ly excreted in the l i ver and ki dneys.
The durati on of the hypotensive effect after a si ngl e dose is about 8 hours. The transdermal
administrati on of cl oni di ne requires about 48 hours to achi eve therapeuti c level s. The decrease i n
systol i c bl ood pressure is more promi nent than the decrease i n diastolic bl ood pressure.
Homeostatic cardi ovascul ar refl exes are maintai ned, avoi ding probl ems of orthostati c hypotensi on.
There seem to be no effects on glomerul ar fi l trati on rate.
Side Effects. The most common si de effects of cl onidi ne are sedation and a dry mouth. However,
ski n rashes are frequent wi th chroni c use. Impotence may be seen occasi onall y and orthostati c
hypotensi on i s rare. One of the more worri some compl icati ons of chronic cl oni dine use i s a
withdrawal syndrome on acute di sconti nuati on of the drug. Thi s usual ly occurs about 18 hours
after disconti nuati on. The symptoms are hypertension, tachycardi a, insomni a, fl ushi ng, headache,
apprehensi on, sweati ng, and tremul ousness. It l asts for 24 to 72 hours and i s most l ikely to occur
in pati ents taki ng more than 1.2 mg/day of cloni di ne. The wi thdrawal syndrome has been noted
postoperativel y in pati ents who were withdrawn from clonidine before surgery. It can be confused
with anesthesi a emergence symptoms parti cul arly i n a pati ent wi th uncontrol l ed hypertensi on.
Absent the avai l abi l ity of the oral route i n the surgi cal pati ent, withdrawal can be treated wi th
cl oni dine transdermal ly or more rapi dl y wi th rectal cl oni dine.
Dexmedetomidine
Dexmedetomidi ne i s a more sel ecti ve -2 agoni st than cloni di ne.
119
Its potent -2-agoni sm i s
1620:1 -2 to -1. Compared to cl oni dine, dexmedetomi dine i s seven times more sel ecti ve for -2
receptors and has a shorter hal f-li fe of 1.5 hours. It has a more rapid onset of acti on (less than 5
mi nutes). The ti me to peak effect i s 15 mi nutes. It can be gi ven intravenousl y and has many uses
in anesthesi ol ogy. It provi des excel l ent sedation, reduces bl ood pressure and HR, and profoundl y
decreases plasma catechol ami nes. Li ttl e respi ratory depression is evi dent. Dexmedetomi di ne has
been shown to be an effecti ve anxi ol yti c and sedati ve when used as premedi cati on. Pretreatment
with dexmedetomidi ne, li ke, cl oni dine, attenuates hemodynamic responses to intubati on. Li kewi se,
it decreases the MAC for vol ati l e anestheti cs from 35 to 50% but i ncreases the li kel i hood of
hypotensi on. Dexmedetomidi ne, li ke cl oni dine, i ncreases the range of temperatures not tri ggeri ng
theromoregul ator defenses. It i s l ikel y to promote peri operati ve hypothermia but al so i s effecti ve
against shiveri ng.
120

The fol lowi ng properties of dexmedetomi dine seem parti cularly valuabl e to the anesthesi ol ogist.
121

1. Potent analgesia
2. Sedation and anxi ol ysi s
3. Antisi al ogogue
4. Promotes hemodynaimic stabi l ity
5. Homeostatic refl exes remai n intact
6. Attenuates opi oi d ri gidi ty (in ani mal s)
Dexmedetomidi ne i s provi ded i n 2-mL vi als (100 mcg/mL) and must be dil uted i n 48 mL of 0.9%
sodi um chl ori de to be used i n a controll ed i nfusion devi ce. A l oading i nfusion (1 mcg/kg) must be
gi ven over a 10-mi nute period i n a
P.316
moni tored setti ng. The l oadi ng dose shoul d not be bolused. A transi ent and paradoxi cal
hypertension may be seen during infusion of the loadi ng dose. The HR may be seen to decrease.
The i ncrease in BP is attributed to an i niti al sti mul ati on of -2 receptors i n vascul ar smooth
muscl e. The bl ood pressure usual l y decreases as the central bl ockade of central -2 agoni sm
overri des the peri pheral effect.
120, 121
The state of sedati on must be moni tored as epi sodes of
obstructive apnea have occurred wi th the l oadi ng i nfusi on rel ated to the degree of sedati on.
Nonadrenergic Sympathomimetic Agents
Tabl e 12-4 cl assi fi es the drugs that mimic the SNS into two broad categori es, adrenergic or
nonadrenergi c. Adrenergi c agoni sts exert their acti on through adrenergi c receptors by di rect
stimul ati on or i ndi rectly vi a rel ease of NE. Adrenergi c agoni sts may be catechol ami nes or
noncatechol ami nes by chemi cal confi gurati on. Nonadrenergi c sympathomi metic drugs al so act
indirectl y by infl uenci ng the cAMP-calci um cascade, excl usi ve of the receptors (see Fi g. 12-15).
The functi on of the second messenger (cAMP) and the thi rd messenger (Ca2+) nearl y al ways goes
together. Thi s concept rei nforces the recent appreci ati on of the homogenei ty of action of a wi de
vari ety of drugs previously thought to be unrel ated. Sympathomimeti cs have more pharmacologi c
similarities than differences.
Vasopressin. Vasopressi n and i ts congener (desmopressin) are exogenous preparations of the
endogenous anti di ureti c hormone (ADH). ADH and oxytocin are the two pri ncipal hormones
secreted by the posteri or pituitary. Target si tes for ADH are the renal -coll ecti ng ducts and
vascul ar smooth muscle and cardi ac myocytes. Water absorpti on i s passively reabsorbed from
renal -coll ecti ng ducts i nto extracel l ul ar fluid. Nonrenal acti ons i ncl ude inotropi sm and intense
vasoconstri cti on, accounti ng for i ts al ternative desi gnation as vasopressi n.
122

Argi ni ne vasopressi n (AVP) i s the most active form of ADH. Hi stori cal ly, vasopressi n has been
used for (1) treatment of diabetes i nsi pi dus, (2) di agnosi s of di abetes i nsi pi dus, (3) abdominal
di stenti on, (4) and as an adjunct i n the treatment of GI hemorrhage and esophageal vari ces.
Recentl y, three new i ndi cati ons for the use of vasopressin have emerged. These are (1) pressure
support for septi c shock, (2) cardi ac arrest secondary to ventricular fi bri l lation, and (3) pulsel ess
ventri cul ar tachycardia and heart fail ure.
123
Thi s discussion is l i mi ted to cardiac arrest.

Three AVP receptor subtypes are known. These are V1a, V1b, and V2 receptor subtypes. V1
receptors are found on vascul ar smooth muscl e and cardi ac muscl e. The V2 receptors regul ate
renal functi on. Endogenous ADH is released from the posteri or pi tui tary i n response to changes i n
pl asma osmol al i ty or wi th baroreceptor response to changes in bl ood vol ume or pressure. Release
is sti mulated wi th a 5 to 10% decrease in bl ood vol ume, central bl ood vol ume, cardiac output, or
bl ood pressure sensed by the caroti d and aorti c baroreceptors. Stretch receptors i n the l eft atri um
and pul monary vei ns may al so activate ADH rel ease. It is al so released when the osmoreceptors i n
the hypothalamus sense changes of as l i ttl e as 1% i n osmol al i ty and medi ated by the V2
receptors.
Epi nephri ne i s universal l y the first-li ne drug appl i ed to pulsel ess cardiac rhythms such as
ventri cul ar fi bril l ati on (VF), ventri cul ar tachycardi a, electromechani cal di ssoci ati on, and asystol e.
Despi te good ani mal studi es, there is l i ttl e evi dence from human data that epi nephri ne i mproves
outcome from cardiac arrest. Control led comparative studi es i n humans between hi gh-dose EPI
and standard-dose EPI showed no i ncrease i n survi val or i mproved neurol ogi c outcome i n survivors
recei vi ng hi gh-dose EPI. The search for a more effective vasopressor l ed to the current advocacy
of vasopressi n as a replacement for EPI in shock-refractory pulsel ess rhythms. Survi vors of
cardi ac arrest, compared to nonsurvi vors, had demonstrated higher l evel s of vasopressin both
before and after recei vi ng EPI.
124

Ani mal studi es have shown, both i n open- and cl osed-chest model s, vasopressin caused a l arger
increase i n SVR, cerebral perfusion pressure, and coronary perfusi on pressure than EPI.
Vasopressi n is a more effecti ve vasoconstri ctor than EPI i n the presence of hypoxi a and aci dosi s.
In contrast to EPI, vasopressi n does not seem to i ncrease MV02 or l actate producti on.
122
In the
2000 guidel i nes for advanced cardi ac l i fe support (ACLS) of the Ameri can Heart Associ ati on,
vasopressi n was updated to a cl ass IIb recommendati on (acceptable, possi bl y helpful , not harmful
and supported by fai r evidence) for treatment of cardiac arrest secondary to ventricul ar fibri ll ati on
and ventricul ar tachycardi a. EPI was reassi gned from a previ ous class IIb recommendati on to
cl ass i ndeterminate. At the ti me of this change, there was insuffi cient evidence to recommend
vasopressi n for the treatment of asystol e or el ectromechanical dissoci ati on (cl ass i ndetermi nate).
However a recent study i n out-of-hospi tal human cardi ac arrests has demonstrated that
vasopressi n is superi or to EPI in pati ents wi th asystole.
125
Vasopressi n fol l owed by EPI may be
more effective than EPI al one i n the treatment of refractory cardi ac arrest. As yet, randomi zed
trial s have fai led to demonstrate the superi ori ty of vasopressin over EPI i n survival of i n-hospi tal
cardi ac arrest.
126
These data may be skewed by the co-morbi d factors requi ri ng hospi tal i zati on.
Larger tri als wil l be necessary as to whether survi val to di scharge wi l l be improved by
vasopressi n.
Vasopressi n used for cardi ac arrest is known as vasopressi n injecti on USP and is avai labl e in
vial s of 20 IU/mL. The dose i n cardi ac arrest is 40 IU in 40 mL intravenousl y as a si ngl e dose in a
peri pheral i v l i ne. Extravasati on may cause l ocal ti ssue necrosis. Its use i n vasodi l ated sepsi s i s
by i nfusion pump starting at 0.04 IU/min.
Adenosine. Adenosi ne, avai l abl e for more than 50 years, has been recognized recentl y as a
cl i ni cal ly useful drug. It is a byproduct of ATP and i s found in every cel l in the body. It i s
composed of adenine and a pentose sugar. Production can be i ncreased by sti mul i such as hypoxi a
and ischemia. This ubiquitous nucleosi de has potent el ectrophysi ol ogi c effects i n addi tion to
havi ng a major role in regul ation of vasomotor tone. Adenosi ne is bel ieved to have a
cardi oprotecti ve effect by regulating oxygen suppl y and demand. The cardi ovascul ar effects of
adenosine depend on whi ch of two receptor si tes i s activated, -1 or -2. The -1 receptors i n the
myocardial conducti on system are the most sensi ti ve and medi ate SA node sl owi ng and AV nodal
conducti on delay. The -1 receptor i nhi bi ts producti on of cAMP whose formati on i s sti mulated by
-adrenergi c acti vi ty (see Tabl e 12-7). The -2 smooth muscl e receptors requi re hi gher
concentrations of adenosi ne, which medi ate systemic and coronary vasodi latation. The -2
receptor di rectl y i ncreases the rate of formati on of cAMP (see Tabl e 12-7) and functi ons
i ndependentl y of acti vi ty. Intravenous adenosi ne, therefore, has si gni fi cant negati ve
chronotropi c effects on the SA node as well as negati ve dromotropi sm on the AV node. Thus,
adenosine regulates atrial and ventri cular rates i ndependently of each other.
Adenosi ne hyperpol ari zes atrial myocytes and decreases their acti on potenti al durati on via an
increase i n outward K+ current. These are the acetyl chol i ne-regul ated K+ channel s. Adenosi ne
mi mi cs the effects of acetyl chol i ne i n many ways, including an extremel y short pl asma half-li fe of
mere seconds. Adenosi ne al so antagonizes the inward Ca2+ current produced by catechol ami nes.
Thi s anti dysrhythmic mechanism of Ca2+ channel blockade i s thought to be an indirect effect and
important onl y when stimul ati on i s present. This trai t suggests

a possi bl e rol e in counteri ng catechol ami ne-induced dysrhythmia. Thus, adenosi ne exhi bi ts some
of the traits of a Cl ass IV antidysrhythmi c. However, the pri mary anti dysrhythmi c effect of
adenosine i s to i nterrupt reentrant AV nodal tachycardi a, which most l i kel y rel ates to i ts K+
current, rather than Ca2+ current effects.
The chi ef i ndi cati on for adenosine i s paroxysmal supraventricul ar tachycardi a (PSVT), whi ch i t may
termi nate i n a matter of seconds. PSVT refers to a broad category of narrow compl ex tachycardi as
with acute onset and cessati on. The most common forms are AV nodal reentry tachycardi a and AV
reci procati ng tachycardi a. PSVT accounts for about one-third of all cases of peri operati ve
dysrhythmi a. Cl i ni cal studies support the use of adenosi ne for the treatment of Wol ff-Parki nson-
White (W-P-W) syndrome and other reentrant tachycardi as i nvol vi ng the AV node.
127
The same
characteri sti cs that make adenosine an effective therapeuti c agent may also make it an ideal
agent for di agnosi ng other types of dysrhythmi a. The i nci dence of incorrect diagnosis of
supraventricul ar dysrhythmi a has been reported to be as hi gh as 15% usi ng conventi onal
means.
128
Thi s can lead to util i zati on of harmful medicati ons. For exampl e, a broad compl ex
tachycardi a can ei ther be a VT or an SVT wi th aberrant conducti on. Verapami l can be fatal i f the
dysrhythmi a is VT because the drug is l ong l asting.
129
However, the fl eeti ng action (9 to 10
seconds) of adenosi ne assures that no harm wi l l be done i f the broad compl ex i s of ventricul ar
P.317
origi n provi ding a combined therapeuti c and diagnosti c test. Adenosi ne wi ll stop SVT in 90% of
cases i n whi ch the AV node forms one of the li mbs of the reentrant ci rcuit such as AV
reci procati ng tachycardi a and AV nodal reentry; 60% wi ll convert wi th the first dose. However,
adenosine has no effect on ectopic atri al dysrhythmi a such as ectopi c foci, mul tifocal SVT, or
fl utter/fi bri l l ati on. Approxi mately 10% of SVT do not i nvol ve AV nodal reentry. Adenosi ne wi ll
neverthel ess sl ow AV nodal conducti on i n these cases, decrease the ventricular rate, and all ow
inspecti on of P waves. Thus, adenosi ne may be useful i n unmasking atri al fibrillation when fast
ventri cul ar responses are noted.
A number of side effects have been reported wi th the use of adenosi ne, i ncl udi ng fl ushi ng,
headache, dyspnea, bronchospasm, and chest pai n. The majority of these are bri ef (seconds) and
not cl ini cal ly si gnificant. Transi ent new dysrhythmi a (65%) wil l be noted at the ti me of
cardi oversi on, but these di sappear during the hal f-li fe of the drug. Major hemodynami c changes
are rare but consi st of hypotensi on and bradycardi a. Adenosi ne shoul d be gi ven by means of a
rapid iv bol us with fl ush because of i ts extremely short hal f-li fe of less than 10 seconds. The
initi al adul t dose i s 6 mg (100 to 150 mg/kg pediatri cs), whi ch can be fol lowed by 12 mg withi n 1
to 2 minutes if the i ni ti al dose i s wi thout effect.
128
The 12-mg dose may be repeated once. The
anti dysrhythmic effects of adenosi ne occurs as soon as the drug reaches the AV node.
Phosphodiesterase Inhibitors. Phosphodi esterase i nhi bi tors have pharmacol ogi c properti es
approachi ng the characteri sti cs of the i deal i notropi c agent (see Tabl e 12-17).
130, 131
They do not
rel y on stimul ati on of and/or receptors. They are the product of a search for a nonglycosidi c,
noncatechol ami ne i notropi c agent. These drugs combi ne positi ve i notropism wi th vasodi lator
acti vi ty. They selectivel y inhi bi t PDE III.
132, 133
PDE I and II hydrol yze al l cycl i c nucl eoti des,
whereas PDE III acts speci fi cal ly on cAMP. The PDE III i nhi bi tors apparentl y interact wi th PDE III
at the cell membrane and i mpede the breakdown of cAMP.
132, 134
cAMP level s i ncrease and protein
kinase are activated to promote phosphoryl ati on of the SR i n a cascade manner si mi l ar to the
effects of adrenergi c drugs. In cardiac muscl e, phosphorylati on i ncreases the slow i nward
movement of calci um current, promoti ng i ncreased i ntracell ul ar cal ci um stores. Thus, i notropism
increases. In vascul ar smooth muscl e, increased cAMP activity accounts for the vasodi l ati on,
decreased peri pheral vascul ar resi stance, and l usi tropi sm. Amri none, l ike ni troprussi de and
ni trogl yceri n, promotes di astol i c rel axati on, which promotes ventri cul ar fi l li ng.
135

A vari ety of i ntravenous PDE i nhi bitors are undergoi ng cl ini cal tri al s. The rel ati ve contribution of
i notropi sm and vasodi l ati on di ffers with each. Amri none and mil rinone are the onl y PDE i nhi bitors
rel eased for cl i ni cal use i n the Uni ted States. Amrinone i s the prototypi cal PDE III i nhi bi tor. The
degree of hemodynami c effect of these drugs depends on the dose, degree of inotropi c reserve,
and state of cAMP depl eti on.
Amrinone. Amrinone produces mi l d inotropi c activity and strong vasodi latory effects. The
characteri sti cs of amri none, compared wi th those of the ideal inotropi c agent (see Tabl e 12-12),
rank it near the i deal drug. It i s the fi rst oral inotrope avai lable si nce the i ntroducti on of di gitali s.
However, it i s not currentl y prescri bed i n its oral form. Studies of si ngl e-dose and short-term oral
and iv amrinone show dose-rel ated i mprovements at rest i n the cardiac index and the l eft
ventri cul ar stroke i ndex (40 to 80% increase); left ventri cul ar end-di astoli c pressure (40%
decrease); pulmonary capil l ary wedge pressure (16 to 44% decrease); pul monary artery pressure
(17 to 33% decrease); right atrial pressure (16 to 44% decrease); l eft ventri cular ejecti on
fracti on (50% increase); and systemic vascul ar resi stance (23 to 50% decrease). Si gni fi cantl y, HR
and mean arterial pressure are not affected.
Peak response with an i v dose occurs after 5 minutes and reveals no evi dence of tol erance over
short-term tri als (24 hours); i t is compati bl e wi th other adrenergi c agoni sts. It is an effecti ve
inotropi c agent i n pati ents receiving -bl ockers. Its efficacy i n the patient who has been
di gi tal i zed has been demonstrated.
Intravenous amrinone therapy should be initi ated wi th a 0.75-mg/kg bol us gi ven over 2 to 3
mi nutes. It is continued wi th a mai ntenance i nfusi on of 5 to 10 mg/kg/min, adjusted by
hemodynamic monitori ng. An addi ti onal bol us dose of 0.75 mg/kg may be gi ven 30 mi nutes after
initiation of therapy. Care must be taken not to gi ve the bol us too qui ckl y because sudden
decreases in peri pheral vascul ar resistance may occur and resul t in severe hypotensi on.
Hypotensi on i s not a major cli nical problem wi th appropri ate monitori ng of ventri cul ar fil l ing
pressures. The infusi on shoul d not exceed a total dai l y dose of 10 mg/kg, i ncl udi ng the bol us
doses. Amrinone has the same range of infusi on rates as dopami ne and DBT, and dose calcul ati on
fol l ows the rul e of si x descri bed i n Tabl e 12-14.
Amrinone has two uncommon si de effects. Dose-rel ated thrombocytopeni a occurs in some pati ents
taki ng l ong-term oral medi cation. Thi s usual ly responds to dose reducti on. Acute i v amrinone has
not produced thrombocytopeni a.
136
Centril obul ar hepatic necrosis occurs i n dogs gi ven hi gh doses
of amri none for peri ods exceedi ng 3 months. There i s no evi dence of such an effect i n humans.
Milrinone. Mil rinone i s a derivati ve of amri none. It has nearly 20 times the inotropi c potency of
the parent compound. Mil rinone i s acti ve both i ntravenously and oral ly and has benefici al short-
term hemodynami c effects i n pati ents wi th severe refractory congesti ve heart fail ure.
137

Improvement of CO appears to resul t from a combi nation of enhanced myocardi al contracti l i ty and
peri pheral vasodi l ati on. Treatment wi th oral mi l ri none for up to 11 months has been effecti ve and
well tol erated wi thout evi dence of fever, thrombocytopenia, or gastrointestinal effects.
138

Mi l ri none recently has been approved for short-term i v therapy of congesti ve heart fai l ure.
139
It i s
administered wi th a l oadi ng dose of 50 mg/kg over 10 mi nutes. The mai ntenance i v i nfusion rate
ranges from a minimum of 0.375 mg/kg/min to a maximum of 0.75 mg/kg/min (not to

exceed 1.13 mg/kg/day). Dosage must be adjusted i n renal fai lure patients as mi l ri none is
excreted in the uri ne pri maril y i n unconjugated form.
Enoximone. Enoxi mone is a PDE III inhi bi tor that has proven benefici al in patients suffering from
severely impai red myocardi al function.
140
Enoxi mone is structural ly unrel ated to digi tal i s,
catechol amines, or amrinone. It has not been i mpl i cated in pl atel et compromise. Its hemodynami c
effects are si mi lar to those produced by amrinone. It appears to be a more potent i notropi c agent
than amri none, whose inotropi c effect has been questi oned. It produces pulmonary and systemi c
arteriol ar vasodi l ation and can thus be cl assi fi ed as an inodi l ator. Any i ncrease i n myocardi al
oxygen consumpti on (MVO
2
) by the i ncrease in i notropism is countered by a decrease i n afterload
and reduced ventri cul ar si ze. The drug has been admi ni stered by both the bol us techni que and
infusi on. It has been used primaril y in pati ents wi th cardi ogenic shock and for weani ng from
cardi opul monary bypass. Its use was insti tuted in pati ents who were proven refractory to
catechol amine therapy. A defi ni tive dosi ng therapy has not been establi shed but several studi es
have given a 1- to 2-mg/kg bolus followed by an infusion of 3 to 10 g/kg/mi n. In al l cases CI and
SV increased with a decrease i n ventri cul ar fi l li ng pressure, and PVR. No increase in heart rate
was noted. The bol us techni que al one has been hel pful i n weaning pati ents from cardi opul monary
bypass wi thout affecti ng heart rate or produci ng arrhythmias.
Glucagon. Glucagon i s a si ngle-chai n pol ypeptide of 29 amino aci ds that i s secreted by pancreas a
cel ls i n response to hypogl ycemi a. The li ver and kidney are responsi bl e for i ts degradation. Known
effects of this hormone in humans incl ude the foll owi ng:
82, 141
(1) i nhibi tion of gastri c moti l i ty, (2)
enhanced uri nary excreti on of i norgani c electrolytes, (3) increased i nsul i n secretion, (4) hepatic
gl ycogenol ysi s and gl uconeogenesi s, (5) anorexi a, (6) i notropi c and chronotropic cardi ac effects,
and (7) relaxati on of smooth muscl e (bil i ary, i.e., sphincters).
Littl e attenti on was gi ven to gl ucagon unti l 1968, when i t was demonstrated to produce posi tive
inotropi c and chronotropic effects i n the cani ne heart. Gl ucagon enhances the acti vati on of adenyl
cycl ase i n a manner si mil ar to that of NE, EPI, and isoproterenol . These cardi ac actions of
gl ucagon are not bl ocked by -bl ockade or catechol ami ne depletion. Glucagon, i n contrast to the
xanthi nes, rarely causes dysrhythmia, even in the face of i schemic heart disease, hypokalemia,
and di gi tal i s toxi ci ty. Glucagon may possess anti dysrhythmi c acti vi ty in di gitali s toxi ci ty because i t
has been shown to enhance AV nodal conducti on i n patients wi th varyi ng degrees of AV bl ock.
Thus, i t shoul d be used careful l y in pati ents wi th atri al fi bri l lation. An i v dose of 1 to 5 mg of
gl ucagon i ncreases cardi ac index, mean arteri al pressure, and ventri cul ar contracti li ty, even i n the
presence of di gi tal i s therapy. After a bol us dose, i ts acti on di ssi pates i n approxi matel y 30
mi nutes. A continuous i nfusion of 5 g/kg/mi n i s augmented by an i ni ti al bol us of 50 g/kg. Onset
P.318
of acti on occurs i n 1 to 3 mi nutes and peaks at 10 to 15 mi nutes.
Nausea and vomi ting are common si de effects in the awake pati ent, especi al l y fol lowi ng a bol us
dose. Hypokal emi a, hypogl ycemia, and hypergl ycemi a are also seen. Gl ucagon is also useful in
treating i nsul i n-induced hypogl ycemi a. Despi te the obvi ous benefi ts of gl ucagon i n cardi ac
patients, i ts use has not become popul ar. Thi s may be rel ated to i ts hi gh cost and the mul tipl e
metabol i c and physi ol ogic effects that are common after i ts admini stration. Thi s pancreati c
hormone may be of hemodynamic benefit when more conventi onal approaches have proved
refractory i n the foll owi ng setti ngs: (1) l ow CO syndrome fol l owi ng cardi opulmonary bypass, (2)
low CO syndrome with myocardi al infarction, (3) chronic congesti ve heart fail ure, and (4)
excessive -adrenergi c bl ockade.
Digitalis Glycosides. The most i mportant actions of the digi tal i s gl ycosi des are those affecti ng
myocardial contractil i ty, conducti on, and rhythm. The gl ycosi de most li kel y to be used by the
anesthesi ol ogi st i s di goxin. The pri nci pal uses of di goxin are for the treatment of congestive heart
fai l ure and to control supraventri cul ar cardiac dysrhythmi a such as atri al fi bril l ati on. Di goxin i s
one of the few posi ti ve inotropes that does not i ncrease HR. Di goxin enhances myocardi al
inotropi sm and automatici ty but sl ows i mpul se propagati on through the conducti on tissues.
142

Despi te nearl y two centuries of use, its mechani sm of acti on i s onl y modestl y certai n. Di gi tal is
reciprocall y faci li tates cal ci um entry i nto the myocardi al cel l by bl ocki ng the Na+, K+ adenosi ne
triphosphatase pump. This calci um infl ux may account for i ts posi ti ve i notropic action because thi s
inotropi c response i s not catechol ami ne- or -receptor-dependent and i s therefore effecti ve i n
patients taki ng -bl ocking drugs. The inhi bi ti on of thi s enzyme transport mechani sm also resul ts
in a net K+ l oss from the myocardi al cel l. Thi s contributes to digi tal i s toxi ci ty with hypokalemia.
Cal cium potentiates the toxi c effects of di gi tal is. Extreme cauti on shoul d be observed when
calci um i s given to a pati ent taki ng di gi tal i s or when di gi tal i s admi nistrati on i s contempl ated i n the
patient wi th hypercal cemi a.
Synchrony of the cardiac beat i s an i mportant determi nant of CO, and di goxi n can be benefi ci al
when heart fai l ure i s caused by a tachydysrhythmi a, even in i schemic myocardi al disease.
However, the use of - or cal cium channel blockers i s i ncreasi ng i n thi s regard because they both
reduce overal l myocardial oxygen consumption.
Di gi tal i s has been of no benefit i n cardiogeni c shock and has proved potenti all y injuri ous in
patients with uncompl i cated myocardial infarction because of i ts vasoconstri cti ve properti es and
effects on myocardi al oxygen consumpti on i n the absence of cardi omegal y.
Care must be taken to rule out conditions in which the use of digi tal i s is of no benefi t and i s
potential ly harmful. These include mi tral stenosis with normal sinus rhythm and constri cti ve
peri cardi tis with tamponade. Si gns and symptoms of i di opathi c hypertrophi c subaortic stenosi s are
often exacerbated by di gi tal is. Wi th i ncreased strength of contracti on, the muscul ar obstructi on
can be markedl y increased. The same is true for the use of di gi tal i s i n pati ents wi th i nfundibular
pul moni c stenosis, as occurs wi th tetral ogy of Fal lot. Any augmentation of contractil i ty may
further reduce an al ready dimi ni shed pul monary bl ood fl ow. Beware of di gi tali s toxic reactions i n
the ol der age group and i n pati ents suffering from arterial hypoxemi a, aci dosi s, renal compromi se,
hypothyroi di sm, hypokal emi a, or hypomagnesemi a as wel l as i n pati ents receiving qui ni di ne or
calci um channel bl ockers.
The i ssue of prophylacti c digi tal i zati on of patients wi th dimi ni shed cardiac reserve who are about
to undergo major surgi cal procedures remai ns controversi al .
142
Indications for preoperati ve
di gi tal is i n which the prophylacti c admi ni stration of digoxi n shoul d be consi dered incl ude the
fol l owing: (1) previous heart fail ure, (2) increased heart si ze, (3) coronary fl ow disturbances
according to electrocardi ogram, (4) age over 60 years, (5) age over 50 years before l ung surgery,
(6) antici pated massi ve bl ood loss, (7) atrial fl utter or fi bri ll ati on, (8) cardi ovascul ar surgery, and
(9) rheumati c val vul ar l esi ons.
When entertai ni ng the possibi l ity of peri operati ve di gi tal i s admi ni strati on, the fol l owi ng poi nts
must be consi dered. (1) Myocardial oxygen bal ance i s threatened in the nonfail i ng, nondi lated
heart. (2) The therapeutic-to-toxi c rati o of di gitali s i s narrow. (3) Inotropic drugs that are less
toxi c and reversibl e are readil y avai labl e. (4) Verapami l or -blockers are more efficacious for
supraventricul ar tachydysrhythmi as not i ni tiated by heart fail ure. (5) Digi tal i s may cause seri ous
dysrhythmi a in the unstabl e pati ent. (6) Serum potassi um concentrati ons may fluctuate i n the
surgi cal pati ent. (7) Any cardiac dysrhythmia

that occurs i n the presence of di gi tal i s must be considered a toxi c phenomenon. (8) Digi tal i s-
induced cardiac dysrhythmi as are di ffi cul t to treat. (9) Renal compromi se wil l result i n toxi c
effects wi th standard mai ntenance doses. (10) Cardi oversion may be dangerous after di gi tal i s
administrati on. (11) After i niti ation of digi tal i s therapy, the admini stration of al ternative drugs
becomes more compl i cated.
Calcium Salts. Calci um is of great importance i n the genesi s of the cardiac action potenti al and i s
the key to control l ing i ntracel l ul ar energy storage and uti li zation. Movement of extracel l ul ar
calci um across membranes also governs the functi on of uterine smooth muscle as wel l as the
smooth muscl e of the bl ood vessel s. The sympathomimeti c drugs promote the transmembrane
infl ux of cal ci um, whereas the -bl ockers and calci um channel bl ockers inhi bi t such movement.
The Ameri can Heart Associ ati on has recommended agai nst the use of cal ci um duri ng cardi ac arrest
except when hyperkal emi a, hypocalcemi a, or cal ci um-entry inhi bitor toxi ci ty i s present.
143

Traditi onal l y, calci um gluconate has been preferred i n pedi atri c pati ents and cal cium chl ori de i n
adul t pati ents. Previ ous data hel d that calci um chl oride produced consi stentl y higher and more
predi ctabl e l evel s of ioni zed cal ci um.
144
Studi es have shown, however, that ioni zation of any of the
preparati ons i s immedi ate and equal l y effective.
145
Intravenous cal ci um appears effective for the
transi ent reversal of hypotension thought to be the resul t of myocardi al depressi on from the
potent volatil e anestheti c drugs.
146
Some cli ni cians feel that recurrent intraoperati ve hypotensi on
response to cal ci um chl ori de may be an i ndi cation for the admi ni strati on of digoxin. Calcium
chl ori de i s al so gi ven at the termi nation of cardiopul monary bypass to offset the myocardi al
depressi on associ ated with hypothermi c potassium cardi oplegi a and citrate. The use of cal cium
sal ts i s cl earl y i ndi cated duri ng rapid or massi ve transfusions of ci trated bl ood.
147
Ci trate bi nds
calci um, and rapi d i nfusi on rates of citrated blood resul t i n myocardi al depressi on that i s
reversi bl e by cal ci um.
Three forms of calci um sal ts are avai labl e: calci um chl ori de, cal ci um gl uconate, and cal ci um
gl uceptate. Cal ci um chl ori de produces onl y transient (10 to 20 mi nutes) increases i n CO.
142
If
inotropi c effects are needed for a l onger peri od of ti me, other i notropi c agents should be sel ected.
Bol us doses of 2 to 10 mg/kg (1.5 mg/kg/mi n) of cal ci um chl ori de can produce moderate
improvement in contractil i ty. The rapid admi nistrati on of calci um sal ts, if the heart i s beati ng, can
produce bradycardi a and must be used cauti ousl y in the pati ent who i s di gi tal i zed because of the
hazard of produci ng toxi c effects. Cal ci um gl uceptate can be gi ven i n a dose of 5 to 7 mL (4.5 to
6.3 mEq) and cal ci um gl uconate i n a dose of 10 to 15 mL (4.8 to 7.2 mEq). These doses are
approxi mately equi val ent to that suggested for cal ci um chl ori de. Cal ci um gluconate i s unstabl e
and is no longer i n frequent use. Al l of the cal cium sal ts wi ll preci pi tate as calci um carbonate i f
mi xed wi th sodi um bi carbonate.
Antidepressant Drugs
Monoamine Oxidase Inhibitors. Monoami ne oxidase inhi bi tors (MAOIs) and the tri cycli c
anti depressants are used to treat psychoti c depressi on. These drugs are not used in the practice
of anesthesi a but are a source of potenti al l y serious anestheti cs interactions i n pati ents who are
taki ng them chronicall y. Thei r use is rapi dl y decl ining as the nontricycl ic anti depressants such as
Prozac are more efficaci ous and produce fewer si de effects. Tabl e 12-19 li sts the anti depressants
that have been i n use and i s offered onl y to be historicall y compl ete. Few of the MAO inhi bi tors or
tricycl ic anti depressants wi l l be encountered i n an anesthesi a practi ce today wi th the excepti ons of
phenel zi ne (Nardi l) and amitri ptyl ine (Ami tril , Elavi l ). Thei r pharmacol ogic acti ons and side effects
are a direct resul t of thei r effect on the cascade of catachol ami ne metabol i sm. The nontri cycli cs
al so produce their antidepressant effects via thi s cascade but li nked to thei r i nhi bi ti on of CNS
neuronal uptake of serotoni n.
P.319
TABLE 12-19 Antidepressant Drugs
NONPROPRIETARY NAME TRADE NAME
Monamine Oxidase Inhibitors
Isocarboxazi d Marplan
Pargyl ine Eutonyl
Phenel zi ne Nardi l
Tranyl cypromine Parnate
Tricyclic Antidepressants
Imiprami ne Imavate, Janimi ne, Presami ne, SK-Prami ne, Tofrani l
Desi prami ne Norprami n, Pertofrane
Ami tri ptyl i ne Ami tri l, El avil , Endep
Nortriptyl ine Aventyl , Pamel or
Doxepi n Adapi n, Si nequan
Protriptyl i ne Vi vacti l
Amoxapi ne Asendin
Maprotil i ne Ludiomil
Nontricyclics
Trazodone Desyrel
Fl uoxetine Prozac
Bupropri on Wel l butri n
MAOIs (see Tabl e 12-19) bl ock the oxi dati ve deaminati on of endogenous catecholami nes i nto
inactive vani ll yl mandel i c aci d (see Fi g. 12-12). They do not i nhibi t synthesi s. Thus, bl ockade of
monoamine oxidase woul d produce an accumul ati on of NE, EPI, dopami ne, and 5-
hydroxytryptami ne i n adrenergicall y acti ve ti ssues, i ncl udi ng the brai n. All evi ati on of depression
may be related to el evati ons of the endogenous catechol ami nes. Overdose wi th MAOIs i s
expressed as SNS hyperacti vi ty. They may produce agi tation, hall uci nations, hyperpyrexi a,
convul si ons, hypertension, and hypotensi on. Orthostati c hypotensi on i s a common compl aint in
patients taki ng MAOIs.
148

The acti on of sympathomi metic ami nes i s potenti ated i n patients taki ng MAOIs. Indi rect-acti ng
sympathomimeti cs (ephedrine, tyramine) produce an exaggerated response as they tri gger the
rel ease of accumul ated catecholamines. Foods contai ning a hi gh tyrami ne content such as cheese,
red Ital i an wi ne, and pi ckl ed herri ng can also preci pitate hypertensi ve cri ses.
148
SNS reflex
stimul ati on i s al so intensi fi ed by tyrami ne. Meperi di ne has al so been reported to produce
hypertensi ve crisi s, convul sions, and coma wi th MAO i nhi bi tors. Hepatotoxi ci ty has been reported
that does not seem to be rel ated to dosage or durati on of treatment. Its i nci dence i s low but
remai ns a factor i n sel ecti ng anesthesi a.
The anestheti c management of patients taki ng MAOIs remai ns controversial , although the need to
di sconti nue them preoperati vel y i s i n question. Currentl y, recommendations for management
incl ude disconti nuati on of the drugs for at l east 2 weeks before surgery; however, thi s
recommendation is not based on controll ed studi es but rather is the resul t of li mited case reports
that suggest potent drug i nteracti ons.
149
Few adverse effects i n humans taking MAOIs gi ven
anal gesi cs, opi oid anesthesia, or regi onal bl ocks have been reported.

However, opi oi ds that cause rel ease of catechol ami nes (meperi di ne) shoul d be avoi ded i n these
patients. Symptoms of SNS overdose or interacti ons because of MAOIs can be treated effecti vel y
wi th - and -bl ockers or di rect-acti ng vasodi lators.
Tricyclic Antidepressants. Thi s group of anti depressant drugs i s referred to as tri cycl i c
anti depressants because of their structure. The important tri cycl ic antidepressants are l isted i n
Tabl e 12-19. These drugs have al most replaced the MAOIs because of fewer side effects. Al l of
these agents block uptake of NE into adrenergic nerve endi ngs. Just as wi th the MAOIs, hi gh doses
of the tri cycl i c anti depressants can i nduce sei zure acti vi ty that is responsi ve to diazepam.
Neurolepti c drugs may potenti ate the effects of tri cycl i c anti depressants by competi ti on with
metaboli sm i n the l iver. Chronic barbi turate use i ncreases metabol i sm of the tricycl ic
anti depressants by mi crosomal enzyme induction. Other sedatives, however, potenti ate the
tricycl ic anti depressants i n a manner si mi lar to that occurri ng wi th the MAOIs. Atropi ne al so has
an exaggerated effect because of the antichol inergic effect of tri cycl i c anti depressants. Prol onged
sedati on from thi opental has been reported. Ketami ne may al so be dangerous i n pati ents taki ng
tri cycl i c anti depressants by produci ng acute hypertensi on and cardi ac dysrhythmi a.
Despi te these seri ous i nteracti ons, di scontinuati on of these drugs before surgery is probabl y not
necessary. The l atency of onset of these drugs is from 2 to 5 weeks; however, the excretion of
tri cycl i c anti depressants i s rapi d, wi th approxi matel y 70% of a dose appeari ng i n the uri ne during
the fi rst 72 hours. One mi ght consider a di scontinuati on of the drug for 72 hours, but the ri sk of
recurrent depressi on may be greater than that of any untoward drug reacti on. The long latency
peri od for resumption of treatment mi li tates agai nst interrupted treatment. A thorough knowl edge
of the possi bl e drug i nteracti ons and autonomic countermeasures now avai labl e obviates
postponement.
Nontricyclic Antidepressants. The nontri cycli c antidepressants are l isted in Tabl e 12-19. Thei r
mechani sm of acti on i s not ful l y known but al l have i n common selective inhi bi ti on of neuronal
uptake of serotoni n. Thi s potentates the behavi oral changes induced by the serotoni n precursor,
5-hydroxytryptophan.
150
The avai labil i ty of sympathetic antagonists for possibl e si de effects
duri ng anesthesi a weighs i n favor of conti nuati on of therapy versus the ri sk of exacerbati on of a
severe depressi on.
151

P.320
Prozac (fl uoxeti ne) is a popul ar oral nontricycl ic anti depressant. Unl i ke desyrel, the eli mi nati on
half-li fe of prozac i s 1 to 3 days and can lead to si gni fi cant accumulati on of the drug. Prozac' s
metaboli sm, l i ke that of other compounds includi ng tri cycl i c anti depressants, phenobarbi tal ,
ethanol , and pentothal , i nvol ves the P450IID6 system; concomi tant therapy wi th drugs also
metabol i zed by thi s enzyme system may lead to drug interactions and prolongation of effect of the
benzodiazepi nes.
Wel l butri n and Zyban are the same drug, namely bupropri on hydrochlori de. Zyban, however, is
a sustai ned-rel ease drug. Wel lbutri n is used as an anti depressant whereas Zyban is marketed
as a nonni coti ne ai d to smoking cessati on. These drugs shoul d not be used concomitantly.
Overdose i s possibl e wi th resultant sei zures. Sei zure acti vi ty i s dose related. The neurochemical
mechani sm of the anti depressant effect of bupropri on i s not known. It does not inhi bi t monoamine
oxi dase and is a weak blocker of the neuronal uptake of serotoni n and norepi nephri ne. It also
inhi bits the neuronal uptake of dopami ne to some extent. No systemati c data have been col l ected
on the i nteracti ons of buproprion and other drugs. The mechani sm by which Zyban enhances the
abi li ty to abstain from smoki ng i s unknown but perhaps i t assists the pati ent through the mental
vici ssi tudes of ni coti ne wi thdrawal . Hi gh doses hi gher than 300 mg can resul t i n seizures.
152

Adrenergic AntagonistsSympatholytics
Antagonists. Drugs that bi nd sel ecti vel y to -adrenergi c receptors block the acti on of
endogenous catechol ami nes or moderate the effects of exogenous adrenergics. The resul tant
effects may be ascri bed together the bl ockade effect to -adrenergi c agonists or to unopposed -
adrenergi c receptor acti vi ty. The effect i s smooth muscle rel axati on. The response to the
vasculature may vary over a wide range in a single vascul ar bed dependi ng on i ts i ntrinsi c state of
constri cti on. Vessel s wi th higher i ni tial tone have a greater response to -bl ockade. Promi nent
cl i ni cal effects of -bl ockers i ncl ude hypotensi on, orthostati c hypotensi on, tachycardi a and miosi s;
nasal stuffi ness, diarrhea, and inhi bi ti on of ejaculati on are common side effects.
The -bl ockers may be cl assi fi ed according to binding characteristics (Tabl e 12-20).
Phenoxybenzmi ne is an oral -bl ocker that produces an irreversibl e bl ockade. It i s a relatively
nonselecti ve -bl ocker. Phentol ami ne, tolazol ine, and prazosi n are characteri zed by reversi ble
bi ndi ng and antagoni sm.
Phentol ami ne i s 100 times more potent on -1 receptors than on -2 receptors. Prazosi n is also
markedl y specific for -1 receptors, whereas phentol amine has nearl y equal blocking acti vi ty on
both subsets. Phentol ami ne, by bl ocki ng presynapti c i nhi bi tory -2 receptors, causes greater NE
TABLE 12-20 -Adrenergic Blocking Drugs
TYPE OF ANTAGONISM SELECTIVITY
Phenoxybenzami ne Noncompeti tive

1
>
2
Phentol ami ne Competitive

1
=
2
Tol azol i ne Competitive

1
=
2
Prazosi n Competitive

1
>>
2
Yohi mbi ne Competitive

2
>>
1
rel ease from the presynaptic termi nal.
There are many -bl ockers i n use today for beni gn prostati c hypertrophy as wel l as essenti al
hypertensi on. When pati ents are taki ng these drugs chroni cal ly, one should keep in mind that the
normal autonomic response to stress, i nhal ati on anestheti cs, or extensi ve regi onal anesthesia may
be blunted. El evati ons of catecholami nes wil l not refl exl y increase peripheral vascul ar resistance
and may actual l y decrease if vascul ar receptors are unopposed. The effects are si mil ar to the
acute sympatholysi s seen wi th spi nal or epi dural anesthesi a. -bl ockers are often used in
combi nation with diureti cs and other antihypertensi ves. Vol ume depl eti on may not be evi dent on
preoperati ve exami nation but unmasked wi th the inducti on of anesthesia and the onset of a
marked hypotensi on. Thi s hypotensi on i s usual l y responsi ve to vol ume repl eti on and the
temporary use of a di rect acti ng -agoni st such as neosynephrine. There i s no cause for
di sconti nuati on of these drugs before surgery but prel oadi ng wi th i v fluids is suggested to ensure
adequate central vol ume.
Phentolamine. Phentolami ne is used al most excl usi vel y i n the di agnosis and treatment of
pheochromocytoma. It is a competitive antagonist at -1 and -2 receptors. Phentol ami ne may
al so have some anti histaminic and chol i nomi metic acti vi ty. The chol i nomi meti c acti vi ty may resul t
i n abdomi nal crampi ng and di arrhea, both of whi ch are bl ocked by atropi ne. Tachycardi a and
hypotensi on are al so common si de effects.
Intravenously, phentol amine produces peri pheral vasodi l atati on and a decrease i n systemi c blood
pressure withi n 2 mi nutes l asti ng from 10 to 15 mi nutes. Blood pressure reduction eli cits
baroreceptor refl exes and NE release, the result of

whi ch i s an i ncreased heart rate and cardi ac output. Cardi ac arrhythmi as and angi na pectori s may
accompany phentol amine admini stration. It can be gi ven i n does of 30 to 70 g/kg iv to produce a
transi ent decrease in bl ood pressure. It can al so be used as a conti nuous infusi on to maintai n
bl ood pressure duri ng resecti on of a pheochromocytoma.
Phenoxybenzamine (Dibenzyline). Phenoxybenzami ne acts as a nonsel ective -adrenergi c
antagonist. -bl ockade i s 100 times more potent on postsynapti c -1 receptors than at -2
receptors. The onset of -bl ockade i s slow, taki ng up to 60 minutes to reach peak effect even with
iv admini stration. Thi s is related to the ti me requi red for structural modi fi cati on of the
phenoxybenzami ne mol ecul e to become acti ve. The eli mi nation hal f-li fe i s about 24 hours.
Orthostati c hypotensi on i s promi nent especi al l y i n the presence of preexi sti ng hypertensi on or
hypovolemia. Cardiac output i s often increased and renal bl ood fl ow i s not greatl y al tered except
in preexi sti ng renal vasoconstri cti on or stenosis. Coronary and cerebral vascul ar resistance i s not
changed. In the past i t was the drug of choi ce for treating patients wi th pheochromocytoma in
preparati on for surgery. It has been repl aced with shorter acting, more speci fi c drugs such as
phentol ami ne.
Prazocin (Minipres). Prazoci n i s rel ati vel y selective for -1 receptors that l eaves the inhi bi ti ng
effect of -2 receptor activi ty on norepi nephri ne rel ease i ntact. As a resul t, i t is l ess l i kel y that
nonselecti ve -antagonists evoke reflex tachycardi a. Prazoci n dil ates both arteri oles and vei ns.
Cardi ovascul ar effects i ncl ude total body reducti ons in systemic vascul ar resistance and venous
return. When combi ned wi th a di ureti c, i t is an effecti ve anti hypertensive drug. It shoul d not be
used wi th cloni di ne or -methyl odopa as i t appears to decrease thei r effecti veness. Prazosi n may
al so cause bronchodi lation.
Several new oral -1-bl ockers are now on the market that have been found useful for benign
prostatic hypertrophy (BPH) and hypertensi on. The anesthesiol ogi st may commonl y encounter
patients taki ng these medicati ons on a chroni c basis and must be aware of thei r possibl e
interactions with anesthetics. Doxazosi n is a l ong-acti ng sel ecti ve -1-bl ocker used for both i n
treati ng beni gn prostati c hypertrophy and hypertension. The most common si de effect, as wi th al l
-bl ockers, i s orthostati c hypotension and di zzi ness. Tamsul osin (fl omax) is another -bl ocker that
i s used for BPH. It i s not i ndi cated for hypertension but i t i s capabl e of produci ng orthostati c
P.321
hypotensi on.
Antagonists. -adrenergi c-bl ockers were i ntroduced i n the 1960s. Cardi ovascul ar pharmacol ogy
has been domi nated by the age of these sympathol yti c agents that ushered out the age of the
pressor. As more i ndi cati ons for thei r use have been found, more compounds have been
devel oped. They are among the most common drugs used i n the treatment of cardiac di sease and
hypertensi on. At present, there are -bl ocking agents avai labl e for oral or intravenous use in the
Uni ted States. A vari ety of drugs are avai lable wi th -bl ocking acti vi ty that may be di sti ngui shed
by di fferi ng pharmacoki netic and pharmacodynami c properties. Exampl es of some of the drugs
avai labl e and thei r diversity of acti ons are l i sted i n Tabl e 12-21.
-bl ockers can be cl assi fi ed accordi ng to whether they are sel ecti ve or nonsel ective on the -1 or
-2 receptor and whether they possess i ntri nsi c sympathomimetri c activi ty (ISA). For exampl e, a
TABLE 12-21 -Adrenergic Blocking Drug
DRUG TRADE
NAME
RELATIVE
1

SELECTIVITY
MEMBRANE-
STABILIZING
ACTIVITY
INTRINSIC
SYMPATHO-
MIMETIC
ACTIVITY
PLASMA
HALF-
LIFE
(hr)
ORAL
AVAILABIL
(%)
Propranolol Inderal 0 + 0 34 36
Nadol ol Cogard 0 0 0 1424 34
Ti mol ol Blocadren 0 0 0 45 50
Pi ndol ol Vi sken 0 + ++ 34 86
Esmolol Brevibloc ++ 0 0 016
Acebutolol Sectral + + + 34 37
a
Atenol ol Tenormi n ++ 0 0 69 57
Metoprolol Lopressor ++ 0 0 34 38
Betaxolol Kerl one +++ + 0 1422 89
Penbutol ol Levatol 0 0 + 5 85
Carteol ol Cartrol 0 0 + 6 85
a
Pri mari l y hepatic, but active metabol ites are formed that must be renal l y excreted.
-bl ocker with sel ecti ve properti es for the -1 receptor woul d bind to the cardiac receptors,
whereas a nonselective -bl ocker would bi nd to both -1 (cardi ac) and -2 (vascul ar, bronchi al
smooth muscl e, and metaboli c) receptors. Their bi ol ogi cal potency and affi ni ty for receptor
subtypes i s determi ned by their abil i ty to i nhi bi t tachycardi a and vasodi l atati on i nduced by
isoproterenol , a pure nonsel ecti ve agoni st. Nonsel ecti ve antagonists are referred to as fi rst-
generati on -bl ockers. These i ncl ude propranol ol , nadol ol , sotalol , and ti molol. Second-generati on
drugs are those consi dered sel ective for -1 adrenergic bl ockade. These i nclude atenol ol , esmol ol ,
and metoprol ol .
Those -bl ockers possessi ng ISA exert the parti al effect of a parti al agoni st whi le blocking
receptors by more potent agoni sts. ISA mi ght be advantageous in pati ents needi ng -bl ockers
but who are troubl ed by bradycardia or worsening ventricul ar fai l ure.
153
A di sti nct advantage to
ISA in -bl ockers has not been shown i n cl ini cal studi es.
Over the past decade, and because of their selecti vi ty, the use of -bl ockers has expanded to
incl ude the treatment of congestive heart fai lure (CHF).
154
CHF was once a contrai ndi cati on for the
use of -bl ockers. This i s the result of better understandi ng of the fl uid nature of up- and
downregulation of receptor densi ty once thought to be static.
Sel ecti ve -bl ockade coul d be of greater benefi t in treatment of pati ents wi th obstructi ve ai rway
di sease, di abetes, or peri pheral vascul ar di sease. However, it must be emphasi zed that speci fi ci ty
is a rel ati ve term and not absol ute. Nonsel ecti ve bl ocki ng effects may be seen i n al l tissues i f
hi gher blood levels are reached wi th sel ecti ve drugs (see Fi g. 12-13). For example, the use of -
1 sel ecti ve bl ockers in pati ents wi th obstructi ve or reacti ve ai rway di sease remains controversi al.
Patients with reacti ve airway disease may devel op serious reducti ons i n ventil atory functi on even
wi th -1 sel ecti ve antagoni sts.
155
Other drugs are avail able for treatment of supraventricular
arrhythmi as and hypertension in asthmati cs.
Sympatheti c acti vati on generall y resul ts i n increased ci rcul ati ng glucose l evels secondary to
enhanced gl ycogenol ysi s, li pol ysi s, and gl uconeogensi s. Admi ni strati on of -2-bl ockers to insul in-
dependent di abeti cs reduces thei r abi l i ty to recover from hypogl ycemi c epi sodes.
156
-2
antagonists are preferable.
-bl ocker therapy shoul d be continued unti l and after the ti me of surgery. This i ssue i s no longer
controversi al for several reasons. Acute withdrawal of antagoni sts may produce a hemodynami c
withdrawal syndrome si mi l ar to thyrotoxicosi s.
58
Control of HR and bl ood pressure peri operati vel y
is easi er if chronic medi cati ons are conti nued for the co-morbi d factors for whi ch they were
prescribed. HR i s a major determi nant of myocardi al oxygen demands. Tachycardi a i s known to
increase the ri sk of poor outcome i n pati ents wi th i schemi c heart disease,
157
therefore
hemodynamic control of HR and BP (work) i s important i n reduci ng peri operati ve ri sk. In a
compl ete turnabout from a decade ago, several well -founded studi es have shown the benefits of
prophyl acti c -bl ockade wi th atenol ol i n pati ents at risk for i schemi c cardi ac disease.
158
The
reduction in peri operati ve morbi dity and mortali ty i n these groups of patients was si gni fi cant.
Several of the -bl ockers l isted i n Tabl e 12-21 al so have a l ocal anesthetic-li ke effect on
myocardial membranes at hi gh doses. Thi s effect i s si mil ar to that of qui ni dine in that phase 0 of
the cardiac action potential i s depressed, sl owi ng conducti on. This membrane-stabi l izing acti vi ty i s
caused by the D-isomer, whereas the L-isomer is responsi ble for -bl ocking activity. The cl inical
si gni fi cance of membrane-stabi l izing acti vi ty i s uncl ear.
Propranolol. Propranol ol i s the prototype -bl ocking drug agai nst whi ch all others are compared.
It i s nonselective and has no i ntrinsi c sympathomi metic acti vi ty but does have membrane-
stabi l izing acti vi ty at hi gher doses. It i s avai l abl e i n both iv and oral forms. It i s hi ghl y li pophi li c
and i s metabol i zed by the l i ver to more water-solubl e metaboli tes, one of which, 17-OH
propranolol , has weak -bl ocking acti vi ty. There i s a si gni fi cant first-pass effect by the l i ver after
oral admi ni strati on of the drug. It i s hi ghl y protei n bound, and the free drug l evel may be al tered
by other hi ghl y bound drugs. The eli mi nation hal f-li fe i s approxi matel y 4 hours, but the
pharmacol ogic hal f-li fe is around 10 hours.

P.322

Hemodynami c effects incl ude decreased HR and contracti l ity. The major factors contri buti ng to the
decrease i n bl ood pressure by propranol ol are decreased CO and reni n rel ease. Systemi c vascular
resistance may i ncrease on acute admi ni strati on owi ng to blockade of -2 receptors i n the
peri pheral vasculature. With chroni c admi ni strati on, however, peri pheral vascul ar resi stance
decreases. Thi s is thought to be secondary to decreased reni n rel ease and, possi bl y, decreased
central SNS outfl ow. Compl icati ons wi th the use of propranol ol i ncl ude bradycardi a, heart bl ock,
worseni ng of congesti ve heart fail ure, bronchospasm, and sedati on. Duri ng anesthesi a wi th
halothane, i t may cause severe bradydysrhythmi as.
Nadolol. Nadolol i s a noncardi osel ective -bl ocker with no membrane-stabi l izing acti vi ty or
intrinsic sympathomi meti c acti vi ty. It i s approximatel y equipotent to propranol ol, but i ts effects
are prol onged owing to sl ower eli mi nation. It i s rel ati vel y l i pid insol ubl e and i s excreted 70%
unchanged in uri ne and 20% in the feces. The el i mi nation half-li fe i s 24 hours. Because it i s li pi d
insol ubl e, i t does not cross the bl ood-brai n barri er, and sedati on i s l ess of a probl em than wi th
propranolol . Hemodynami c effects are the same as for propranol ol . The mai n advantage of the
drug is the capabi l ity for once per day dosi ng.
Timolol. Timol ol is al so noncardi osel ective wi th l ittle intri nsic sympathomi meti c activi ty and no
membrane-stabi l izing acti vi ty. It is the onl y -bl ocker used as the l -isomer rather than the
racemic mi xture. It is 5 to 10 ti mes as potent as propranol ol . Hepatic metabol i sm accounts for
approxi mately 66% of i ts el i mi nati on, and another 20% i s found unchanged i n the urine. The
el i mi nation half-li fe i s 5.6 hours, and the pharmacologi c half-li fe i s approxi matel y 15 hours. It was
first used topi cal ly for treatment of gl aucoma but i s now used i n hypertension and has been shown
to decrease the ri sk of rei nfarcti on and death fol l owi ng myocardial infarction.
159
Its hemodynami c
effects and si de effects are si mi l ar to those of other -bl ockers. The anesthesi ol ogi st shoul d al so
be aware that ti molol eye drops may be absorbed systemi cal l y and cause bradycardi a and
hypotensi on that are refractory to treatment wi th atropi ne.
160

Pindolol. Pindol ol is a nonsel ecti ve -bl ocker with membrane-stabi l izing acti vi ty and intri nsi c
sympathomimeti c activity. It i s 10 to 40 ti mes as potent as propranol ol . It i s l i pid sol ubl e and
metaboli zed by the l i ver but not as avi dl y extracted; therefore, its bi ol ogi c avail abil i ty after oral
administrati on i s more predictabl e. It i s excreted 40% unchanged in the uri ne. The el iminati on
half-li fe i s 3.5 hours. It is useful i n the treatment of angina pectoris, cardiac dysrhythmia, and
hypertensi on. As di scussed earl i er, the cl i ni cal useful ness of the i ntrinsi c sympathomi metic
acti vi ty property i s uncl ear.
Oxprenolol. Oxprenol ol i s simil ar to pindol ol except for l ess i ntri nsi c sympathomimeti c acti vi ty
and l ower potency.
Metoprolol. Metoprol ol i s a rel ati vely sel ecti ve -bl ocki ng drug wi th -bl ocking effects at
moderate and hi gh doses. It has nei ther intri nsic sympathomi meti c acti vi ty nor membrane-
stabi l izing acti vi ty. It has a possibl e advantage i n pati ents with reacti ve ai rway disease at oral
doses up to 100 mg/day
-1
. In thi s case, i t should probabl y be used wi th a -2 mimetic drug. It is
mostly metabol ized i n the li ver, wi th only about 5% excreted unchanged in the uri ne. The
el i mi nation hal f-li fe i s 3.5 hours. It has recently become avai labl e i n i v as wel l as oral form;
therefore, i t may be useful duri ng anesthesi a.
Atenolol. Atenol ol is si mi lar to metoprol ol in that it i s rel ati vel y cardi oselective and has no
intrinsic sympathomimeti c acti vi ty or membrane-stabi l izing acti vi ty. It is l ess li pophi li c, however,
and is el i mi nated pri mari l y by renal excreti on. The eli mi nation hal f-li fe i s 6 to 7 hours. The l ack of
first-pass metaboli sm resul ts in more predi ctabl e bl ood l evel s after oral dosi ng.
Acebutolol. Acebutol ol i s a cardiosel ecti ve -bl ocker with intri nsic sympathomimeti c acti vi ty and
membrane-stabi l izing acti vi ty. It is metabol i zed i n the l iver and is subject to extensi ve first-pass
metabol i sm. The pri mary metabol i te i s di acetol ol , whi ch has a pharmacol ogic profil e simi lar to that
of the parent drug and i s excreted renal ly. The pharmacol ogic effects of the drug, therefore, are
dependent on both hepatic transformati on and renal excretion. The eli mi nation hal f-li fe of
acebutol ol i s 3 to 4 hours and of di acetol ol 8 to 13 hours. El i mi nati on i s prol onged in the el derl y
P.323
and pati ents wi th renal di sease. Acebutol ol , l i ke pi ndolol , has i ntri nsi c sympatheti c acti vi ty that
makes it more advantageous than the other -bl ockers i n patients wi th bradydysrhythmi as or
myocardial fail ure.
Esmolol. Esmolol has several uses in the peri operati ve period.
161
The most uni que feature of the
drug is the ester functi on i ncorporated i nto the phenoxypropanol ami ne structure. Thi s al l ows for
rapi d degradati on by esterases i n the red bl ood cel l s and a resul tant pharmacologi c half-li fe of 10
to 20 mi nutes.
161
Esmolol i s cardi osel ecti ve and appears to have l i ttl e effect on bronchi al or
vascul ar tone at doses that decrease HR i n humans. It has been used successful ly in l ow doses i n
patients wi th asthma
162
but cauti on i s agai n advised when usi ng -bl ockers i n these pati ents.
163

Esmolol is metabol i zed rapi dl y i n the bl ood by an esterase l ocated i n the red bl ood cel l cytopl asm.
It i s different from the plasma choli nesterase and i s not i nhi bited to a si gni fi cant degree by
physostigmi ne or echothi ophate but i s markedl y i nhi bi ted by sodium fluori de. There are no
apparent i mportant cl inical interactions between esmol ol and other ester-contai ning drugs. At the
hi ghest infusi on rates (500 g/kg/mi n), esmol ol does not prol ong neuromuscular blockade by
succi nyl choli ne.
Esmolol has proven to be useful i n the peri operati ve peri od because of i ts capabi l i ty to be
administered i ntravenousl y and i ts short hal f-li fe.
164
Thi s feature permi ts a tri al of -bl ockade i n
doubtful si tuati ons. Esmol ol has been shown to blunt the response to intubati on of the trachea
161

and i s moderatel y effecti ve i n treating postoperati ve hypertension.
165
Most reported studi es i n
humans have used doses of 50 to 500 g/kg/mi n. The most benefi ci al approach seems to be a
loadi ng dose of 500 g/kg over 30 seconds, fol l owed by conti nuous infusi on of 50 to 300
g/kg/mi n. Peak bl ockade appears to occur wi thin 5 minutes. On di sconti nuation of the i nfusi on,
serum level s decli ne wi th an el iminati on hal f-li fe of 9 mi nutes. The HR response to i soproterenol
returns to control in 20 mi nutes.
Betaxolol. Betaxol ol hydrochl ori de i s a -1 sel ecti ve (cardiosel ecti ve) adrenergi c receptor
antagonist and i s freely sol ubl e i n water. It has weak membrane-stabi l izing activity and no
intrinsic sympathomi meti c (parti al agonist) activity. The preferential effect on -1 receptors i s not
absol ute. Some -2 inhi bi tory activity can be expected i n the bronchi al and vascular muscul ature
at hi gher doses. Absorption of an oral dose i s compl ete, with an absol ute bioavail abil i ty of 90%
that i s unaffected by ingesti on of food or alcohol. The mean eli minati on hal f-li fe i s from 11 to 22
hours. It i s eli mi nated pri maril y by the l i ver but secondari l y through the ki dneys. Betaxolol i s
i ndi cated i n the management of hypertensi on. It may be used alone or concomi tantl y with other
anti hypertensive agents.
Penbutolol. Penbutolol i s a syntheti c receptor antagonist for oral admi ni strati on. It is a
nonselecti ve receptor antagonist wi th some i ntri nsi c sympathomimeti c acti vi ty. Penbutol ol does
not appear to have any membrane-stabi l izing properti es, as does propranol ol . Pl asma el i mi nation
half-li fe i s 5 hours i n normal subjects. Ni nety percent of radioacti ve penbutolol was found to be
excreted in the uri ne. There i s no change in the effecti ve half-li fe of penbutol ol i n healthy pati ents
versus those on renal dial ysis. It i s indicated pri mari l y for the treatment of

hypertensi on and may be used i n combinati on wi th other anti hypertensives.
Carteolol. Carteol ol i s a syntheti c, nonselective, -adrenergi creceptor-bl ocking agent wi th
intrinsic sympathetic acti vi ty. It possesses no signi ficant membrane-stabi l izing (local anestheti c)
acti vi ty and is wi thout val ue i n treati ng i ntrinsic arrhythmi as. Carteol ol has equi vocal effects on
reni n secreti on because of i ts intri nsi c sympathomimeti c activity, in contrast to -bl ockers wi thout
such acti vi ty, which inhi bi t reni n. Carteol ol i s wel l absorbed with a half-li fe of approxi mately 6
hours. About 50 to 75% of the drug is el i mi nated by the ki dneys; thus, renal i mpai rment increases
its half-li fe i n proporti on to the reducti on i n creati ni ne cl earance. Carteol ol i s primari ly indi cated
for the management of hypertension but may be used i n combi nati on with other potent drugs.
Mixed Antagonists
Labetalol. Labetal ol is an anti hypertensi ve drug wi th bl ocking acti vi ty at both and receptors.
The rel ati ve -/-bl ocking effects are dependent on the route of admi ni strati on. After oral
P.324
administrati on, the rati o of / effecti veness i s 1:3; however, when gi ven i ntravenousl y, i t i s 1:7
(i .e., i t i s three and seven ti mes more potent on than on receptors, respecti vel y). The
effects are pri mari ly on -1 receptors, whereas the effects on nonsel ecti ve.
Hemodynamic effects consist primari l y of decreased peri pheral resi stance and decreased or
unchanged HR wi th l i ttl e change i n CO. Serum reni n activity is decreased. Mai ntenance of l ower
HRs i n the presence of decreased systemi c bl ood pressure i s benefi ci al in control l ing the
myocardial oxygen suppl y/demand rati o and i s a major benefi t of labetal ol i n pati ents wi th
coronary artery disease.
Labetal ol i s el iminated by hepati c gl ucuronide conjugati on. The eli mi nation hal f-li fe after i v
administrati on i s 5.5 hours and 6 to 8 hours after oral use. El i mi nati on i s not markedly prol onged
in pati ents wi th hepatic or renal fai l ure. Another advantage of the drug is the abi li ty to convert
from iv to oral forms of the same drug after the patient is stabl e. For treatment of hypertension
when used as a bol us, the i niti al dose i s 0.25 mg/kg iv over 2 mi nutes, then repeated every 10
mi nutes to a total of 300 mg. When used as a conti nuous infusi on, i t is usuall y started at 2
mg/mi n and ti trated to effect. Because there i s an enhanced effect by i nhal ati on anestheti cs,
these doses shoul d be decreased when used i ntraoperati vel y.
Compli cati ons and contrai ndicati ons are simi lar to those for the -bl ockers. Labetal ol shoul d be
used wi th cauti on i n pati ents wi th compromi sed myocardial functi on because it may worsen heart
fai l ure. Al so, owi ng to -bl ocking acti vi ty, the drug may i nduce bronchospasm in asthmati cs. As
wi th other -bl ockers, abrupt wi thdrawal i s not recommended.
Calcium Entry Blockers
Cal cium is regarded as the uni versal messenger in cell s and pl ays a cri ti cal rol e i n a number of
bi ologi c processes. It i s involved in bl ood coagul ati on, a broad array of enzymati c reacti ons, the
metaboli sm of bone, neuromuscul ar transmission, the el ectri cal acti vati on of vari ous exci tabl e
membranes, as wel l as endocrine secreti on and muscle contracti on. Cal cium ini ti ates several
physi ol ogi c events i n the speci al i zed automati c and conducti ng cel l s in the heart. It i s i nvol ved i n
the genesis of the cardi ac acti on potenti al , and it l inks exci tation to contraction and control s
energy stores and uti li zati on. Movement of extracel l ul ar calci um across membranes also governs
the functi on of smooth muscl e i n bronchi and i n coronary, pulmonary, and systemi c arteri ol es.
Membrane calci um channel s are known to exi st that provi de a pathway for calci um i nfl ux across
cell membranes that differs from cal ci um effl ux movements associ ated with active pumps or
exchange. The inward calci um channel exhi bi ts two di sti nguishi ng properti es: (1) sel ecti vi ty in
that they have the abi l ity to di sti nguish between i on speci es and (2) exci tabi li ty i n that they have
the property of responding to changes i n membrane potenti al. Separate, ion-specific, channel s for
sodium and cal ci um i nflux are thought to exist. The status of these channel s can vary to produce
three ki neti c states: resti ng, activated, and i nactivated. Sodi um channel s are referred to as fast
channel s because the transi tion among resting, acti vated, and inactivated states i s more rapi d
than among the calci um channel s. Thus, cal cium channel s are often referred to as membrane
sl ow channel s.
166

Classification of calcium entry bl ockers has been di fficul t since their di scovery. They were ini ti all y
thought to be -adrenergi c-bl ocking drugs because of thei r sympatholyti c action. Later they were
call ed calci um antagoni sts. It is cl ear, however, that these drugs are not true pharmacol ogi c
antagonists of cal ci um. Instead, they interact wi th the cel l membrane to control the i ntracell ular
concentration of cal ci um. The correct termi nology for thi s group of drugs appears to be cal ci um
entry blockers. Sl ow channel i nhi bitors or calci um channel bl ockers are al ternate terms. The
mol ecul ar structures of three cl ini cal ly useful calci um entry blockers are seen in Fi gure 12-31.
Calcium entry blockers are a heterogeneous group of drugs with dissimil ar structures and
el ectrophysiol ogi c and pharmacol ogi c properti es. Despi te structural di ssi mi l ari ti es, thi s group
shares some i mportant acti ons that are consi stent wi th the known importance of extracel lular
calci um and adrenergi c functi on. Any drug that al ters sl ow-channel ki neti cs coul d be expected to
produce vasodi latation, to depress cardi ac conduction velocity (dromotropi sm), to depress
contracti l ity (i notropism), and to decrease HR (chronotropi sm). Al l cal ci um entry bl ockers

do thi s, but wi th varyi ng degrees of potency in the i ntact human and i n vi tro (Tabl e 12-22).
167

Thus, despi te thei r si mil ari ti es, these drugs cannot be consi dered therapeuti cal ly i nterchangeabl e.
Clinically, nifedipine is a potent coronary artery vasodi l ator with li ttl e di rect effect on cardiac
conducti on. It may reduce dysrhythmi a secondari l y when increased coronary blood fl ow is of
benefi t. Verapamil i s val ued for its speci fi c anti dysrhythmi c activity, but i t is a myocardi al
depressant wi th l i ttl e vasodi lator acti vi ty. Verapami l al so has sl ightl y greater l ocal anesthetic
acti vi ty (fast-channel inhi bi ti on) than procaine on an equi molar basi s.
168
The si gni fi cance of thi s
observation in humans has not been establ ished. The structural heterogenei ty of thi s group of
drugs al so suggests more than one site and mechani sm of acti on. Al though the molecul ar basi s of
the action of these compounds i s unknown, they are l i pophi l i c, and i t appears l i kel y that they work
by produci ng conformati onal changes in the cell membranes.
P.325
FIGURE 12-31. Structural formulas of the cal cium entry blockers demonstrate dissimil ar
structures consi stent wi th thei r di ssimil ar electrophysiol ogi c and pharmacol ogi c properti es.
They al so share some si mi lariti es but cannot be consi dered therapeuti cal ly interchangeable.
Ni fedi pi ne and ni trendi pi ne are structural l y si mi lar and are both potent vasodi l ators; BAY K
8644 i s also si mil ar but is a cal cium channel agoni st.
TABLE 12-22 Autonomic Effects of Calcium Entry Blockers in Intact Humans
VERAPAMIL DILTIAZEM NIFEDIPINE LIDOFLAZINE
Negati ve i notropi c + 0/+ 0 0
Negati ve chronotropi c + 0/+ 0 0
The useful pharmacologic effects of the cal ci um entry blockers have been confi ned al most sol el y to
the cardiovascul ar system, al though the li st of uses wi ll l i kel y grow.
166
Tabl e 12-23 li sts some of
the areas of i nvesti gati on i n whi ch they appear to be of cli ni cal benefit. Cal cium entry bl ockers
have been descri bed, perhaps erroneousl y, as selective sl ow-channel bl ockers. A review of the
li terature, however, suggests that these agents are not selective but rather that the sl ow-channel
effects on the cardi ovascul ar system are just more apparent. Their lack of sel ectivity should not
be surprisi ng consi deri ng the criti cal rol e cal ci um pl ays in a wi de variety of bi ologi c processes. The
sensi ti vi ty of a given ti ssue to the calci um entry blockers i s rel ated to that ti ssue' s dependence on
extracel lul ar cal cium for i ts function. Thi s woul d expl ai n the sensi tivity of the cal cium-dependent
myocardium and smooth muscl e to these blockers on the one hand and the apparent i nsensi ti vi ty
of stri ated muscle on the other. Extracel l ul ar calci um is relatively i nsignificant i n the functi on of
stri ated muscle, where the SR i s the major storage organell e of calci um. Stri ated muscl e can
recycle i ntracel lular cal ci um for prol onged peri ods, whi ch is i n keeping wi th i ts functi on of
sustained contraction as opposed to the rhythmi c or cycl i c contracti on of the myocardium and
smooth muscl e.
The drugs are al l absorbed vi a the gastroi ntesti nal tract, but the extensive fi rst-pass hepati c
extraction of verapami l li mits i ts bi oavai labil i ty oral l y (Tabl e 12-24). Onset of acti on i s equi val ent
for al l three drugs and i s consistent wi th rapi d membrane transport. Al l three drugs are
Negati ve dromotropi c ++++ +++ 0 0
Coronary vasodil ati on ++ +++ ++++ ++++
Systemi c vasodi l ati on ++ ++ ++++ +++
Bronchodilation 0/+ 0/+
TABLE 12-23 Uses of Calcium Channel Blockers
Vascular Disorders Nonvascular Disorders
Systemi c hypertensi on Bronchi al asthma
Pul monary hypertension Esophageal spasm
Cerebral arteri al spasm Dysmenorrhea
Raynaud' s phenomenon Premature labor
Mi grai ne
extensi vel y protei n bound and subject to the effect of changes in pl asma protei n concentrati on
and competi ti on from other protei n-bound drugs and metabol i tes, but fi nal el iminati on of
verapami l and ni fedi pi ne i s pri mari l y renal .
TABLE 12-24 Comparative Pharmacology of Calcium Entry Blockers
VERAPAMIL DILTIAZEM NIFEDIPINE
Dose
Oral 80160 mg tid 6090 mg ti d 1020 mg ti d
iv 75150 g/kg 75150 g/kg 515 g/kg
Absorption
Oral (%) >90% >90% >90%
Bioavailability
Oral (%) <20% ?<20% 6070%
a
Onset
Oral 1520 mi n 2030 mi n 1520 mi n
iv 1 mi n ? 1 mi n
Subl i ngual 3 mi n
Peak Effect
Oral 5 hr 30 mi n 12 hr
iv 530 mi n ? 13 hr
Elimination
half-life
27 hr 4 hr 45 hr
Plasma protein
binding
90% 80% 90%
Verapamil
Verapamil i s a cal ci um entry bl ocker that is admi ni stered intravenousl y for termi nating
supraventricular tachydysrhythmias. Nearly all forms of supraventricul ar tachydysrhythmi as are
caused by reentry usi ng ei ther the sinoatri al or the AV node as part of the ci rcui t. Verapami l
termi nates these cardiac dysrhythmias by decreasing nodal conducti vi ty, converti ng the
uni di recti onal block of reentry to a bi -di recti onal bl ock. In thi s regard, its action on
supraventricul ar dysrhythmi a is si mi l ar to that of qui nidi ne on ventricul ar reentry cardiac
dysrhythmi a.
Verapamil does not al ter the acti on potenti al upstroke i n fi bers whose resti ng membrane potenti al
i s more negati ve than -60 mV (i .e., fast-acti on potenti al s).
169
It does sl ow or prevent
depol arizati on i n cardi ac ti ssue wi th a resting membrane potenti al that i s l ess negati ve than -50
mV (i .e., cal cium-dependent upstroke). Verapami l, therefore, has profound effects on pacemaker
cel ls, whi ch depend on the cal cium current for depol ari zati on.
170
It depresses the rate of si nus
di scharge, reduces conducti on vel oci ty, and i ncreases refractori ness of the AV node. A dose-
dependent i ncrease in the PR i nterval and AV i nterval i s produced on the el ectrocardi ogram. This
has been descri bed as a qui ni di ne-like effect similar to that produced by Cl ass IA anti dysrhythmi c
drugs (e.g., procai nami de), which are also effecti ve for supraventri cul ar dysrhythmia. In contrast
to the procai nami de, verapami l does not i ncrease the QRS or Q-T interval because i t lacks acti vi ty
on the sodi um-dependent action potenti al s.
Verapamil i s a fi rst-li ne drug for treatment of supraventri cul ar tachydysrhythmi as (Tabl e 12-25).
The i nci dence of successful terminati on of paroxysmal atrial tachycardi a wi th verapamil i n adults
has approached 90%.
171
It i s also effecti ve i n treati ng atri al fibri ll ati on and atri al flutter by ei ther
converting to a si nus rhythm or sl owi ng the ventricular response. The ventri cular rate wi ll sl ow as
a resul t of decreased conduction vel ocity through the AV node even when conversi on is not
produced. Cauti on must be exercised i n treating pati ents when the underl yi ng cause of the atri al
tachycardi a, atri al fi bri ll ati on, or atrial fl utter i s the Wol ff-Parki nson-White syndrome. An
Metabolism 70% Deacetylated 80% to l actone
Fi rst-pass hepati c
Elimination
Renal 75% 35% 70%
Gastroi ntesti nal
(l i ver)
15% 75% <15%
Side effects Consti pati on,
headache, vertigo,
hypotensi on,
atri oventri cul ar
conducti on
di sturbances
Headache, dizziness,
flushi ng,
atri oventri cul ar
conducti on
di sturbances,
consti pati on
Headache,
hypotensi on,
flushi ng, di gi tal
dysesthesias, l eg
edema
a
Li ght sensi ti ve.

accessory bypass tract l i es near the AV node that parti ci pates i n the re-entry of these
tachydysrhythmi as. Verapami l may termi nate the tachydysrhythmi a by i ts speci fi c depressant
effects on the AV node, which is one li mb of the re-entrant pathway. It may al so i ncrease
conducti on vel oci ty i n the accessory tract, in whi ch case the HR may actual ly increase.
Verapamil has no adverse effects on bronchi al asthma or obstructi ve lung disease and may be
sel ected over propranolol i n patients wi th these condi tions. It shoul d be avoided i n pati ents wi th
si ck sinus syndrome, AV block, and the presence of heart fail ure, unl ess the heart fai lure i s the
resul t of a supraventricular tachycardi a.
Studi es further support the hypothesi s that Ca
2+
partici pates directl y i n the genesis of ventri cul ar
dysrhythmi a.
172
When sodi um channel s are i nacti vated by hypoxia, stretch, or hyperkal emi a, the
remai ni ng Ca
2+
can produce a depol ari zi ng current i n these abnormal cell s, especi al l y i n the
presence of catechol ami nes. The conversion of a fast response cel l to a cel l wi th slow response
characteri sti cs presents al l the necessary ingredi ents for the reentry phenomenon: sl ow
depol ari zati on and del ayed conducti on. The resul ting ventricul ar dysrhythmi a can usual ly be
termi nated with one of the Cl ass I drugs as l ong as the resting membrane potential of the sl ow
response i s between 80 and 60 mV. Verapami l has been effecti ve i n termi nati ng ventricul ar
tachycardi as and premature depolari zations i n about two-thirds of the treatment tri al s when other
drugs have fail ed. The resting membrane potential of these abnormal sl ow response foci has
been postul ated to be l ess negative than 60 mV, a range i n whi ch li docaine woul d be i neffecti ve
on the cal cium current conducti on and depol ari zati on. More i nformation is needed before
recommendations can be made for verapamil i n treati ng dysrhythmi a other than supraventri cul ar
tachydysrhythmias. Other drugs are

si gni fi cantl y more effective for the ini ti al treatment of ventricul ar dysrhythmi a.
P.326
TABLE 12-25 Actions of Calcium Entry Blockers
Verapamil
Vasodi l ator
systemi c vascul ar resistance heart rate ejection fracti on and cardi ac output
Small decrease in l eft ventri cul ar dP/dt
Littl e or no change i n coronary resi stance conducti on through atri oventri cular node (
P-R i nterval )
Shoul d not be gi ven wi th di gital i s or bl ockers
Diltiazem
More like verapami l than ni fedi pi ne
Dil ates coronary more than systemi c vessel s and has l ess marked hemodynami c effects
than ni fedi pi ne or verapami l
Littl e effect on cardi ac output
Does not cause tachycardi a
Effects on conducti on system simil ar to those of verapami l
Less i notropi c effect than verapami l
Nifedipine
Rapi d onset of acti on, may be used subl i ngual l y
Potent peri pheral vasodi l ator, may be useful i n treatment of hypertension
Has l i ttl e cl i ni cal l y i mportant negati ve i notropi c acti vi ty
Less tendency to produce cardi ac decompensation than verapami l
Littl e effect on nodal acti vi ty and no antiarrhythmi c acti vi ty; therefore causes no
el ectrocardi ographi c changes
Increased coronary blood flow in normal and i schemi c myocardi um
P.327
The i mportant si de effects of verapami l are di rectl y rel ated to i ts predomi nant pharmacol ogi c
acti on (see Tabl e 12-25). It may produce unwanted AV conducti on delays and bradycardia,
resul ti ng in cardiovascular col lapse. Verapami l must be used carefull y, if at al l, in the presence of
propranolol . The combi ned effect has produced compl ete heart bl ock in ani mal s and humans. It
must be used carefully in di gi tal i zed pati ents for the same reason. No such interacti ons exist wi th
ni fedi pi ne. The combi nati on of -bl ockade and ni fedi pi ne may be benefi ci al i n pati ents wi th
ischemi c heart di sease because the refl ex tachycardi a seen wi th ni fedi pi ne can be countered with
-bl ockade.
Nifedipine
Ni fedi pi ne i s the most potent cal cium entry blocker when tested i n isolated ti ssue preparations. It
i s an equi potent cardi ac depressant and vasodi lator. Depression of inotropi sm and cardi ac
conducti on, however, i s not evi dent i n the i ntact human. It does not affect barorefl ex mechani sms
and, as a resul t, the marked vasodi l ati on i s accompani ed by i ncreased SNS tone and afterload
reduction (see Tabl e 12-25).
166
A compensatory tachycardi a may result, and CO may actuall y
increase as a resul t of the afterl oad reducti on.
The most specific therapeuti c appli cati on for ni fedipi ne is coronary vasospasm (vari ant of
Pri nzmetal ' s angi na). It has been more successful than nitrogl yceri n for thi s purpose because it
produces a more profound and predi ctable coronary vasodi l ation. It has al so been extremel y
useful i n other types of ischemi c heart di sease, ranging from unstabl e angina to myocardi al
infarcti on. The decrease i n myocardi al oxygen demand that resul ts from the reduced afterl oad and
reduced l eft ventricul ar vol ume appears to be the mechani sm for the reli ef of angi na. Coronary
vasodil ati on i s another factor, but it i s not known i f thi s i s the antiangi nal effect i n pati ents wi th
coronary artery di sease. The dil ati ng effect may l ast onl y 5 mi nutes, but the anti angi nal effect
may last more than 1 hour.
Diltiazem
The hemodynami c effects of di l ti azem li e somewhere between those of verapami l and ni fedi pi ne.
166

It i s less potent than ei ther of these two agents. Dil tiazem i s a good coronary artery di lator but a
poor peri pheral vasodi l ator. It often produces bradycardi a and del ayed conducti on, and refl ex
tachycardi a is not a probl em. It appears to be an effecti ve oral drug for the treatment of coronary
di sease i n whi ch cardi ac dysrhythmi as are troublesome. Cardi ac dysrhythmi as are noti ceabl y a
part of the cl i ni cal pi cture i n pati ents suffering from coronary spasm. Intravenous admini stration
of dil tiazem is effecti ve therapy for supraventri cul ar tachycardi as i ncl udi ng PSVT, atri al
fibri ll ati on, atri al flutter, and reentrant tachycardi as such as Wol ff-Parki nson-White syndrome.
173

Li ke verapami l , di l ti azem acts by prol ongi ng AV nodal conduction. The peri pheral vascular effects
of dil tiazem, though, are l ess severe, making i t a more desirabl e therapeuti c choice i n most cases.
A bol us dose of 0.25 mg/kg i s admi nistered over 2 mi nutes and may be repeated at 0.35 mg/kg i f
necessary after 15 mi nutes. An i nfusi on of 5 to 15 mg/hr may be necessary to mai ntain the
reduction of HR.
Nicardipine
Ni cardipi ne hydrochlori de i s a cal ci um channel blocker that can be admini stered oral l y and
intravenously. It is the onl y cal ci um channel blocker that can be ti trated i ntravenously to achi eve
bl ood pressure response. Ni cardi pine i s a smooth muscl e rel axant produci ng vasodil ati on of
peri pheral and coronary arteri es. It has a rapid onset of acti on, and the major effects last 10 to
15 mi nutes. Toxi c metaboli c products are not produced. It has mi ni mal cardiodepressant effects
and does not decrease the rate of the sinus node pacemaker or sl ow conducti on through the AV
node. Renal fai l ure does not affect the dosage, but the dosage shoul d be reduced i n the el derl y
and those with hepati c dysfuncti on. It i s compati bl e wi th most crystal l oi d sol uti ons. Si de effects of
ni cardi pi ne i ncl ude headache, l i ghtheadedness, flushi ng, and hypotension. Reflex tachycardi a i s
not a frequent fi ndi ng with ni cardipi ne, as is the case wi th ni troprussi de, hydral azine, or
ni fedi pi ne.
Nimodipine
Ni modi pine i s hi ghl y l i pophil i c. It has a greater vasodil ati ng effect on cerebral arteri es than on
vessel s el sewhere because of i ts li pophi li sm, whi ch promotes crossi ng the bl ood-brai n barri er.
Cli nical studi es demonstrate a favorabl e effect on the severi ty of neurol ogi c defi ci ts caused by
cerebral vasospasm fol l owi ng subarachnoid hemorrhage. However, no radiographic evi dence has
been presented that nimodi pi ne ei ther prevents or rel i eves spasm of these arteries. The
mechani sm for cl i ni cal i mprovement i s not known. It is pri maril y an oral drug that i s rapi dly
absorbed, wi th a T-termi nal half-li fe of approximatel y 8 to 9 hours. Earl i er el i mi nation rates are
much more rapid, whi ch resul ts in a need to redose every 4 hours. The bi oavai labi li ty of an oral
dose is onl y 13%. Dosage shoul d be reduced i n pati ents wi th hepatic dysfunction. The pri mary
i ndi cati on for ni modi pine i s for the i mprovement of neurol ogi c defi ci ts caused by spasm fol l owi ng
subarachnoi d hemorrhage from a ruptured aneurysm.
Felodipine
Fel odi pi ne i s a second-generati on calci um channel i nhi bi tor. Ni modi pi ne and fel odi pi ne have
demonstrated selecti vi ty for vascular ti ssue beds. Whereas ni modi pine preferenti al ly di lates
cerebral vessel s, fel odi pi ne preferential ly di lates peri pheral resi stance vessel s. Neither has
si gni fi cant effects on cardi ac muscle. Thi s has important cl i ni cal i mpl icati ons i n the treatment of
hypertensi on. Earl y studies i ndi cate that 10 to 20 mg of fel odi pi ne dai l y wil l reduce bl ood pressure
wi thout reduci ng CO or HR. Coronary bl ood flow i ncreases, but no effect on ventricul ar contracti on
or rel axati on has been reported. This woul d make the drug appropri ate for the acti ve hypertensi ve
patient.
Calcium Entry Blockers and Anesthesia
Evi dence i ndi cates that hal othane depresses slow-channel ki neti cs. Al l of the potent i nhal ati on
anesthetics behave i n a si mi l ar fashi on i n that they depress myocardi al contracti l ity and vascul ar
tone i n a dose-rel ated manner. Most studi es indi cate that the calci um entry bl ockers and
inhalation anestheti cs exert addi tive effects on the inward cal ci um current.
167
Opi oid anesthetics
do not appear to add anything to the effects of the calci um entry blockers. Several recent studies
indicate an interacti on between the calci um entry bl ockers and the neuromuscul ar bl ocking drugs
si mi l ar to that seen with the myci n anti bi otics.
166
Thi s interacti on i s not well defi ned, but i n vi tro
and in vivo studies indicate a reduced margi n of safety wi th these drug combi nations. Cal cium
entry bl ockers appear to augment the effects of both depol ari zi ng and nondepolari zi ng muscl e
rel axants.
174
These observati ons serve as a word of caution because thei r cl i ni cal significance has
not been defi ned. Prol onged apnea and rel axati on have been reported when verapamil was used to
treat a supraventricular tachycardi a in a pati ent wi th Duchenne' s muscul ar dystrophy.
175

Cal cium entry blockers shoul d be continued unti l the ti me of surgery to mai ntai n control of angi na
pectoris, hypertensi on, or cardi ac dysrhythmi a.
166
It coul d be anti ci pated that sudden

di sconti nuati on of these drugs theoreti cal l y could produce a rebound of symptoms, al though thi s
phenomenon has not been reported. Up-regul ati on of calci um receptors would probabl y occur
duri ng peri ods of entry bl ockade.
Verapamil may i ncrease the toxici ty of di goxi n, the benzodi azepi nes, carbamazepi ne, oral
hypogl ycemi cs, and possi bl y quinidi ne and theophyl l i ne.
176
Cardi ac fai l ure, AV conduction
di sturbances, and si nus bradycardia may be more frequent wi th concurrent use of -bl ockers, and
severe hypotensi on and bradycardi a may occur wi th bupivacaine. Decreased l i thium effect and
li thi um neurotoxi ci ty have both been reported with the concurrent use of verapamil .
177
The effects
of verapamil may also be i ncreased by ci meti di ne.
Vasodilators
Increased awareness and treatment of hypertensi on over the last 20 years has resulted i n
increasi ng numbers of pati ents presenti ng for anesthesi a and surgery who are taki ng one or more
P.328
anti hypertensi ve medi cati ons. These drugs are numerous, affect mul tipl e organ systems, and have
the potenti al for many deleteri ous i nteracti ons in the perioperati ve peri od. Most anti hypertensive
drugs bl unt the ANS or its effector organs or cause refl ex i ncreases i n ANS outflow. Most
anesthetic agents al so inhi bi t ANS tone to some degree and may therefore have addi ti ve effects
with antihypertensive drugs. In addi ti on, pati ents wi th hypertension may exhibi t greater l abil i ty i n
bl ood pressure i ntraoperati vel y and rebound hypertensi on i n the postoperative peri od. The
anesthesiol ogi st should therefore mai ntai n a thorough understanding of the commonl y used
anti hypertensi ve drugs. A rati onal approach to thei r peri operati ve use i ncl udes deci sions as to
holdi ng or conti nuing them preoperati vel y, possi bl e i nteracti ons with anestheti c drugs, and
resumpti on of treatment postoperati vel y. The commonl y used antihypertensi ve drugs are grouped
bel ow accordi ng to thei r pri mary mechanism of acti on and di scussed bri efl y with emphasi s on
consi derati on for the anesthesi ol ogi st.
Diuretics
Diuretics are the most common prescri bed drugs for hypertensi on. Thei r basic mechani sms of
acti on are decreased pl asma and extracel lul ar vol umes. Al though the thiazi des and furosemi de
have been shown to have vasodi l ating properti es, the cl i ni cal signi fi cance of thi s effect is uncl ear.
Chronic diureti c therapy results i n decreased intravascul ar vol ume. The cardi ovascul ar response to
inducti on of anesthesia may therefore be accentuated, resul ti ng i n hypotension and tachycardi a.
Other probl ems associ ated wi th di uretic use i ncl ude hypokal emi a, hyponatremi a, hypocalcemi a,
and hypergl ycemi a. Chroni c hypokalemia is common wi th di ureti c therapy and may predispose the
patient to cardi ac arrhythmias.
178
The cl inical rel evance of peri operati ve hypokal emi a i s uncl ear
and has sti rred consi derabl e debate among anesthesi ol ogi sts as to whether surgery should be
postponed unti l pl asma potassi um level s are treated.
179

Sympatholytics
Sympatholyti c drugs incl ude those that block central SNS outfl ow or NE release from the
presynaptic neuron at the effector si te. Currently included in this group are -methyl dopa and
cl oni dine.
-Methyldopa. -methyl dopa i s a catechol derivative that i s enzymati cal l y converted to active
compounds by enzymes i n the catecholami ne synthesis chai n (see Fi g. 12-9). -methyl dopami ne
and -methl ynorepi nephri ne are the primary metabol i tes. The preci se mechanism responsibl e for
decreased SNS tone is uncl ear, but i t i s thought that -methyl norepi nephri ne, whi ch i s stored in
presynapti c vesi cl es, i s rel eased and stimul ates presynapti c -2 receptors, thereby i nhi biti ng NE
rel ease. Because of the unique metabol ism of -methyl dopa to the acti ve compound and the
storage of the metabol ite i n presynaptic vesi cl es, both the ti me to onset and durati on of acti on are
l ong. Even after i v admi ni strati on, the peak effect may not be seen for several hours. Al though the
el i mi nation hal f-li fe i s 2 hours, the effect of an oral dose may l ast up to 24 hours.
Clonidine
Cloni di ne stimul ates presynapti c -2 receptors and i nhi bi ts NE release from both central and
peri pheral adrenergi c termi nal s. It al so has some -1 agoni st acti vi ty and in high oral doses may
cause paradoxi cal hypertensi on by sti mulating vascular -1 receptors. Under normal
ci rcumstances, the -2 effects predominate. The promi nent anti hypertensive effect is thought to
be secondary to sti mul ation of -2 receptors i n the vasomotor centers of the medul la obl ongata.
112

Whether these are presynaptic or postsynapti c receptors remains controversial ; however, the end
resul t i s decreased SNS and enhanced vagal tone. Peri pheral ly, there is decreased plasma renin
acti vi ty as wel l as decreased EPI and NE l evel s.
180

Cardi ovascul ar effects of cl oni dine i nclude decreased peripheral vascul ar resistance and HR. The
cardi ovascul ar response to exerci se i s usual l y maintai ned. Promi nent si de effects i ncl ude
hypotensi on, sedati on, and dry mouth. One of the more worri some compl icati ons of cloni di ne use
is the occurrence of a wi thdrawal syndrome on acute disconti nuati on of the drug. Thi s usual ly
occurs about 18 hours after di sconti nuati on and consi sts of hypertensi on, tachycardia, insomni a,
flushi ng, headache, apprehension, sweati ng, and tremulousness. It lasts for 24 to 72 hours and is
most l ikely to occur i n pati ents taki ng more than 1.2 mg/day of cl oni dine. The withdrawal
syndrome has been noted postoperati vely i n patients who were taken off cloni di ne for surgery. It
can be confused wi th anesthesi a emergence symptoms, particul arl y in a pati ent wi th uncontrol led
hypertensi on. Cloni di ne i s not avai l abl e for iv use, but symptoms of the wi thdrawal syndrome as
well as routi ne postoperati ve hypertensi on can be treated wi th cl oni dine admini stered
transdermal ly or rectal l y.
181
Withhol di ng cl onidi ne pri or to surgery i s not recommended.

Dexmedetomidine
Dexmedetomidi ne i s a more sel ecti ve -2 agoni st than cloni di ne.
119
It has a much shorter hal f-li fe
(about 1.5 hours) and a more rapid onset of action (5 mi nutes). The ti me to peak effect i s 15
mi nutes. Intravenous dexmedetomi di ne provi des excel l ent sedation, l oweri ng of bl ood pressure
and HR, and profound decreases in pl asma catechol amines. Little respiratory depressi on i s
evident. Other studi es have shown i t to be an effective anxiolytic and sedative when used as
premedi cation for anesthesia for mi nor gynecologic surgery. In an ani mal model, dexmedetomidi ne
produces stereospeci fi c and dose-dependent decreases i n MAC.
182

Fl acke li sted the potential uses of sympatholyti c drugs in the future. In addi tion to the reducing
effect of MAC and the absent respi ratory depression, the fol l owing properti es seem particul arl y
val uabl e to the anesthesi ol ogi st:
182
(1) They are potent anal gesics. (2) They are sedati ves and
anxi ol ytics. (3) They are anti sial ogogues. (4) They may promote hemodynami c stabil i ty. (5)
Homeostatic refl exes remain i ntact. (6) They attenuate opi oi d rigi di ty (i n ani mals). (7) Thei r
ci rculatory acti ons can be reversed. Cl onidi ne has al so been used successful l y as a substi tute for
opi ates and nicoti ne duri ng wi thdrawal. It reduces sympathetic hyperacti vi ty wi th head injury and
can be used as an anal gesic i n the subarachnoi d and epi dural spaces for the treatment of pain.

Converting Enzyme Inhibitors
The reni nangiotensi n system is i ntegral ly rel ated to the ANS i n control l ing bl ood pressure (see
Fi g. 12-16). The central rol e of the reni n-angiotensi n-al dosterone system i n the regulati on of flui d
bal ance and hemodynami cs was not ful l y appreci ated unti l the di scovery and cl i ni cal appli cati on of
inhi bitors of the ACE. Captopri l, enalapri l , and li sinopri l inhi bi t converting enzyme and thereby
prevent the conversion of angiotensin I to the active angiotensin II. These drugs have been hi ghl y
effecti ve i n the treatment of al l l evels of essential hypertension as wel l as renovascul ar and
mali gnant hypertensi on. The cardi ovascul ar effects normall y involve onl y decreased peri pheral
vascul ar resi stance. CO may remai n normal or increase whi l e the fi ll i ng pressure remai ns
unchanged. Thus, these drugs have been effective i n the management of congesti ve heart fai l ure
as wel l .
183
There is usuall y no increase i n SNS tone in response to the l owered bl ood pressure.
ACE i nhi biti on general l y results i n reducti ons i n angi otensi nal dosterone, NE, and pl asma
anti di ureti c hormone. Thi s suppression is accompani ed by a decrease in aldosterone and an
improvement in cumulative plasma potassi um l evels, whi ch are benefi ci al in both congestive heart
fai l ure and hypertensi on. It can be concl uded that the major humoral responses to chroni c
congesti ve heart fail ure, even overl ooki ng the effects of the di ureti cs, are affected by the rel ease
of angi otensi n, al dosterone, and i ncreased SNS tone.
Captopri l, the fi rst orall y active compound, has proven highly effective i n the treatment of all
level s of hypertension and congesti ve heart fail ure (Tabl e 12-26). Enal april i s a second-generati on
(nonsulfhydryl ) ACE inhi bi tor. The omi ssi on of the sulfhydryl group possi bl y di mi ni shes si de
effects. Both captopri l and enal apri l combi ne a hi gh degree of cl i ni cal efficacy wi th a l ow rate of
si de effects. Both are el iminated via renal excreti on and shoul d be gi ven i n reduced doses i n
patients with renal dysfuncti on. Captopril has a shorter hal f-li fe and requi res more frequent dosing
than enal april . Enalapril has to be converted by esterase in the l i ver and other ti ssues into the
acti ve compound enal april at. Many new ACE i nhibitors are bei ng devel oped that are el iminated vi a
hepati c routes and may prove advantageous i n renal fai lure. Lisi nopri l i s one of these ACE
inhi bitors that is absorbed as the active form and is very long- acting.
P.329
The ACE i nhibi tors are associ ated wi th few side effects and are i ncreasi ngl y popular in
treating hypertensi on. Captopril may produce reversi ble neutropeni a, dermati ti s, and
angioedema. Enal apri l produces syncope, headache, and di zzi ness i n about 1% of el derl y pati ents.
All ACE inhi bi tors may cause hypotensi on i n patients who are hypovolemic and taki ng di ureti c
therapy. Di uretic therapy shoul d be di scontinued 1 week before starti ng ACE inhi bi tor therapy. The
hypotensi ve effects are al so enhanced by the concomi tant use of cal ci um channel blockers. The
TABLE 12-26 The Angiotensin-Converting Enzyme (ACE)
AGENT MAJOR STUDIES CHARACTERISTICS
Captopri l Qual i ty of l i fe; SAVE; di abeti c
nephropathy; ISIS-IV (earl y Stage
AMI, trial negati ve)
The fi rst ACE i nhibi tor; overal l
the best studi ed
Enal april CONSENSUS; SOLVD (preventi on
and treatment arms); V-HeFT I
and II
Longer acti ng; the best-studi ed
in heart fail ure
Benazepril None Long plasma hal f-li fe (22 hr)
Cil azepri l None Long ti ssue hal f-li fe
Fosi nopril None Renal and hepati c eli mi nation
may all ow safer use in renal or
hepati c fail ure
Peri ndopri l None Long plasma hal f-li fe (35 hr),
less initi al hypotension
Quinapril QUIET (Qui napril Ischemi c Event
Tri al : postangiopl asty, end-poi nts
AMI, sudden death; ready 1995)
Potent bi ndi ng to ti ssue ACE
prolongs effective hal f-li fe
Rami pril AIRE (acute i nfarction rami pri l
effi cacy)
Long plasma hal f-li fe (>33 hr),
proven use in postinfarct CHF
Trandol apri l TRACE Study (Trandolapri l Cardi ac
Evaluati on Study) on hi gh-ri sk AMI
patients; ready 1995
Long plasma hal f-li fe (20 hr);
hi ghl y l i pid sol ubl e wi th potenti al
for tissue bi ndi ng
Li si nopri l GISSI-III: earl y-stage AMI,
mortal i ty reduced by 11%
Acti ve as is; water sol ubl e; long
acti ng
CHF, congesti ve heart fai l ure.
ACE i nhi bitors bl unt the hypokal emi c effects of thi azi de di ureti cs and may magni fy the potassi um-
spari ng effects of spi ronolactone, tri amterene, and ami l ori de. In additi on, nonsteroi dal anti -
infl ammatory drugs, i ncludi ng aspi rin, may magni fy the potassi um-retai ni ng effects of ACE
inhi bitors.
Vasodilators
The drugs that di rectl y relax smooth muscl e to cause vasodi l ation refl exi vel y i ncrease ANS tone
and are i ncl uded here for the sake of a compl ete discussion of anti hypertensive drugs.
59
These are
di scussed with emphasis on peri operati ve use.
Hydralazine. Hydral azi ne i s the most commonl y used vasodi l ator and can be gi ven by the i m, i v,
and oral routes. It rel axes smooth muscl e tone di rectl y, wi thout interacting wi th adrenergi c or
chol i nergi c receptors. The mechanism of action is unknown. It i s most potent in coronary,
spl anchni c, renal, and cerebral vessel s, causing i ncreased bl ood fl ow i n each of these organs. The
decrease i n cardi ac afterl oad i s benefi cial , but, unfortunately, there is usual l y a concomitant reflex
tachycardi a that may be severe. It is commonly combi ned wi th a bl ocker such as propranolol . It
may al so cause fl ui d retenti on and is usual l y gi ven chronicall y with a diureti c.
112
Hydral azi ne

i s metabol i zed by hepati c acetyl ation, and oral bi oavai l abi l ity may be l ow owi ng to first-pass
metaboli sm. The el iminati on hal f-li fe i s about 4 hours, but the pharmacol ogi c hal f-li fe i s much
longer as a resul t of avi d bindi ng of the drug to smooth muscl e. The effecti ve hal f-li fe i s
approxi mately 100 hours. Si de effects i ncl ude a l upus-li ke syndrome, drug fever, skin rash,
pancytopeni a, and peri pheral neuropathy. The i v dose we recommend for peri operati ve use i s 5 to
10 mg i n an i v bolus every 15 to 20 mi nutes unti l blood pressure control i s achi eved. It may al so
be given 10 to 40 mg i m, but the response is sl ower.
Sodium Nitroprusside. Sodi um ni troprussi de is an extremel y potent vasodi lator that is avail able
only for i v admini stration. It acts di rectly on smooth muscle, causi ng both arterial and venous
di l ati on.
59
The mechanism of acti on is not entirely clear but appears to i nvol ve bi ndi ng to
receptor on the surface of the myocyte, fol l owed by acti vati on of an i ntracel lular vasodi lator
intermedi ate. The action of sodi um ni troprussi de on both venous and arteri al si des of the
ci rculati on causes decreases in cardi ac preload as wel l as afterload. Thi s resul ts in decreased
cardi ac work; however, i t has been suggested that sodi um ni troprussi de may further compromi se
ischemi c myocardi um in the presence of occlusi ve coronary artery disease by shunting bl ood away
from the i schemic zone.
184

Sodi um ni troprussi de i s useful duri ng the peri operati ve period. It lowers bl ood pressure wi thi n 1
to 2 minutes, wi th the effect di ssi pati ng withi n 2 mi nutes after infusi on i s stopped. It i s extremel y
potent and shoul d be admini stered through a central venous l i ne by i nfusi on pump whi l e
conti nuousl y moni toring arteri al pressure. The starti ng dose is 0.25 to 0.5 g/kg/mi n. It can be
increased slowl y as needed to control bl ood pressure, but chances for toxi city are greater i f the
dose of 10 g/kg/mi n i s exceeded. The dose requi red for steady-stateinduced hypotension is
vari able.
Chemical l y, sodium ni troprusside consi sts of a ferrous i ron atom bound with fi ve cyani de
mol ecul es and one nitri c group. The ferrous iron reacts wi th sul fhydryl groups i n red bl ood cel l s
and rel eases cyani de. Cyani de i s reduced to thi ocyanate in the l i ver and excreted i n the uri ne. The
half-li fe of thi ocyanate i s 4 days, and i t accumul ates i n the presence of renal fai l ure. There is no
evidence, however, that preexi sti ng hepati c or renal fai l ure increases the l i kel ihood of cyani de
toxi ci ty. Admini stration of hi gh doses of sodi um ni troprussi de can resul t i n cyani de toxici ty. The
cyanide mol ecul e bi nds to cytochrome oxi dase, i nterferi ng with electron transport and causi ng
cel lul ar hypoxi a. Thi s can be recogni zed by i ncreasi ng tol erance to the drug, elevated mi xed
venous PaO
2
, and metabol i c aci dosis. The treatment of cyani de toxi city consi sts of (1)
administrati on of amyl ni trate (by inhalation or directl y i nto the anesthesi a circui t), (2) infusi on of
sodium ni tri te 5 mg/kg over 4 to 5 mi nutes, and (3) admi ni strati on of sodi um thi osulfate 150
mg/kg i n 50 mL water over 15 minutes.
The hypotensi ve effects of sodi um ni troprussi de may be potenti ated by i nhal ati on anesthetics and
P.330
bl ood loss; therefore, close peri operati ve moni toring i s essential . It is commonl y used to i nduce
hypotensi on for decreasi ng bl ood l oss i n pati ents predi sposed to major hemorrhage.
Admi ni strati on of sodi um ni troprussi de causes a reflex i ncrease i n sympatheti c tone and renin
rel ease.
185
Drugs that bl unt these refl exes markedly enhance i ts effects. Preoperati ve treatment
with propranol ol or captopril decreases the amount of sodi um ni troprussi de requi red for produci ng
hypotensi on and thus decreases the potential for toxi ci ty.
186

Glyceril Trinitrate. Glyceril tri nitrate, or nitrogl yceri n, is a venodi l ator used to treat myocardi al
ischemi a. Its predomi nant acti on i s on venul es, causi ng i ncreased venous capaci tance and
decreased cardiac prel oad. Effects on the arteri al si de are minimal except at very hi gh doses.
Upon i v admi ni strati on effects can be seen wi thi n 2 mi nutes, and they usuall y resol ve withi n 5
mi nutes of di sconti nui ng the drug. Si de effects are mi ni mal , and there is no potenti al for cyanide
toxi ci ty as wi th ni troprussi de. Use of ni trogl yceri n for control of peri operative hypertension has
been reported
187
but because of its rel ati vel y weak arteriol ar acti on, i t is not as useful as other
drugs as an anti hypertensi ve agent. In obstetri c pati ents wi th preecl ampsia, however, i t may be
chosen over ni troprussi de to ci rcumvent potential cyanide toxi ci ty to the fetus.
188

Diazoxide. Di azoxi de i s a direct-acti ng vasodi lator that may be gi ven i v and i s useful in
hypertensi ve emergenci es. It has a greater effect on resi stance than capaci tance vessels, thus
decreasing cardiac afterload wi th l ittle effect on prel oad. It al so causes fl ui d retenti on and i nduces
a refl ex sympathetic response.
112
The hypotensi ve effect i s potenti ated by di uretics,
sympathol ytics, and hypovol emi a. Diazoxi de i s usuall y administered as an i v bol us of 300 mg for a
70-kg adul t. It i s 90% bound to serum al bumi n; therefore, a substanti al porti on of the i ni tial bol us
may not reach the si te of action. Rapi d boluses (30 seconds) of 100 mg every 5 mi nutes are often
recommended as an al ternati ve to al l ow more free drug to reach the arteriol es.
112
The hypotensi ve
effect i s usual l y obtai ned i n 5 to 10 minutes and l asts 5 to 12 hours.
Calcium Entry Inhibitors
The calcium entry blockers verapami l , ni fedi pi ne, and ni trendi pi ne may al so be useful for treating
hypertensi on i n the peri operati ve period (see Adrenergic Antagoni sts: Calci um Channel Bl ockers
secti on).
Treatment of Postoperative Hypertension
The wi de variety of anti hypertensive agents di scussed previ ousl y makes the treatment of
hypertensi on i n the recovery room easi er because we can now choose from among multi ple routes
of administration and vari abl e onsets and durati ons of action of the di fferent agents.
189
However,
treatment may become confusing unl ess the basic pharmacol ogy of each drug i s understood. Those
drugs avai labl e for onl y oral admi ni strati on are not routi nel y used because of unrel i abl e
gastrointesti nal function during thi s peri od. The etiol ogy of postoperati ve hypertensi on in each
case should be consi dered. A determi nati on should be made i f thi s requi res emergency therapy or
i s just urgent. Pai n shoul d be eli mi nated by assurance of adequate anal gesia pri or to therapy with
anti hypertensive agents. Al so, because of the compl ex pathophysi ology of hypertensi on, a
thorough knowl edge of each patient and hi s or her conditi on i s mandatory in choosi ng a treatment
regi men. The medi cati ons requi red for preoperati ve control may provide the most i nformati on i n
determi ni ng what wi ll be necessary postoperati vel y. In parti cul ar, the use of drugs that may have
an associ ated wi thdrawal syndrome such as cl onidi ne or -bl ockers shoul d be noted as well as i f
they were wi thhel d pri or to surgery. The vol ume status of the pati ent i s al so i mportant. Fl ui d
overload may requi re diureti c therapy. Vol ume depl etion or hemorrhage may predi spose to severe
hypotensi on i n response to routi ne doses of sympathol yti cs or vasodi l ators.
For severe el evati ons of bl ood pressure that requi re i mmediate treatment, sodi um ni troprussi de is
the drug of choice. Intravenous ni cardipi ne can be gi ven and effecti ve before a sodi um
ni troprusside i nfusi on can be prepared. Labetal ol , metoprol ol , and esmol ol may also be used
intravenously. Esmolol has the advantage of bei ng rapi dl y ti tratabl e.
190
-methyl dopa may be used
intravenously but takes much l onger to work than cloni di ne. Cloni di ne can be gi ven per rectum
and begi ns to act i n 10 to 20 minutes.
181
If conditi ons permi t, i t is helpful to use the drugs the
patient was taki ng preoperati vel y to ease the transi ti on i n the postoperati ve peri od. Cauti on must
be exerci sed i f the hypertension is the resul t of excessi ve

exogenous catechol amines, pheochromocytoma, or thyrotoxi cosis. -bl ockade should be started
before -bl ockade. The hypertensi on may, i n fact, worsen i f receptors are bl ocked fi rst, l eavi ng
the receptors unopposed.
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Nonopi oi d Intravenous Anesthesi a
Chapter 13
Nonopioid Intravenous Anesthesia
Paul F. White
Gladys Romero
KEY POINTS
The concept of i ntravenous (IV) anesthesi a has evol ved from pri mari l y i nducti on of anesthesia to
total IV anesthesi a (TIVA). TIVA has assumed increasi ng importance for therapeuti c, as wel l as
Wi th the excepti on of ketamine, i ntravenous (IV) anestheti cs l ack anal gesic
properties.
Dexmedetomidi ne i s an -2 agoni st with sedative and opi oi d-spari ng effects.
Low doses of IV anestheti cs produce sedati on, whi l e hi gh doses produce
hypnosi s (or unconsci ousness).
All nonopi oi d IV anesthetics produce dose-dependent central nervous system
(CNS) depressi on.
Compared to thi opental and propofol , methohexital produces less CNS
depressi on.
Propofol possesses unique antiemeti c and appeti te-sti mul ati ng properties.
Etomi date produces less cardiovascul ar depressi on than the barbi turates and
propofol .
Ketamine possesses anal gesic and psychomimeti c properti es.
Mi dazolam possesses amnesti c and anxi ol yti c properti es.
IV anesthetics i n combi nati on with potent opioi d anal gesics and/or l ocal
anesthetics can be used to produce total intravenous anesthesi a (TIVA).
di agnosti c, procedures in both adul ts and chil dren. This change has been a resul t of the
devel opment of rapi d, short-acti ng IV hypnoti c, analgesic, and muscl e rel axant drugs; the
avai labi li ty of pharmacoki neti c and dynami c-based IV del i very systems; and the development of
the electroencephal ogram (EEG) base cerebral monitor, whi ch measures the hypnotic component
of the anestheti c state. This chapter focuses on the pharmacol ogi c properti es and cl i ni cal uses of
the currentl y avail able nonopi oi d IV anestheti cs.
Foll owi ng i ts introducti on i nto cl i ni cal practice, thi opental qui ckl y became the gold standard of IV
anesthetics agai nst which al l the newer IV drugs were compared. Many di fferent hypnoti c drugs
are currentl y avail able for use during IV anesthesi a (Fi g. 13-1). However, the ideal IV anesthetic
has not yet been devel oped. The physi cal and pharmacol ogic properti es that an i deal IV anesthetic
would possess i ncl ude the foll owing:
1. Drug compatibi l ity and stabi li ty i n soluti on.
2. Lack of pai n on injecti on, venoi rri tation, or l ocal ti ssue damage from extravasation.
3. Low potential to rel ease hi stami ne or preci pitate hypersensiti vi ty reacti ons.
4. Rapi d and smooth onset of hypnotic acti on wi thout exci tatory activity.
5. Rapi d metabol i sm to pharmacol ogi cal l y i nacti ve metabol i tes.
6. A steep dose-response rel ationship to enhance ti tratabi li ty and mi ni mi ze accumul ation.
7. Lack of acute cardiovascular and respi ratory depressi on.
8. Decreases in cerebral metabol i sm and i ntracrani al pressure.
9. Rapi d and smooth return of consciousness and cogni ti ve ski l ls wi th resi dual anal gesia.
10. Absence of postoperati ve nausea and vomi ti ng, amnesi a, psychomi meti c reacti ons, di zzi ness,
headache, or prol onged sedati on (hangover).
Despi te thiopental ' s proven cli ni cal useful ness, safety, and wi despread acceptance over many
decades, it i s not the i deal IV anestheti c. The sedativehypnoti c drugs that have been more
recently introduced i nto cl i ni cal practi ce (e.g., mi dazol am, ketami ne, etomi date, propofol) have
proven to be extremel y val uabl e i n specific cl inical si tuati ons. These newer compounds combi ne
many of the characteri sti cs of the i deal IV anestheti c but fai l i n aspects where the other drugs
succeed. For some of these IV sedativehypnoti cs, disadvantages have l ed to restricted
indicati ons (e.g., ketamine, etomidate) or wi thdrawal

from cl i ni cal use (e.g., Al thesin, propani did, el tanol one). Because the opti mal pharmacologi c
properties are not equall y important i n every cli ni cal si tuati on, the anesthesiologi st must make the
choi ce that best fi ts the needs of the i ndivi dual pati ent and the operati ve procedure.
GENERAL PHARMACOLOGY OF INTRAVENOUS HYPNOTICS
Mechani sm of Act i on
A wi dely accepted theory of anestheti c acti on i s that both IV and i nhal ati onal anestheti cs exert
thei r pri mary sedati ve and hypnoti c effects through an i nteracti on with the i nhibi tory -
aminobutyri c aci d (GABA) neurotransmi tter system.
1
GABA i s the pri nci pal i nhi bi tory
neurotransmitter withi n the CNS. The GABA and adrenergic neurotransmi tter systems
counterbal ance the acti on of exci tatory neurotransmi tters. The GABA type A (GABA
A
) receptor i s a
receptor compl ex consi sti ng of up to five gl ycoprotei n subuni ts. When the GABA
A
receptor is
acti vated, transmembrane chl ori de conductance increases, resulti ng i n hyperpol ari zation of the
postsynapti c cel l membrane and functi onal i nhibiti on of the postsynapti c neuron. Sedati ve
hypnoti c drugs i nteract wi th di fferent components of the GABA-receptor compl ex (Fi g. 13-2).
However, the al l osteri c (structural ) requi rements for acti vation of the receptor are di fferent for IV
and volatil e anestheti cs.
2

FIGURE 13-1. Chemical structures of currentl y avail able nonopi oi d IV anestheti cs.
P.335
Benzodi azepines bi nd to specifi c receptor sites that are part of the GABA
A
-receptor compl ex. The
bi ndi ng of benzodi azepi nes to thei r receptor si te i ncreases the effici ency of the coupl i ng between
the GABA receptor and the chl ori de i on channel . The degree of modul ati on of the GABA-receptor
functi on i s li mi ted, which explai ns the cei li ng effect produced by benzodi azepi nes with respect to
CNS depressi on. The CNS properti es of benzodi azepi nes (e.g., hypnosi s, sedati on, anxiol ysi s, and
anti convul sant effects) are presumed to be associ ated wi th stimul ati on of di fferent receptor
subtypes and/or concentrati on-dependent receptor occupancy. It has been suggested that a
benzodiazepi ne receptor occupancy of 20% provi des anxi olysi s, whi l e 30 to 50% receptor
occupancy i s associ ated wi th sedati on, and 60% receptor occupancy i s requi red for hypnosi s (or
unconsci ousness).
The i nteracti on of barbi turates and propofol with speci fic membrane structures appears to
decrease the rate of di ssoci ati on of GABA from i ts receptor, thereby increasi ng the durati on of the
FIGURE 13-2. A. Thi s model depi cts the postsynapti c site of GABA and gl utamate wi thi n the
CNS. GABA decreases the exci tabil i ty of neurons by i ts acti on at the GABA
A
-receptor compl ex.
When GABA occupi es the bi ndi ng si te of this compl ex, i t al l ows inward fl ux of chlori de i on,
resul ti ng in hyperpolarizing of the cel l and subsequent resi stance of the neuron to stimul ati on
by exci tatory transmi tters. Barbi turates, benzodiazepi nes, propofol, and etomi date decrease
neuronal exci tabi l ity by enhanci ng the effect of GABA at thi s compl ex, faci l itati ng this
inhi bitory effect on the postsynaptic cell . Glutamate and i ts anal og N-methyl -D-aspartate
(NMDA) are exci tatory ami no aci ds. When glutamate occupi es the bi ndi ng si te on the NMDA
subtype of the gl utamate receptor, the channel opens and al l ows Na
+
, K
+
, and Ca
2+
to ei ther
enter or l eave the cel l. Fl ux of these ions l eads to depol ari zati on of the postsynapti c neuron
and ini ti ati on of an acti on potential and acti vati on of other pathways. Ketamine bl ocks thi s
open channel and prevents further i on fl ux, thus inhi bi ti ng the excitatory response to
gl utamate. (Reprinted with permission from Van Hemel rijck J, Gonzales JM, Whi te PF: Use of
intravenous sedative agents. In Rogers MC, Ti nker JH, Covino BG, Longnecker DE (eds):
Pri nci pl es and Practice of Anesthesi ol ogy, p 1131. St. Loui s, Mosby, 1992.) B. Schemati c
model of the GABA
A
-receptor compl ex i l lustrating recogni tion si tes for many of the
substances that bi nd to the receptor. C. Model of the NMDA receptor showi ng si tes for
antagonist acti on. Ketami ne bi nds to the site l abel ed PCP (phencycl i dine). The pentameric
structure of the receptor, composed of a combi nation of the subuni ts NR 1 and NR 2, is
il l ustrated. (Al tered with permi ssi on from Leeson TD, Iversen LL. The gl ycine site on the
NMDA receptor: Structure-acti vi ty relationshi ps and therapeuti c potenti al . J Med Chem
37:4054, 1994.)
GABA-acti vated opening of the chl oride i on channel (Fi g. 13-2). Barbi turates can al so mi mi c the
acti on of GABA by directl y acti vati ng the chl oride channel s. The proposed mechanism of action of
thiopental relates to i ts abil i ty to functi on as a competiti ve i nhibi tor at the ni coti c acetytchol ine
receptors (AChRs) i n the CNS.
3
Etomidate augments GABA-gated chl oride currents (i .e., i ndi rect
modul ati on) and at hi gher concentrations evokes chl oride currents in the absence of GABA (i .e.,
di rect acti vati on). Al though the mechani sm of acti on of propofol is si mi lar to that of the
barbi turates (i .e., enhanci ng the activity of the GABA-acti vated chl oride channel ), it al so
possesses i on channel bl ocking effects in cerebral cortex ti ssue and ni coti nic acetyl chol i ne
receptors, as wel l as an i nhi bitory effect on lysophosphati date si gnal i ng i n l i pi d medi ator
receptors.
4

Ketamine produces a functi onal di ssociation between the thalamocorti cal and li mbi c systems,
a state that has been termed di ssociative anesthesia. Ketami ne depresses neuronal functi on
in the cerebral cortex and thalamus, whil e simul taneousl y acti vating the l i mbi c system. Ketamine' s
effect on the medial medullary reti cul ar formati on may be involved i n the affecti ve component of
its noci cepti ve acti vi ty. The CNS effects of ketami ne appear to be primari ly rel ated to i ts
antagonistic

acti vi ty at the N-methyl -D-aspartate (NMDA) receptor (Fi g. 13-2). Unl i ke the other IV anesthetics,
ketami ne does not i nteract with GABA receptors; however, i t bi nds to non-NMDA glutamate
receptors and ni coti nic, muscari ni c, monoami nergic, and opi oi d receptors. In addi ti on, i t al so
inhi bits neuronal sodi um channel s (producing a modest l ocal anestheti c acti on) and cal ci um
channel s (causing cerebral vasodi l atati on).
The central ly active -2 adrenergic receptor agoni st, dexmedetomidi ne, has potent sedati ve
and anal gesi c-spari ng properties. The drug al so has effects on the perioperal -2 receptors
invol ved in regul ating the cardiovascular system by i nhibi ting norepinephrine rel ease. This cl ass of
anesthetic drugs can also reduce the tonic l evel s of sympatheti c outflow from the CNS and
augment cardi ac vagal activity.
5, 6

P har macoki net i cs and Met abol i sm
An understandi ng of basic pharmacoki neti c pri nci ples i s integral to the understanding the
pharmacol ogic acti ons and i nteracti ons of IV anestheti c and adjuncti ve drugs and wil l all ow the
anesthesi ol ogi st to devel op more opti mal dosi ng strategi es when usi ng IV techniques. Although
li pi d sol ubi l ity faci l itates di ffusi on of IV anesthetics across cel l ul ar membranes i ncl udi ng the
bl oodbrain barrier, onl y the nonionized form i s abl e to readi l y cross neuronal membranes. The
rati o of the un-ioni zed-to-ioni zed fracti on depends on the pKa of the drug and the pH of the body
flui ds.
The rapi d onset of the CNS effect of most IV anestheti cs can be expl ai ned by thei r hi gh l i pi d
solubi li ty and the rel ati vel y high proportion of the cardiac output (20%) perfusi ng the brai n.
However, a vari abl e degree of hysteresis exists between the bl ood concentrati on of the hypnotic
drug and its onset of action on the CNS. The hysteresis i s rel ated i n part to diffusion of these
drugs i nto brai n ti ssue and nonspecific CNS receptor bi ndi ng. However, the number of CNS bi ndi ng
si tes i s usual ly saturable and only a smal l fracti on of the avai l abl e bi ndi ng si tes needs to be
occupi ed to produce cl i ni cal effects. Al though the total amount of drug i n the bl ood i s avai l abl e for
di ffusion, the diffusi on rate wi l l be more l i mi ted for IV anestheti cs wi th

a hi gh degree of pl asma protein bi ndi ng (90%) because onl y the free unbound drug can di ffuse
across membranes and exert central effects. When several drugs compete for the same bi ndi ng
si tes, or when the protei n concentrati on i n the bl ood i s decreased by preexi sti ng di sease (e.g.,
hepati c fail ure), a hi gher fraction of the unbound drug wi l l be available to exert an effect on the
CNS. Si nce onl y unbound drug i s avai labl e for uptake and metabol i sm i n the l i ver, hi ghl y protei n-
bound drugs may have a l ower rate of hepati c metabol i sm as a resul t of thei r decreased hepati c
extraction rati o (i .e., the fracti on of the hepati c bl ood fl ow that is cleared of the drug).
The pharmacoki neti cs of IV hypnotics are characteri zed by rapi d di stri buti on and subsequent
P.336
P.337
redi stri buti on i nto several hypotheti cal compartments, fol l owed by el i mi nati on (Tabl e 13-1). The
initi al pharmacol ogi c effects are rel ated to the activity of the drug i n the central compartment.
The primary mechani sm for termi nati ng the central effects of IV anestheti cs admi ni stered for
inducti on of anesthesia i s redi stribution from the central highly perfused compartment (brai n) to
the larger but less wel l perfused peri pheral compartments (muscl e, fat). Even for drugs with a
hi gh hepati c extracti on rati o, el i mi nation does not usual ly pl ay a major rol e i n termi nating the
drug' s CNS effects because el i mi nati on of the drug can onl y occur from the central compartment.
The rate of el iminati on from the central compartment, the amount of drug present i n the
peri pheral compartments, and the rate of redi stributi on from the peri pheral compartments back
into the central compartment determi ne the ti me necessary to eli minate the drug from the body.
Most IV anesthetic agents are el imi nated via hepatic metabol i sm foll owed by renal excretion of
more water-solubl e metaboli tes. Some metabol ites have pharmacol ogi c acti vi ty and can produce
prol onged drug effects (e.g., oxazepam, desmethyl di azepam, norketami ne). Moreover, there i s
consi derable interpati ent variabil i ty i n the cl earance rates for commonl y used IV anestheti c drugs.
The el iminati on clearance i s the distributi on vol ume cleared of drug over ti me and i s a measure of
the effi cacy of the el i mi nation process. The sl ow eli mi nation of some anestheti cs i s due i n part to
thei r hi gh degree of protei n bi ndi ng that reduces thei r hepati c extracti on ratio. Other drugs may
have a hi gh hepati c extracti on rati o and eli mi nation cl earance despite extensi ve pl asma protei n
bi ndi ng (e.g., propofol ), i ndi cati ng that protei n bi ndi ng i s not al ways a rate limiting factor.
For most drugs, the hepati c enzyme systems are not saturated at cl i ni cal l y relevant drug
concentrations, and the rate of drug el iminati on wi l l decrease as an exponenti al functi on of the
drug' s pl asma concentration (first-order kineti cs). However, when hi gh steady-state pl asma
TABLE 13-1 Pharmacokinetic Values for the Currently Available Intravenous SedativeHypnotic
Drugs
DRUG NAME DISTRIBUTION
HALF-LIFE
(min)
PROTEIN
BINDING
(%)
DISTRIBUTION
VOLUME AT
STEADY STATE
(L/kg)
CLEARANCE
(mL/kg/min)
ELIMINATION
HALF-LIFE (h)
Thi opental 24 85 2.5 3.4 11
Methohexital 56 85 2.2 11 4
Propofol 24 98 210 2030 423
Mi dazolam 715 94 1.11.7 6.411 1.72.6
Diazepam 1015 98 0.71.7 0.20.5 2050
Lorazepam 310 98 0.81.3 0.81.8 1122
Etomi date 24 75 2.54.5 1825 2.95.3
Ketamine 1116 12 2.53.5 1217 24
concentrations are achieved wi th prol onged i nfusi ons, hepatic enzyme systems can become
saturated and the el i mi nati on rate becomes i ndependent of the drug concentration (zero-order
kineti cs). The el iminati on hal f-li fe (t
1/2
) is the time required for the anestheti c concentration to
decrease by 50% duri ng the termi nal phase of the pl asma decay curve. The t
1/2
i s dependent on
the vol ume to be cl eared (the distri buti on vol ume) and the effi ci ency of the metabol ic cl earance
system. Because thei r volumes of di stri buti on are si mi l ar, the wide vari ati on i n el i mi nation half-
li fe val ues for the IV anestheti cs i s a reflecti on of di fferences i n their clearance val ues.
When a drug i nfusi on i s administered without a l oadi ng dose, 3 to 5 ti mes the t
1/2
value may be
requi red to reach a steady-state pl asma concentrati on. The steady-state concentrati on obtai ned
duri ng an anestheti c infusi on depends on the rate of drug admi ni stration and i ts cl earance rate.
When an infusion is discontinued, the rate at which the pl asma concentrati on decreases i s l argel y
dependent on the cl earance rate (as refl ected by the termi nal eli mi nation half-li fe val ue). For
drugs with shorter el imi nati on hal f-li ves, pl asma concentrati on wil l decrease at a rate that al lows
for a more rapi d recovery (e.g., propofol ). Drugs wi th l ong el iminati on hal f-li fe val ues (e.g.,
thiopental and diazepam) are usual l y onl y admini stered by conti nuous IV infusi on when the
medical condi tion requi res long-term treatment (e.g., el evated intracrani al pressure [ICP] as a
resul t of brai n i njury or prol onged sedati on i n the ICU because of respi ratory fai lure).
Careful ti trati on of an anesthetic drug to achieve the desired cli ni cal effect i s necessary to
avoi d drug accumul ati on and the resul tant prolonged CNS effects after the infusi on has been
di sconti nued. Al though the val ue of the termi nal hal f-li fe i ndi cates how fast a drug i s eli mi nated
from the body, a more useful i ndicator of the acceptabil i ty of a hypnoti c i nfusi on for mai ntenance
of anesthesi a or sedation i s the context-sensi ti ve half-ti me, a val ue deri ved from computer
si mulations of drug infusi ons.
7
The context-sensi ti ve half-ti me i s defi ned as the time necessary for
the effect-compartment (i.e., effect si te) concentrati on to decrease by 50% i n rel ati on to the
duration of the i nfusi on. The context-sensi ti ve half-ti me becomes parti cul arl y i mportant i n
determi ni ng recovery after prol onged infusi ons of sedativehypnoti c drugs. Drugs (e.g., propofol )
may have a rel atively short context-sensi ti ve half-ti me despi te the fact that a large amount of
drug remai ns present in the deep (less wel l perfused) compartment. The slow return of the
anesthetic from the deep compartment contributes l i ttl e to the concentrati on of drug in the central
compartment from whi ch i t i s rapidl y cl eared. Therefore, the concentrati on in the central
compartment rapi dl y decl i nes below the hypnoti c threshold after disconti nuati on of the i nfusi on,
contri buti ng to short emergence times despi te the fact that a substanti al quanti ty of anestheti c
drug may remain in the body.

Marked i nterpati ent variabi li ty exi sts i n the pharmacoki netics of IV sedativehypnoti c drugs.
Factors that can infl uence anesthetic drug disposi tion incl ude the degree of protei n bi ndi ng, the
effi ci ency of hepati c and renal el imi nati on processes, physi ologi c changes wi th agi ng, preexi sti ng
di sease states, the operative si te, body temperature, and drug i nteracti ons (e.g., coadmi ni strati on
of vol ati l e anestheti cs). For exampl e, i ncreased age, lean body (muscle) mass and total body
water decrease, results i n an increase i n the steady-state vol ume of distri buti on of most IV
anesthetics. The increased distri buti on vol ume and decreased hepatic cl earance leads to a
prolongation of their t
1/2
val ues. Moreover, a decrease of the vol ume of the central compartment
may result i n hi gher i ni ti al drug concentrati ons and can at l east partial ly expl ai n the decreased
inducti on requi rement i n the el derl y. Addi ti onal l y, the sl ower redi stri buti on from the vessel -ri ch
ti ssues to intermedi ate compartments (muscl es) also contributes to the age-rel ated decrease in
the induction dose requirements.
7
Al though prol ongation of the el iminati on hal f-ti me does not
provi de an expl anati on for the decreased i nducti on dose requi rement, i t i s responsi bl e for
produci ng hi gher steady-state pl asma concentrations at any given infusion rate.
The hepatic cl earance of IV anesthetics wi th a hi gh (e.g., etomi date, propofol , ketamine) or
intermedi ate (e.g., methohexital, mi dazol am) extracti on ratio i s l argely dependent on hepati c
bl ood flow, wi th most of the drug bei ng removed from the bl ood as i t flows through the li ver (so-
call ed perfusion-li mi ted cl earance). The el i mi nati on rate of drugs wi th l ow hepatic extracti on ratios
(e.g., thi opental , di azepam, l orazepam) i s dependent on the enzymati c acti vi ty of the l iver and is
l ess dependent of hepatic bl ood flow (so-call ed capaci ty-li mi ted cl earance). Hepatic blood flow
P.338
decreases duri ng upper abdomi nal surgery and, as a resul t, hi gher bl ood l evel s of drugs wi th
perfusi on-li mi ted cl earance are achi eved at any given infusion rate. Wi th agi ng, a decreased
cardi ac output and a redi stributi on of bl ood flow can partl y explai n the l ower cl earance rate for
drugs with perfusi on-li mi ted cl earance. Whi l e concomi tant admi nistrati on of vol ati le anestheti cs
(whi ch are known to decrease li ver bl ood fl ow) has l ittl e i nfluence on the el i mi nati on of thiopental ,
they can decrease the cl earance of etomi date, ketami ne, methohexi tal , and propofol. Other factors
that decrease hepati c blood fl ow include hypocapnia, congesti ve heart fai lure, intravascul ar
vol ume depl eti on, circul atory col lapse, -adrenergi c bl ockade, and norepi nephri ne admi ni strati on.
Hepati c di sease can i nfl uence the pharmacoki netics of drugs by: (1) al teri ng the pl asma protei n
content and changi ng the degree of protei n bi ndi ng, (2) decreasi ng hepati c bl ood fl ow and
producing i ntrahepatic shunting, and (3) depressi ng the metabol ic enzymati c activi ty of the li ver.
Therefore, the infl uence of hepati c disease on pharmacokineti cs and dynamics of IV anestheti cs is
di fficul t to predi ct. Renal di sease can al so al ter the concentrati on of plasma and ti ssue protei ns,
as wel l as the degree of protein bi ndi ng, thereby produci ng changes i n free drug concentrations.
Because IV anestheti c agents are pri maril y metaboli zed by the l i ver, renal i nsuffici ency has l i ttl e
infl uence on their rate of metabol i c inactivati on or el imi nati on of the pri mary compound.
P har macodynami c Ef f ect s
The pri nci pal pharmacol ogi c effect of IV anestheti cs i s to produce progressi vel y increasi ng
sedati on and ul ti matel y hypnosi s as a resul t of dose-dependent CNS depressi on. However, al l
sedati vehypnoti cs also di rectl y or i ndi rectl y affect other major organ systems. The relationshi p
between the dose of a sedati vehypnoti c and its CNS effects can be defi ned by dose-response
curves. Al though most IV anesthetics are characteri zed by steep dose-response curves, they are
not al ways parall el (Fi g. 13-3). The characteristics of a dose-response curve can only be
interpreted i n relation to the speci fi c response for whi ch i t was constructed.
FIGURE 13-3. Dose-response rel ati onships for sedation with mi dazol am () and di azepam
(). The l evel of sedation (2 = awake and alert to 6 = asl eep and unarousabl e) was assessed
5 mi nutes after bol us doses of mi dazolam (0.05, 0.1, or 0.15 mg/kg) or di azepam (0.1, 0.2,
or 0.3 mg/kg). Val ues represent mean val ues SEM. (Repri nted wi th permi ssi on from Whi te
When steady-state pl asma concentrations are achi eved, i t can be presumed that the plasma
concentration is i n quasi -equil i bri um wi th the effect-si te concentration. Under these
ci rcumstances, i t i s possi ble to describe the rel ati onshi p between drug and effect usi ng a
concentration-effect curve (Fi g. 13-4). Because of the pharmacodynami c vari abil i ty that exists
among i ndi vi dual s, the pl asma drug concentrati on necessary to obtai n a parti cul ar effect i s often
descri bed i n terms of an effective concentrati on range, the so-call ed therapeuti c wi ndow. Effi cacy
of an IV anesthetic relates to the maximum effect that can be achieved wi th respect to some
measure of CNS functi on. Depending on the drug effect under consi deration, the effi cacy of
sedativehypnotics may appear to be l ess than 100%. For exampl e, i t i s vi rtual l y impossibl e to
produce a burst-suppressi ve EEG pattern wi th a benzodi azepi ne. Potency, on the other hand,
rel ates to the quanti ty of drug necessary to obtain the maximum CNS effect. The relative potency
of sedati vehypnoti cs also vari es dependi ng on the end poi nt chosen. In the presence of an
antagonist drug (e.g., flumazenil), the maxi mal response that can be obtai ned wi th a
benzodi azepi ne agoni st i s further reduced because of competiti on for the same CNS receptor
bi nding sites.
PF, Vascones LO, Mathes SA, et al : Compari son of mi dazol am and diazepam for sedati on
duri ng pl asti c surgery. J Pl ast Reconstruct Surg 81:703, 1988.)
FIGURE 13-4. The concentrati on of thi opental versus ti me and spectral edge i n an el derl y
patient (top) and in a younger patient (bottom). Sol id hori zontal bars represent the l ength
of thi opental infusi on. Fi ll ed circles represent the measured thi opental concentrati on (l i near
scal e), and the soli d l i ne next to them represents the fitted data from the pharmacokinetic
model . The axi s for spectral edge has been i nverted for vi sual clarity. (Repri nted with
permi ssi on from Homer TD, Stanski DR: The effect of i ncreasing age on thi opental disposi tion
The i nfl uence of sedativehypnoti cs on cerebral metabol i sm, cerebral hemodynami cs, and ICP i s of
parti cul ar i mportance duri ng neuroanesthesi a. In pati ents wi th reduced cerebral compl i ance, a
smal l i ncrease in cerebral bl ood vol ume can cause a l i fe-threatening i ncrease in ICP. Most
sedati vehypnoti c drugs cause a proporti onal reducti on i n cerebral metabol i sm (CMRO
2
) and
cerebral bl ood fl ow (CBF), resul ti ng i n a decrease i n ICP. Although a decrease in CMRO
2
probabl y
provi des onl y a modest degree of protecti on agai nst

CNS ischemia or hypoxia, some hypnoti cs appear to possess cerebroprotecti ve potential .
Expl anati ons for the al l eged neuroprotective effects of these compounds i ncl ude a bi ochemical role
as free-radical scavengers and membrane stabi li zers (barbiturates and propofol) or NMDA-receptor
antagonists (ketami ne). Wi th the exception of ketami ne, al l sedativehypnoti cs also l ower
intraocul ar pressure (IOP). The changes i n IOP general ly reflect the effects of the IV agent on
systemi c arteri al pressure and intracrani al hemodynami cs. However, none of the avai labl e
sedati vehypnoti c drugs protect agai nst the transi ent increase i n IOP that occurs wi th
laryngoscopy and i ntubati on.
Most IV hypnoti cs have si mi l ar EEG effects. Activati on of hi gh-frequency EEG acti vi ty (15 to 30
Hz) i s characteri sti c of l ow concentrati ons (so-call ed sedati ve doses) of IV anestheti cs. At hi gher
concentrations, an increase i n the rel ati ve contri buti on of the l ower frequency hi gher ampl itude
waves i s observed. At high concentrati ons, a burst-suppressi ve pattern develops wi th an increase
in the i soel ectri c peri ods. Most sedativehypnoti c drugs have been reported to cause occasional
EEG sei zure-li ke activity. Interesti ngl y, the same drugs al so possess anti convul sant properti es.
8

When consideri ng possi ble epil eptogeni c properti es of CNS-depressant drugs, i t is i mportant to
di fferenti ate between true epi leptogenic activi ty (e.g., methohexital) and myocloni c-li ke
phenomena (e.g., etomi date). Myocl oni c acti vi ty i s general l y consi dered to be the result of an
imbal ance between exci tatory and i nhi bitory subcorti cal centers, produced by an unequal degree
of suppressi on of these brai n centers by l ow concentrati ons of hypnoti c drugs. Epi l epti c activity
refers to a sudden al terati on i n CNS sei zure-li ke acti vi ty resulti ng from a high vol tage electri cal
di scharge at either corti cal or subcorti cal si tes, wi th subsequent spreadi ng to the thal ami c and
brainstem centers. As a resul t of its vasoconstri cti ve effects on the cerebral vascul ature, propofol
may be useful for treatment of intractable mi graine headaches.
9

Although some i nduction drugs can increase airway sensi ti vi ty, coughi ng and ai rway i rritati on
(e.g., bronchospasm) are usual l y a result of mani pul ati on of the ai rway during li ght level s of
anesthesia rather than to a direct drug effect. Wi th the excepti on of ketami ne (and to a l esser
extent etomi date), IV anestheti cs produce dose-dependent respi ratory depression, whi ch is
enhanced i n patients with chroni c obstructi ve pulmonary di sease. The respi ratory depression is
characteri zed by a decrease i n ti dal vol ume and minute venti lation, as wel l as a transi ent
ri ghtward shi ft i n the CO
2
response curve. Fol l owi ng the rapi d i njecti on of a l arge bol us dose of an
IV anestheti c, transient apnea l asti ng 30 to 90 seconds i s usuall y produced. Ketamine causes
mi ni mal respiratory depression when admini stered i n the usual induction doses, whi l e etomi date i s
associated wi th l ess respi ratory depressant effects than the barbi turate compounds or propofol.
Prel iminary experi ence has demonstrated that dexmedetomidi ne has mi ni mal depressant effects on
respiratory functi on.
10

Many di fferent factors contri bute to the hemodynamic changes associ ated wi th IV i nducti on of
anesthesia, i ncl udi ng the pati ent' s preexi sti ng cardiovascular and fl ui d status, resti ng sympatheti c
nervous system tone, chroni c cardi ovascular drugs, preanestheti c medi cati on, the speed of drug
injecti on, and the onset of unconsci ousness. In addi tion, cardiovascul ar changes can be attri buted
to the di rect pharmacol ogi c acti ons of anestheti c and anal gesic drugs on the heart and peri pheral
vascul ature. Intravenous anestheti cs can depress the CNS and peri pheral nervous system
responses, bl unt the compensatory baroreceptor reflex mechani sms, produce di rect myocardi al
and anestheti c requi rement. Anesthesi ol ogy 62:714, 1985.)
P.339
depressi on, and l ower peri pheral vascul ar resi stance (and/or dil ate venous capaci tance vessel s),
thereby decreasing venous return. Profound hemodynamic effects occur at i nduction in the
presence of hypovol emi a because a hi gher than expected drug concentration i s achi eved in the
central compartment. Not surpri si ngl y, the acute cardi oci rculatory depressant effects of al l IV
anesthetics are accentuated i n the el derly, as well as in the presence of preexi sti ng cardiovascul ar
di sease (e.g., hypertensi on).
The sympatholyti c effects of dexmedetomi di ne may be useful for produci ng control l ed
hypotensi on.
10
The effects of IV anestheti cs on neuroendocrine function are also influenced by the
surgi cal sti muli . Al though IV anestheti cs are al l eged to i ncrease anti di ureti c hormone
(vasopressi n) secreti on, i t i s probabl y secondary to the surgical stress. Increases i n this stress
hormone can resul t in i ncreased peri pheral vascul ar resi stance and a reducti on of uri ne output.
Simil arl y, glucose tol erance appears to be decreased by surgi cal stress, resulti ng i n elevations i n
the glucose concentrati on. Most IV sedativehypnoti c drugs l ack i ntri nsi c anal gesic activity. In
fact, thi opental has been al leged to possess so-call ed anti analgesi c activity (i .e., appearing to
lower the pain threshol d). In contrast to the other drugs in thi s cl ass, ketami ne, and
dexmedetomi di ne, appears to possess analgesi c-li ke acti vi ty.
Hyper sensi ti vi t y ( Al l er gi c) React i ons
All ergi c reacti ons to IV anesthetics are rare but can be severe and even l i fe threateni ng.
Intravenous drug admi ni strati on bypasses the normal protecti ve barri ers against entrance of
foreign mol ecules i nto the body. Wi th the excepti on of etomi date, all IV i nducti on agents have
been all eged to cause some hi stami ne release. However, the i nci dence of severe anaphylacti c

reacti ons i s extremely l ow wi th the currentl y avail able IV i nducti on agents. The hi gh frequency of
al lergi c reacti ons to the cremophor ELcontai ning formul ati ons led to the earl y wi thdrawal of
several IV anesthetics containi ng thi s sol ubi l izing agent (e.g., propofol EL, propani did, Althesi n).
The possi ble mechani sms for i mmunol ogi c reacti ons include: (1) di rect acti on on mast cell s, (2)
cl assi c compl ement activati on after previous exposure and anti body formation, (3) complement
acti vation through the alternati ve pathway without previ ous anti gen exposure, (4) anti gen
anti body reacti ons, and (5) the mi xed type of anaphyl actoi d reacti ons.
Severe anaphylacti c reacti ons to IV anesthetics are extremely uncommon; however, profound
hypotensi on attributed to nonimmunologicall y medi ated histamine rel ease has been reported wi th
thiopental use. Although anaphyl actic reactions to etomi date have been reported, it does not
appear to rel ease histamine and i s consi dered to be the most immunol ogicall y safe IV
anesthetic. Whil e propofol does not normal l y trigger hi stami ne rel ease, li fe-threatening
anaphyl actoi d reacti ons have been reported i n patients with a previ ous history of mul ti pl e drug
al lergi es. Barbi turates can al so preci pi tate episodes of acute i ntermittent porphyri a (AIP) and thei r
use is contrai ndi cated in patients who are predi sposed to AIP. Al though benzodi azepi nes,
ketami ne, and etomi date are reported to be safe i n humans, these drugs have been shown to be
porphyrogenic i n animal model s.
COMPARATIVE PHYSICO-CHEMICAL AND CLINICAL
PHARMACOLOGIC PROPERTIES
Bar bi t ur at es
The most commonly used barbiturates are thi opental (5-ethyl -5-[1-methyl butyl ]-2-thiobarbi turi c
acid), methohexi tal (1-methyl -5-al lyl -5-[1-methyl -2-pentynyl ] barbi turi c aci d), and thi amyl al (5-
al lyl -5-[1-methyl butyl ]-2-thiobarbi turi c aci d). Thi opental (Pentothal) and thi amyl al (Surital) are
thiobarbi turates, whi le methohexi tal (Brevital) i s an oxybarbi turate. Thi amyl al i s sli ghtl y more
potent than thi opental but has a si mil ar pharmacol ogi c profi l e. Al though the l-isomers of
thiopental and thyamyl al are twi ce as potent as the D-isomers, both hypnotics are commerci all y
avai labl e as racemi c mixtures. Because methohexi tal has two asymmetri c centers, it has four
stereoisomers. The -l-isomer is 4 to 5 times more potent than the -l -isomer, but i t produces
excessive motor responses. Therefore, methohexi tal is marketed as the racemic mixture of the two
P.340
-isomers.
All three barbi turates are avai labl e as sodium salts and must be dissol ved i n i sotoni c sodi um
chl ori de (0.9%) or water to prepare sol uti ons of 2.5% thi opental, 1 to 2% methohexi tal , and 2%
thiamylal . If refri gerated, sol utions of the thiobarbi turates are stable for up to 2 weeks. Sol uti ons
of methohexi tal are stabl e for up to 6 weeks. When barbi turates are added to Ringer' s l actate or
an aci dic soluti on contai ni ng other water-solubl e drugs, preci pitati on wi l l occur and can occl ude
the IV catheter. Al though the typi cal sol ution of thi opental (2.5%) i s hi ghl y al kali ne (pH 9) and
can be irri tati ng to the tissues i f i njected extravenousl y, i t does not cause pai n on i njecti on and
venoirri tati on i s rare. In contrast, a 1% methohexital soluti on frequentl y causes di scomfort when
injected i nto smal l vei ns. Intra-arterial i njecti on of thi obarbi turates is a seri ous compl i cation as
crystal s can form in the arteri ol es and capi l lari es, causi ng i ntense vasoconstri cti on, thrombosi s,
and even ti ssue necrosis. Accidental i ntra-arterial i njecti ons shoul d be treated promptl y wi th
intra-arterial admi ni strati on of papaverine and l i docaine (or procai ne), as wel l as a regi onal
anesthesia-induced sympathectomy (stel l ate gangli on bl ock, brachi al pl exus bl ock) and
hepari ni zati on.
Thi opental is metabol i zed i n the li ver to hydroxythi opental and the carboxyl i c aci d deri vative,
whi ch are more water sol ubl e and have li ttl e CNS acti vi ty. When hi gh doses of thi opental are
administered, a desul furati on reaction can occur wi th the producti on of pentobarbi tal , whi ch has
long-lasti ng CNS-depressant acti vi ty. The l ow eli mi nation cl earance of thi opental (3.4 mL/kg/mi n)
contri butes to a l ong eli mi nation hal f-li fe (t
1/2
of 12 h). Preexisting hepati c and renal di sease
resul ts i n decreased pl asma protein bi ndi ng, thereby increasi ng the free fracti on of thi opental and
enhanci ng i ts CNS and cardi ovascul ar-depressant properti es. Duri ng prol onged conti nuous
administrati on of thiopental , the concentrati on in the ti ssues approaches the concentrati on i n the
central compartment, wi th terminati on of i ts CNS effects becoming sol el y dependent on
el i mi nation by nonl i near hepati c metabol ism. Methohexital is metabol i zed i n the li ver to inactive
hydroxyderi vatives. The clearance of methohexital (11 mL/kg/min) i s hi gher and more dependent
on hepati c bl ood fl ow than thi opental , resul ting i n a shorter eli mi nati on hal f-li fe (t
1/2
36 h).
The usual i nducti on dose of thiopental i s 3 to 5 mg/kg i n adults, 5 to 6 mg/kg i n chi l dren, and 6 to
8 mg/kg i n infants. Because methohexi tal i s approximatel y 2.7 ti mes more potent than thi opental ,
a dose of 1.5 mg/kg is equi valent to 4 mg/kg of thi opental in adul ts. The dose of barbi turates
necessary to i nduce anesthesia i s reduced i n premedi cated pati ents, pati ents in early pregnancy (7
to 13 weeks' gestati on), and those of more advanced ASA (Ameri can Soci ety of Anesthesiol ogi sts)
physi cal status (III or IV). Geri atri c pati ents requi re a 30 to 40% reducti on i n the usual adul t dose
because of a decrease of the vol ume of the central compartment and sl owed redi stributi on of
thiopental from the vessel -ri ch tissues to l ean muscle.
11
When the cal cul ati on of the i nducti on
dose i s based on the l ean body mass rather than total body wei ght, dosage adjustments for age,
sex, or obesi ty are not necessary. Thiopental i nfusi on i s sel dom used to mai ntain anesthesi a
because of the l ong context-sensi ti ve half-ti me and prol onged recovery peri od. Plasma thi opental
level s necessary to mai ntain a hypnoti c state range between 10 and 20 mg/mL. A typical infusi on
rate necessary to treat intracrani al hypertensi on or i ntractabl e convul sions i s 2 to 4 mg/kg/h. The
pl asma concentrati on of methohexi tal needed to mai ntai n hypnosi s duri ng anesthesi a ranges
between 3 and 5 mg/mL and can be achi eved wi th an infusi on rate of 50 to 120 mg/kg/min.
Barbi turates produce a proporti onal decrease i n CMRO
2
and CBF, thereby lowering ICP. The
maximal decrease in CMRO
2
(55%) occurs when the EEG becomes i soel ectric (burst-suppressi ve
pattern). An isoelectri c EEG can be maintai ned wi th a thi opental i nfusion rate of 4 to 6 mg/kg/h
(resulti ng i n plasma concentrati ons of 30 to 50 mg/mL). Because the decrease i n systemi c arteri al
pressure i s usual l y l ess than the reducti on i n ICP, thi opental shoul d i mprove cerebral perfusi on
and compl i ance. Therefore, thi opental i s wi del y used to i mprove brai n rel axati on duri ng
neurosurgery and to improve cerebral perfusi on pressure (CPP) after acute brain i njury. Al though
barbiturate therapy i s wi del y used to control ICP after brai n injury, the resul ts of outcome studies
are no better than with other aggressi ve forms of cerebral anti hypertensi ve therapy.
It has been suggested that barbiturates also possess neuroprotecti ve properties secondary to
thei r abil i ty to decrease oxygen demand. Al ternati ve expl anati ons have been suggested, i ncl udi ng
a reverse steal (Robi n Hood effect) on CBF, free-radical scavengi ng, stabi l i zati on of li posomal
membranes, as well as excitatory amino aci d (EAA) receptor bl ockade. Based

on evi dence from experi mental studies and a large randomi zed prospecti ve mul tii nstituti onal
study,
12
i t has been concl uded that barbi turates have no pl ace i n the therapy fol l owi ng
resusci tati on of a cardiac arrest pati ent. In contrast, barbi turates are frequently used for
cerebroprotecti on duri ng i ncomplete brai n i schemi a (e.g., carotid endarterectomy, temporary
occl usi on of cerebral arteri es, profound hypotension, and cardiopul monary bypass). By i mprovi ng
the brai n' s tol erance of i ncomplete i schemi a i n pati ents undergoi ng open heart surgery wi th
cardi opul monary bypass, barbi turates are al l eged to decrease the i nci dence of postbypass
neuropsychi atri c disorders.
13
However, during valvular open heart cardi ac surgery, a protecti ve
effect of barbi turate l oadi ng coul d not be demonstrated.
14
The routi ne use of barbi turates during
cardi ac surgery i s not recommended because recent evi dence would suggest that the use of
moderate degrees of hypothermia (33 to 34C) may provide superi or neuroprotecti on wi thout
prolongi ng recovery.
Barbi turates cause predi ctabl e, dose-dependent EEG changes and possess potent anti convul sant
acti vi ty. Conti nuous infusi ons of thi opental have been used to treat refractory status epi lepti cus.
However, low doses of thi opental may i nduce spi ke wave activity i n epil eptic pati ents.
Methohexital has wel l -establ i shed epil eptogeni c effects in pati ents wi th psychomotor epil epsy.
Low-dose methohexi tal i nfusions are frequently used to activate corti cal EEG sei zure discharges i n
patients with temporal l obe epi l epsy. It is al so the IV anestheti c of choice for el ectroconvulsi ve
therapy.
15
Si nce the frequency of epil epti form EEG acti vi ty during i nducti on of anesthesi a wi th
methohexi tal i s si gni fi cantl y less than that whi ch occurs duri ng normal periods of sleep i n epil epti c
pati ents, thi s suggests that hi gher doses of methohexi tal produces anti convul sant acti vi ty.
Methohexital al so causes myocloni c-li ke muscle tremors and other si gns of exci tatory acti vi ty
(e.g., hi ccoughi ng).
Barbi turates cause dose-dependent respi ratory depression.
16
However, bronchospasm or
laryngospasm fol lowi ng induction wi th thi opental is usuall y the resul t of ai rway manipulation in
li ghtl y anesthetized pati ents. Laryngeal refl exes appear to be more acti ve after i nduction wi th
thiopental than wi th propofol . The cardi ovascular effects of thiopental and methohexital i ncl ude
decreases in cardiac output, systemic arteri al pressure, and peri pheral vascular resi stance. The
depressant effects of thi opental on cardiac output are primari ly a resul t of a decrease i n venous
return caused by peri pheral pool i ng, as well as a resul t of a di rect myocardial depressant effect,
whi ch assumes i ncreasi ng i mportance in the presence of hypovol emi a and myocardi al di sease.
17

Use of appropri ate doses can mi nimize the cardi odepressant effects of thi opental , even in i nfants.
Bhutada et al demonstrated that thi opental coul d be used for i nduction in i nfants wi thout
important changes i n heart rate and bl ood pressure during the i ntubation peri od.
18
An equi potent
dose of methohexital produces even l ess hypotensi on than thi opental because of a greater
tachycardi c response to the bl ood pressure l oweri ng effects of the drug. If the bl ood pressure
remai ns stabl e, the myocardi al oxygen demandsupply ratio remai ns normal despi te the i ncrease
in heart rate because of a concurrent decrease i n coronary vascular resi stance.
P r opof ol
Propofol (2,6-di sopropylphenol), an al kylphenol compound, i s vi rtual ly i nsol ubl e i n aqueous
solution. The i ni tial cremophor EL formulati on of propofol was wi thdrawn from cl inical testi ng
because of the high i nci dence of anaphyl actic reactions. Subsequentl y, propofol (10 mg/mL) was
rei ntroduced as an egg l eci thi n emul si on formulati on (Di pri van), consisting of 10% soybean oi l ,
2.25% gl ycerol , and 1.2% egg phosphati de. Pai n on i njection occurs i n 32 to 67% of pati ents
when injected i nto small hand vei ns but can be mi ni mi zed by injecti on i nto larger vei ns and by
pri or admi ni strati on of ei ther l i docaine or a potent opioi d analgesic (e.g., fentanyl or
remi fentani l ). A wi de variety of drugs have been used for reduci ng pai n on injecti on of propofol
(e.g., metoprol ol ,
19
grani setron,
20
dol asetron,
21
and even thiopental
22
). Dil uti ng the formul ation
with addi tional sol vent (Intral i pi d) or changi ng the l i pi d carri er (Li pofundi n) al so reduced propofol -
i nduced i njecti on pai n, probabl y because of a decrease i n the concentrati on of free propofol i n the
P.341
acqueous phase of the emul si on. A new propofol formul ati on with sodium metabi sul phi te (i nstead
of disodi um edetate) as an antimi crobi al has recently been shown to be associated wi th l ess
severe pai n on i njection. Although the presence of the metabisul phi te has rai sed concerns
regardi ng i ts use i n sul phite-al lergi c patients, thi s does not appear to be a cl i ni cal l y i mportant
problem. Of i nterest, a 2% formul ati on is avai labl e for l ong-term sedati on to decrease the fl ui d
vol ume i nfused as wel l as the li pi d load. Recentl y, a l ower-li pi d formul ati on of propofol (Ampofol )
has been introduced i nto cl ini cal practi ce for both general anesthesia
23
and sedati on.
24
The
increased free fracti on of propofol leads to i ncreased pai n when i t is injected i nto small vei ns.
Therefore, it i s i mportant to add l idocai ne to the Ampofol formulation to minimize the pain on
injecti on. A new water-solubl e prodrug of propofol (Aquavan) i s rapi dl y hydrol i zed i n the
ci rculati on to rel ease propofol.
25
It has a sl ower onset than propofol but a si mi l ar recovery profi l e.
Although Aquavan does not produce injecti on si te di scomfort, a burni ng peri neal sensati on has
been reported.
Propofol 's pharmacokineti cs has been studied using single bol us dosi ng and conti nuous i nfusi ons.
26

In studies usi ng a two-compartment ki netic model , the i ni tial di stri buti on hal f-li fe i s 2 to 8
mi nutes and the el i mi nation half-li fe i s 1 to 3 hours. Using a three-compartment model , the initi al
and sl ow di stri buti on half-li fe val ues are 1 to 8 mi nutes and 30 to 70 mi nutes, respectivel y. The
el i mi nation half-li fe depends l argely on the sampl ing time after di scontinui ng the admi ni strati on of
propofol and ranges from 2 to 24 hours. This l ong el imi nati on hal f-li fe i s indi cati ve of the
existence of a poorl y perfused compartment from whi ch propofol sl owl y di ffuses back i nto the
central compartment. Propofol i s rapi dl y cl eared from the central compartment by hepati c
metaboli sm and the context-sensi ti ve hal f-li fe for propofol i nfusions up to 8 hours is l ess than 40
mi nutes. Propofol i s rapi dl y and extensivel y metaboli zed to i nacti ve, water-solubl e sulphate and
gl ucuroni c aci d metabol i tes, whi ch are el imi nated by the ki dneys. Propofol ' s cl earance rate (1.5 to
2.2 l/mi n) exceeds hepati c bl ood flow, suggesting that an extrahepati c route of el i mi nati on (l ungs)
al so contri butes to i ts cl earance. Neverthel ess, changes i n l i ver bl ood fl ow woul d be expected to
produce marked al terati ons i n propofol 's cl earance rate. Surpri si ngly, few changes in propofol ' s
pharmacokineti cs have been reported in the presence of hepati c or renal di sease.
The i nducti on dose of propofol i n heal thy adul ts is 1.5 to 2.5 mg/kg, with blood levels of 2 to 6
g/mL produci ng unconsci ousness dependi ng on the concomi tant medi cati ons (e.g., opioi d
anal gesi cs), the pati ent' s age and physi cal status, and the extent of the surgical stimul ati on.
27
In
one of the fi rst reports descri bi ng the use of propofol for induction and mai ntenance of anesthesi a
with ni trous oxi de, an average i nfusi on rate of 120 g/kg/mi n was required.
28
The recommended
maintenance i nfusi on rate of propofol varies between 100 and 200 g/kg/mi n for hypnosi s and 25
to 75 g/kg/mi n for sedati on. Awakeni ng typi cal ly occurs at pl asma propofol concentrati ons of 1 to
1.5 g/mL.
29
Because a 50% decrease i n the plasma propofol concentrati on i s usual l y requi red for
awakening, emergence foll owi ng anesthesia i s rapi d even fol l owi ng prol onged i nfusi ons.
Analogous to the barbiturates, chi l dren requi re hi gher i nducti on and mai ntenance doses of
propofol on a mg/kg basi s as a resul t of thei r larger central di stri bution vol ume and hi gher

cl earance rate. El derl y and pati ents in poor health require l ower i nducti on and mai ntenance doses
of propofol as a resul t of their smal ler central di stri buti on vol ume and decreased clearance rate.
Al though subhypnoti c doses of propofol produce sedati on and amnesi a,
29
awareness has been
reported even at hi gher infusi on rates when propofol is used as the sol e anestheti c.
30
Propofol
often produces a subjecti ve feel ing of wel l -bei ng and even euphoria, and may have some abuse
potenti al as a resul t of these effects.
31
Propofol possesses dose-dependent effects on
thal amocorti cal transfer of noci cepti ve i nformation. However, pai n-evoked corti cal acti vi ty remai ns
intact after loss of consciousness.
32

Propofol decreases CMRO
2
and CBF, as wel l as ICP.
33
However, when larger doses are
administered, the marked depressant effect on systemi c arterial pressure can significantly
decrease CPP. Cerebrovascular autoregul ati on i n response to changes in systemic arteri al pressure
and reacti vi ty of the cerebral bl ood fl ow to changes i n carbon dioxi de tension are not affected by
propofol . Evidence for a possi ble neuroprotective effect has been reported i n in vi tro preparations,
and the use of propofol to produce EEG burst suppressi on has been proposed as a method for
P.342
provi ding neuroprotection during aneurysm surgery. Its neuroprotecti ve effect may at l east
parti all y be rel ated to the anti oxi dant potential of propofol' s phenol ring structure, whi ch may act
as a free-radical scavenger, decreasi ng free-radi cal i nduced l i pi d peroxidati on. A recent study
reported that thi s anti oxi dant activity may offer many advantages in preventing the
hypoperfusi on/reperfusi on phenomenon that can occur duri ng major l aproscopi c surgery.
34

Although TIVA wi th propofol and an opi oid anal gesi c i s a safe and effecti ve alternati ve to standard
inhalation techni ques (i .e., vol ati l e anestheti c wi th ni trous oxi de) for mai ntenance of anesthesi a,
concerns have been raised regarding the cost-effecti veness of thi s techni que.
35

Propofol produces corti cal EEG changes that are simil ar to thi opental. However, sedative doses of
propofol i ncrease -wave activity anal ogous to the benzodi azepi nes. Inducti on of anesthesi a wi th
propofol i s occasi onal l y accompani ed by exci tatory motor acti vi ty (so-call ed nonepil epti c
myocl oni a). In a study i nvol vi ng patients wi thout a hi story of seizure disorders, exci tatory
movements foll owi ng propofol were not associated wi th EEG sei zure acti vi ty.
36
Propofol appears to
possess profound anti convulsant properti es.
37
Propofol has been reported to decrease spi ke
acti vi ty i n pati ents with corti cal electrodes i mpl anted for resecti on of epil eptogenic foci and has
been used successful l y to termi nate status epi l epti cus. The duration of motor and EEG sei zure
acti vi ty fol lowi ng electroconvul si ve therapy i s si gni fi cantl y shorter wi th propofol than wi th other IV
anesthetics. Propofol produces a decrease in the earl y components of somatosensory and motor-
evoked potential s but does not infl uence the early components of the auditory evoked potenti al s.
Propofol produces dose-dependent respi ratory depression, wi th apnea occurri ng in 25 to 35% of
patients after a typi cal i nducti on dose. A maintenance infusi on of propofol decreases ti dal vol ume
and increases respi ratory rate. The venti latory response to carbon dioxi de and hypoxi a i s also
si gni fi cantl y decreased by propofol. Propofol can produce bronchodi lation in pati ents wi th chroni c
obstructive pul monary di sease and does not i nhi bi t hypoxi c pul monary vasoconstri cti on.
Propofol 's cardi ovascul ar depressant effects are general ly consi dered to be more profound than
those of thi opental . Both di rect myocardi al depressant effects and decreased systemi c vascul ar
resistance have been impl emented as i mportant factors i n produci ng cardi ovascul ar depressi on.
Di rect myocardi al depressi on and peri pheral vasodi l ati on are dose and concentrati on dependent.
In addi tion to arteri al vasodil ati on, propofol produces venodi lation (due both to a reducti on i n
sympatheti c activity and to a di rect effect on the vascul ar smooth muscl e), which further
contri butes to i ts hypotensive effect. The relaxation of the vascular smooth muscl e may be
because of an effect on intracel l ul ar cal cium mobil i zati on or because of an i ncrease i n the
producti on of ni tri c oxide. Experiments in i sol ated myocardi um suggest that the negative inotropi c
effect of propofol resul ts from a decrease i n i ntracell ular cal ci um avai l abi l ity secondary to
inhi biti on of transsarcol emmal cal cium i nfl ux.
Propofol also al ters the baroreflex mechani sm, resul ti ng in a smal l er increase i n heart rate for a
gi ven decrease i n arteri al pressure.
38
The smal ler i ncrease in heart rate with propofol may account
for the l arger decrease i n arterial pressure than with an equi potent dose of thi opental . Recent
studi es suggest that i nduction of anesthesi a wi th propofol attenuates desflurane-mediated
sympatheti c activati on.
39
Age enhances the cardi odepressant response to propofol and a reduced
dosage i s requi red i n the elderl y. Pati ents wi th l i mi ted cardiac reserve seem to tolerate the
cardi ac depressi on and systemi c vasodi l ati on produced by careful l y ti trated doses of propofol and
maintenance infusi ons are i ncreasingl y used at the end of cardi ac surgery when early extubati on i s
desi red.
Propofol appears to possess anti emeti c properti es that contri bute to a l ower inci dence of
emeti c sequelae after general anesthesi a. In fact, subanestheti c doses of propofol (10 to 20
mg) have al so been successfull y used to treat nausea and emesi s i n the earl y postoperati ve
peri od.
40
The postulated mechani sms i nclude anti dopaminergi c activity, depressant effect on the
chemoreceptor trigger zone and vagal nucl ei , decreased rel ease of glutamate and aspartate i n the
ol factory cortex, and reducti on of serotoni n concentrati ons in the area postrema. Interesti ngl y,
propofol also decreases the pruri tus produced by spinal opi oids.
Propofol does not tri gger mal i gnant hyperthermi a (MH) and may be consi dered the inducti on agent
of choi ce in MH-suscepti bl e pati ents. The use of propofol i nfusions for sedati on i n the pedi atri c
intensi ve care uni t has been li nked to several deaths fol l owi ng prol onged admi ni strati on because
of l i pi d accumul ati on and hypotensi on. Al though cl i ni cal doses of propofol do not affect corti sol
synthesis or the response to adrenocorticotropi c hormone (ACTH) sti mulation, propofol has been
reported to i nhi bi t phagocytosi s and kil l ing of bacteri a in vi tro and to reduce prol i ferati ve
responses when added to lymphocytes from cri ti cal ly i ll patients.
41
Because fat emul si ons are
known to support the growth of microorgani sms, contami nati on can occur as a result of di l ution or
fracti onated use.
42

Benzodi azepi nes
The parenteral benzodi azepines include diazepam (Val ium), l orazepam (Ati van), and mi dazol am
(Versed), as wel l as the antagonist fl umazeni l (Romazi con). Diazepam and lorazepam are i nsol ubl e
in water and thei r formul ati on contains propyl ene gl ycol , a ti ssue irri tant that causes pai n on
injecti on and venous i rri tation. Diazepam is avail able in a li pi d emulsi on formul ati on, whi ch does
not cause pain or thrombophl ebi tis but is associ ated wi th a sl i ghtl y l ower bioavail abi l i ty.
Mi dazolam is a water-solubl e benzodi azepi ne that i s avai l abl e in an acidi fi ed (pH 3.5) aqueous
formulation that produces minimal l ocal irritati on after IV or intramuscul ar (IM) i njecti on.
43
At
physi ol ogi c pH, an i ntramolecul ar rearrangement occurs that changes the physicochemi cal
properties of midazolam such that i t becomes more l i pi d sol ubl e.
Benzodi azepines undergo hepati c metabol ism vi a oxi dati on and glucuronide conjugati on. Oxidation
reacti ons are susceptibl e to hepati c dysfuncti on and coadministration of other anestheti c drugs.
Diazepam i s metabol ized to acti ve metabol i tes (desmethyl diazepam, 3-hydroxydi azepam), whi ch
can prol ong di azepam' s resi dual sedati ve effects because of thei r l ong t
1/2
val ues. These
metaboli tes undergo secondary conjugati on to

form inactive water-solubl e glucuroni de conjugates. Drugs that inhi bi t the oxidative metaboli sm of
di azepam i ncl ude the H
2
-receptor bl ocki ng drug ci meti di ne. Severe l i ver disease reduces
di azepam' s protei n-bi nding and hepati c cl earance rate, increases i ts vol ume of distri buti on, and
thereby further prol ongs the t
1/2
val ue. Chroni c renal di sease decreases protei n bi ndi ng and
increases the free drug fraction, resul ting i n enhanced hepatic metabol i sm and a shorter t
1/2

val ue. In el derl y patients, the cl earance rate of diazepam i s signi fi cantl y decreased, prol ongi ng i ts
t
1/2
to 75 to 150 hours.
Lorazepam i s di rectl y conjugated to gl ucuroni c acid to form pharmacologi cal ly inactive
metabol i tes. Age and renal di sease have li ttl e infl uence on the ki neti cs of l orazepam; however,
severe hepati c di sease decreases its clearance rate.
Mi dazolam undergoes extensi ve oxi dati on by hepati c enzymes to form water-solubl e hydroxyl ated
metaboli tes, whi ch are excreted in the uri ne. However, the primary metabol i te, 1-
hydroxymethylmidazol am, has mi l d CNS-depressant acti vi ty. The hepati c cl earance rate of
mi dazol am i s fi ve times greater than l orazepam and 10 ti mes greater than di azepam. Al though
changes i n l i ver bl ood fl ow can affect the cl earance of midazol am, age has rel ati vel y li ttl e
infl uence on mi dazol am' s el i mi nation half-li fe.
The benzodi azepines used i n anesthesia are cl assified as ei ther short- (mi dazol am, fl umazeni l ),
intermedi ate- (di azepam), or l ong-acti ng (l orazepam). Because the di stributi on vol umes are
si mi l ar, the l arge di fference in the el i mi nati on hal f-ti mes i s because of di fferences in thei r
di fferi ng cl earance rates (see Tabl e 13-1). The context-sensi ti ve hal f-ti mes for diazepam and
lorazepam are very l ong; therefore, onl y mi dazol am shoul d be used by conti nuous infusi on to
avoi d excessi ve accumul ati on.
All benzodi azepi nes have anxiol ytic, amnesti c, sedati ve, hypnoti c, anti convulsant, and spi nall y
mediated muscle relaxant properties. Benzodi azepi nes di ffer i n potency and effi cacy wi th regard to
thei r di sti ncti ve pharmacol ogi c properti es.
43
The dose-dependent pharmacologi c acti vi ty i mpl i es
that the CNS effects of various benzodi azepi ne compounds depend on the affini ty for receptor
subtypes and thei r degree of receptor bi ndi ng. Al though benzodi azepi nes can be used as
hypnoti cs, they are pri maril y used as premedi cants and adjuvant drugs because of thei r anxi ol ytic,
sedati ve, and amnesti c properti es. For exampl e, mi dazolam (0.04 to 0.08 mg/kg IV/IM) is the
P.343
most commonl y used premedi cant. In addi ti on, mi dazolam, 0.4 to 0.8 mg/kg admi ni stered orall y
10 to 15 mi nutes before parental separati on, i s an excel l ent premedicant i n chil dren. In contrast
to l orazepam, both di azepam and mi dazol am can be used to i nduce anesthesi a because they have
a relatively short onset ti me after IV admi ni strati on. The hal f-li fe of equil i brati on between the
plasma concentration of midazolam and its maximal EEG effect is only 2 to 3 minutes. The
therapeutic wi ndow to mai ntain unconsci ousness wi th mi dazol am i s reported to be 100 to 200
ng/mL, with awakening occurring at pl asma concentrati ons bel ow 50 ng/mL. However, signi ficant
hypnoti c synergi sm occurs when mi dazolam and opi oid anal gesics are admi ni stered i n
combi nation.
The usual i nducti on dose of mi dazol am i n premedi cated pati ents is 0.1 to 0.2 mg/kg IV, wi th
infusi on rates of 0.25 to 1 mg/kg/min requi red to maintai n hypnosi s and amnesi a i n combinati on
with inhal ati onal agents and/or opi oid anal gesi cs. Hi gher mai ntenance infusi on rates and
prolonged admini stration wi ll result i n accumul ation and prol onged recovery times. Lower infusi on
rates are suffi ci ent to provi de sedation and amnesi a during l ocal and regi onal anesthesia.
44

Patient-control led admini stration of mi dazol am duri ng procedures under local anesthesi a i s well
accepted by pati ents and associ ated wi th few peri operati ve compl icati ons.
45

Benzodi azepines decrease both CMRO
2
and CBF anal ogous to the barbi turates and propofol .
However, in contrast to these compounds, mi dazol am i s unabl e to produce a burst-suppressi ve
(i soel ectri c) pattern on the EEG. Accordi ngl y, there i s a cei li ng effect with respect to the
decrease i n CMRO
2
produced by i ncreasi ng doses of mi dazol am. Mi dazol am i nduces dose-
dependent changes i n regi onal cerebral perfusi on in the parts of the brai n that subserve arousal ,
attention, and memory. Cerebral vasomotor responsi veness to carbon di oxi de i s preserved duri ng
mi dazol am anesthesi a. In pati ents wi th severe head i njury, a bol us dose of mi dazol am may
decrease CPP with l i ttl e effect on ICP. Al though mi dazol am may improve neurol ogic outcome after
incompl ete ischemi a i n ani mal experiments, benzodi azepi nes have not been shown to possess
neuroprotecti ve acti vi ty i n humans. Li ke the other sedativehypnotic drugs, the benzodi azepi nes
are potent anti convul sants that are commonl y used to treat status epi lepti cus.
Benzodi azepines produce dose-dependent respi ratory depressi on. In healthy pati ents, the
respiratory depressi on associ ated with benzodi azepi ne premedi cati on i s insi gnifi cant. However, the
depressant effect i s enhanced i n pati ents wi th chronic respi ratory di sease, and synergi sti c
depressant effects occur when benzodi azepi nes are coadmi nistered wi th opi oi d analgesi cs.
Benzodi azepi nes al so depress the swal lowi ng refl ex and decrease upper airway refl ex acti vi ty.
Both midazolam and diazepam produce decreases in systemic vascul ar resi stance and bl ood
pressure when large doses are admi ni stered for i nducti on of anesthesi a. However, the
cardi ovascul ar depressant effects of benzodiazepi nes are frequentl y masked by the stimul us of
l aryngoscopy and i ntubation. The cardiovascular depressant effects are di rectl y rel ated to the
pl asma concentrati on; however, a plateau plasma concentrati on appears to exi st above whi ch li ttl e
further change in arterial bl ood pressure occurs. In the presence of heart fai lure, the decrease i n
prel oad and afterl oad produced by benzodi azepi nes may be benefi ci al i n i mprovi ng cardi ac output.
However, the cardiodepressant effect of benzodi azepi nes may be more marked i n hypovol emic
patients.
Ro 48-6791, a so-call ed short-acti ng intravenous sedati ve (SAIVS), is a new water-solubl e
benzodiazepi ne that has full agoni sti c acti vi ty at CNS benzodi azepi ne receptors. Compared wi th
mi dazol am, i t i s 2- to 2.5-fol d more potent, has a hi gher pl asma cl earance rate, and has a simil ar
onset and durati on of action.
46
In a recent study involving outpatients undergoi ng endoscopy
procedures, the ti mes to ambulation and to recovery from psychomotor i mpai rment were
decreased compared to midazol am, al though the l ater recovery end poi nts (e.g., fi tness-for-
di scharge) were si mil ar.
47

In contrast to al l other sedativehypnoti c drugs, there i s a speci fi c antagoni st for
benzodiazepi nes. Fl umazenil , a 1,4-imidazobenzodi azepine derivative, has a hi gh affi nity for the
benzodi azepi ne receptor but minimal intrinsic activity.
48
Fl umazeni l 's mol ecul ar structure i s simi lar
to other benzodi azepi nes except for the absence of a phenyl group, whi ch i s repl aced by a
carbonyl group. It i s water sol ubl e and possesses moderate l i pid sol ubi l ity at physi ol ogi c pH.
Fl umazeni l is rapi dl y metabol i zed in the l i ver, and i ts metabol i tes are excreted in the uri ne as
gl ucuroni de conjugates. Fl umazenil acts as a competiti ve antagonist in the presence of
benzodiazepi ne agoni st compounds. The resi dual activity of the benzodi azepines in the presence of
fl umazeni l depends on the rel ati ve concentrati ons of the agoni st and antagoni st drugs. As a resul t,
i t i s possi bl e to reverse benzodi azepi ne-i nduced anesthesi a (or deep sedati on) ei ther compl etel y
or parti al l y dependi ng on the dose of fl umazeni l . Fl umazeni l i s short acti ng, with an el iminati on
half-li fe of ~1 hour.
Recurrence of the central effects of benzodi azepi nes (resedation) may occur after a si ngl e dose of
fl umazeni l because of resi dual effects of the more sl owly eli minated agonist drug.
49
If sustained
antagoni sm i s desi red, i t may be necessary to admi ni ster fl umazeni l as repeated bol us doses or a
conti nuous i nfusi on. In general, 45 to 90 minutes of antagoni sm can be expected

fol l owing fl umazeni l 1 to 3 mg IV. However, the respi ratory depressi on produced by
benzodiazepi nes i s not compl etel y reversed by fl umazeni l .
50
Reversal of benzodi azepi ne sedati on
with fl umazeni l is not associ ated with adverse cardiovascular effects or evidence of an acute
stress response.
51
Al though flumazeni l does not appear to change CBF or CMRO
2
foll owing
mi dazol am anesthesi a for craniotomy, acute increases i n ICP have been reported i n head-injured
patients recei vi ng fl umazeni l.
Et omi dat e
Etomi date is a carboxyl ated i mi dazol e-contai ning anestheti c compound (R-1-ethyl -1-[a-
methyl benzyl ] i mi dazol e-5-carboxyl ate) that is structural ly unrel ated to any other IV anesthetic.
Only the D-isomer of etomi date possesses anestheti c acti vi ty. Anal ogous to mi dazol am (which al so
contai ns an imi dazol e nucl eus), etomidate undergoes an intramolecul ar rearrangement at
physi ol ogi c pH, resul ti ng in a closed-ri ng structure wi th enhanced l i pid sol ubi li ty. The aqueous
solution of etomi date (Ami date) i s unstable at physi ol ogi c pH and i s formul ated i n a 0.2% soluti on
with 35% propyl ene gl ycol (pH 6.9), contri buti ng to a hi gh inci dence of pain on injecti on,
venoirri tati on, and hemolysi s. A new l i pid emul sion formulation (Etomi date-Lipuro) has recently
been i ntroduced i n Europe and appears to be associ ated wi th a l ower i nci dence of side effects
compared to the ori gi nal propyl ene gl ycol formulation.
The standard i nducti on dose of etomidate (0.2 to 0.4 mg/kg IV) produces a rapid onset of
anesthesia. Invol untary myocl oni c movements are common during the i nducti on period as a resul t
of subcorti cal di si nhi biti on and are unrel ated to corti cal sei zure activi ty. The frequency of this
myocl oni c-li ke activity can be attenuated by prior admini stration of opi oid anal gesi cs,
benzodiazepi nes, or smal l sedative doses (0.03 to 0.05 mg/kg) prior to i nducti on of anesthesi a.
52

Emergence ti me after etomi date anesthesi a i s dose dependent but remains short even after
administrati on of repeated bol us doses or continuous i nfusions. For maintenance of hypnosi s, the
target concentrati on i s 300 to 500 ngmL
-1
and can be rapi dl y achi eved by admi ni steri ng a two- or
three-stage infusi on (e.g., 100 mg/kg/mi n for 10 mi n fol lowed by 10 mg/kg/mi n or 100 mg/kg/mi n
for 3 to 5 mi nutes, foll owed by 20 mg/kg/mi n for 20 to 30 mi nutes, and then 10 mg/kg/mi n). The
pharmacokineti cs of etomi date are optimal l y descri bed by a three-compartment open model.
53
The
hi gh cl earance rate of etomi date (18 to 25 mL/kg/mi n) i s a resul t of extensi ve ester hydrol ysi s i n
the li ver (forming i nacti ve water-solubl e metabolites). A si gni fi cant decrease i n pl asma protei n
bi nding has been reported in the presence of uremi a and hepati c ci rrhosi s. Severe hepati c di sease
causes a prolongation of the eli minati on hal f-li fe secondary to an i ncreased vol ume of di stributi on
and a decreased pl asma clearance rate.
Anal ogous to the barbi turates, etomidate decreases CMRO
2
, CBF, and ICP. However, the
hemodynamic stabi li ty associated wi th etomidate wi ll mai ntain adequate CPP. Etomi date has been
used successful l y for both i nducti on and mai ntenance of anesthesia for neurosurgery. Etomi date' s
well -known inhibitory effect on adrenocortical syntheti c function
54
li mits its cli nical useful ness for
long-term treatment of elevated ICP. Al though clear evi dence for a neuroprotective effect in
humans is l acking, etomidate is frequentl y used duri ng temporary arteri al occlusi on and
i ntraoperati ve angi ography (for the treatment of cerebral aneurysms). Etomidate produces an EEG
pattern that i s si mi l ar to thiopental except for the absence of increased acti vi ty at l ower doses.
P.344
Etomi date can induce convulsi on-li ke EEG potenti als i n epi l epti c pati ents wi thout the appearance
of myocloni c or convulsant-li ke motor acti vi ty, a property that has been proven useful for
i ntraoperati ve mappi ng of seizure foci . Etomi date al so possesses anti convul sant properti es and it
has been used to termi nate status epil epti cus. Etomi date produces a si gni fi cant i ncrease of the
ampli tude of somatosensory evoked potenti al s whi l e onl y minimall y i ncreasi ng thei r latency.
Consequently, etomidate can be used to faci li tate the i nterpretation of somatosensory evoked
potential s when the signal qual i ty i s poor.
Etomi date causes mi ni mal cardiorespi ratory depressi on even i n the presence of
cardi ovascul ar and pul monary di sease.
55
The drug does not induce histamine rel ease and can
be safel y used in pati ents wi th reacti ve ai rway disease. Consequently, etomidate is considered to
be the i nduction agent of choi ce for poor-ri sk pati ents wi th cardiorespi ratory di sease, as wel l as in
those situations i n whi ch preservati on of a normal bl ood pressure i s cruci al (e.g., cerebrovascul ar
di sease). However, etomi date does not effecti vel y bl unt the sympatheti c response to l aryngoscopy
and i ntubati on unl ess combi ned wi th a potent opi oid anal gesi c.
Etomi date is associ ated with a hi gh i nci dence of postoperati ve nausea and emesi s when used i n
combi nation with opi oids for short outpatient procedures. In addi tion, the increased mortal i ty in
criti cal ly i ll pati ents sedated wi th an etomidate i nfusi on has been attri buted to its inhibitory effect
on corti sol synthesi s.
56
Etomidate inhi bi ts the activity of 11--hydroxyl ase, an enzyme necessary
for the synthesi s of corti sol , al dosterone, 17-hydroxyprogesterone, and corticosterone. Even after
a si ngl e induction dose of etomidate,
56
adrenal suppressi on persi sts for 5 to 8 hours. Al though the
cl i ni cal significance of short-term bl ockade of cortisol synthesis i s not known, the use of etomi date
for maintenance of anesthesi a has been questioned. Recentl y, etomidate has been reported to
i nhi bi t pl atel et functi on, resulti ng i n prolongation of the bl eedi ng ti me.
57
In spi te of i ts si de effect
profi le, etomi date remains a valuabl e i nducti on drug sti l l for specific i ndi cati ons (i n pati ents wi th
severe cardiovascular and cerebrovascular di sease).
Ket ami ne
Ketamine (Ketal ar or Ketaject) i s an arylcycl ohexyl ami ne that is structural ly rel ated to
phencycl idi ne.
58
Ketamine i s a water-solubl e compound wi th a pKa of 7.5 and i s avai l abl e i n 1%,
5%, and 10% aqueous sol uti ons. The ketami ne mol ecul e contains a chiral center produci ng two
optical isomers. The S(+) isomer of ketamine possesses more potent anestheti c and analgesic
properties despite havi ng a si mi l ar pharmacoki neti c and pharmacodynami c profi l e as the racemic
mi xture (or the R[-] isomer).
59, 60
Al though the S(+)-ketami ne is approved for cli ni cal use in
Europe, the commonl y used sol uti on i s a racemic mixture of the two i somers. Ketami ne i s
extensi vel y metabol ized by hepatic microsomal cytochrome P-450 enzymes and i ts primary
metaboli te, norketami ne, is one thi rd to one fifth as potent as the parent compound. The
metaboli tes of norketami ne are excreted by the kidney as water-sol ubl e hydroxyl ated and
gl ucuroni dated conjugates. Anal ogous to the barbi turates and propofol , ketami ne has relati vel y
short distribution and redi stri buti on hal f-li fe val ues. Ketami ne al so has a high hepatic clearance
rate (1 L/min) and a l arge distri buti on vol ume (3 L/kg), resulti ng i n an el imi nati on hal f-li fe of 2 to
3 hours. The high hepatic extracti on rati o suggests that al terati ons i n hepati c bl ood fl ow can
si gni fi cantl y infl uence ketami ne' s cl earance rate.
Ketami ne produces dose-dependent CNS depression leadi ng to a so-cal l ed di ssoci ati ve
anesthetic state characterized by profound analgesia and amnesia, even though pati ents may
be conscious and maintai n protective refl exes. The proposed mechanism for thi s cataleptic state
incl udes electrophysi ol ogi c

inhi biti on of thalamocorti cal pathways and sti mulation of the li mbic system. Al though it i s most
commonly admi ni stered parenteral ly, oral and i ntranasal admi ni strati on of ketami ne (6 mg/kg) has
been used for premedi cati on of pedi atri c pati ents. Fol lowi ng benzodi azepi ne premedi cati on,
ketami ne 1 to 2 mg/kg IV (or 4 to 8 mg/kg IM) can be used for induction of anesthesi a. The
duration of ketamine-induced anesthesi a is i n the range of 10 to 20 mi nutes after a si ngl e
inducti on dose; however, recovery to ful l ori entati on may requi re an additi onal 60 to 90 mi nutes.
Emergence ti mes are even longer foll owi ng repeated bol us injecti ons or a conti nuous infusi on. S
P.345
(+)-ketami ne has a shorter recovery time compared wi th the racemi c mi xture. The therapeutic
window for maintenance of unconsciousness wi th ketami ne i s between 0.6 and 2 mg/mL i n adults
and between 0.8 and 4 mg/mL i n chi ldren. Analgesic effects are evident at subanestheti c doses of
0.1 to 0.5 mg/kg IV and pl asma concentrati ons of between 85 and 160 ng/mL. A l ow-dose i nfusi on
of 4 g/kg/mi n IV was reported to result i n equi valent postoperative anal gesia as an IV morphine
infusion of 2 mg/h.
As a resul t of its NMDA-receptor bl ocking acti vi ty, i t has been suggested that ketamine shoul d be
hi ghl y effecti ve for preempti ve analgesi a and opi oid-resistant chroni c pai n states.
61
Unfortunately,
a well -control led study fail ed to demonstrate a preempti ve effect when ketami ne was admi ni stered
pri or to the surgi cal i nci si on.
62

An i mportant consi deration in the use of ketami ne anesthesi a rel ates to the hi gh i nci dence of
psychomimeti c reacti ons (namely, hal luci nations, ni ghtmares, altered short-term memory and
cogni ti on) duri ng the early recovery peri od. The i nci dence of these reacti ons i s dose dependent
and can be reduced by coadmi ni strati on of benzodi azepi nes, barbi turates, or propofol . Ketami ne
has been traditi onal l y contraindi cated for pati ents wi th i ncreased ICP or reduced cerebral
compl i ance because it i ncreases CMRO
2
, CBF, and ICP. However, there is recent evi dence that IV
inducti on doses of ketami ne actuall y i ncreases ICP i n traumati cbrain-injury pati ents during
control led ventil ati on with propofol sedation.
63
Pri or admi ni strati on of thi opental or
benzodiazepi nes can bl unt ketami ne-induced i ncreases i n CBF. Si nce ketami ne has antagoni sti c
acti vi ty at the NMDA receptor, i t has been suggested that i t possesses some i nherent protective
effects agai nst brai n i schemi a. Neverthel ess, ketamine can adversely affect neurol ogic outcome in
the presence of brai n ischemia despite i ts NMDA-receptor bl ocking acti vi ty. Corti cal EEG
recordings foll owing ketami ne i nducti on are characteri zed by the appearance of fast acti vi ty (30
to 40 Hz) fol l owed by moderate-vol tage acti vi ty, mi xed wi th hi gh-vol tage waves recurri ng at 3
to 4 second intervals. At higher dosages, ketamine produces a unique EEG burst-suppressi on
pattern (Fi g. 13-5). Although ketami ne-induced myoclonic and sei zure-li ke acti vi ty has been
observed in normal (nonepi l epti c) patients, ketami ne appears to possess anti convulsant activity.
8

Recentl y, several have demonstrated the opioid-spari ng effects of l ow-dose Ketami ne (75 to 200
mcg/kg) when admini stered as an adjuvant during anesthesi a.
64, 65
Interesti ngl y, smal l -dose
ketami ne has al so been used i n the treatment of severe depressi on i n pati ents with chroni c pain
syndromes.
66
However, ketamine can produce adverse effects when admini stered i n the presence
of trici cl yi c antidepressants because both drugs i nhi bi t norepi nephri ne reuptake and coul d produce
severe hypotensi on, heart fail ure, and/or myocardi al ischemi a.
67, 68

Ketamine has wel l -characteri zed bronchodi l atory activity. In the presence of acti ve bronchospasm,
ketami ne is considered to be the IV inducti on agent of choi ce. Ketami ne has been used i n
subanestheti c dosages to treat persi stent bronchospasm i n the operati ng room and ICU. It i s al so
used in combi nation wi th mi dazolam to provi de sedati on and anal gesi a for asthmati c pati ents. In
contrast to the other IV anesthetics, protecti ve airway refl exes are more l i kel y to be preserved
with ketamine. However, i t must be emphasi zed that the use of ketamine does not obvi ate the
need for tracheal i ntubati on i n the pati ent wi th a ful l stomach (because tracheal soil i ng has been
reported in thi s si tuati on). Ketami ne causes mini mal respiratory depressi on i n cl i ni cal l y rel evant
doses and can faci l itate the transiti on from mechani cal to spontaneous venti lation after
anesthesia. However, i ts abi l ity to i ncrease oral secretions can lead to laryngospasm duri ng li ght
anesthesia.
Ketamine has promi nent cardi ovascul ar stimul ati ng effects secondary to di rect sti mulation of the
sympatheti c nervous system. Ketamine i s the onl y anestheti c that actual l y i ncreases peripheral
arteriol ar resi stance. As a resul t of i ts vasoconstrictive properti es, ketami ne can reduce the
magni tude of redi stributi on hypothermi a.
69
Induction of anesthesi a wi th ketamine often produces
si gni fi cant increases i n arteri al blood pressure and heart rate. Al though the mechanism of the
cardi ovascul ar sti mulation is not enti rel y cl ear, i t appears to be centrall y mediated. There i s
evidence to suggest that ketami ne attenuates baroreceptor acti vi ty via an effect on NMDA
receptors i n the nucl eus tractus sol itari us. Because of the i ncreased cardiac work and myocardi al
oxygen consumpti on, ketami ne negatively affects the bal ance between myocardi al oxygen suppl y
and demand. Consequently, i ts use is not recommended in pati ents wi th severe coronary artery
di sease. In contrast to the secondary cardiovascular sti mulation, ketami ne has intri nsic myocardial
depressant properti es that onl y become apparent i n the seri ousl y i l l pati ent wi th depl eted
catechol amine reserves. Because ketami ne can al so i ncrease pul monary artery pressure, its use i s
contrai ndi cated in adul t pati ents wi th poor ri ght ventri cular reserve. Interesti ngl y, the effect on
the pul monary vascul ature seems to be attenuated i n chi l dren.
The anestheti c and anal gesi c potency of S(+)-ketami ne is three ti mes greater than R(-)-ketami ne
and twice that of the racemi c mi xture (Fi g. 13-6), refl ecti ng i ts fourfol d greater affinity at the
phencycl idi ne binding site on the NMDA receptor compared wi th the R(-) isomer.
70
The therapeuti c
index of S(+)-ketami ne is 2.5 times greater than both the R(-)

and the racemi c forms. In additi on, hepati c biotransformati on of S(+)-ketami ne occurs 20% faster
than that of the R(-) enantiomer, contributing to shorter emergence ti mes and a faster return of
cogni ti ve functi on. Both i somers produce si mi l ar cardiovascular sti mulating effects and hormonal
responses duri ng surgery. Al though the i ncidence of dreaming is similar wi th S(+)-ketami ne and
the racemi c mi xture, subjecti ve mood and pati ent acceptance are hi gher wi th the S(+) i somer.
FIGURE 13-5. Progressi ve changes i n the EEG produced by ketami ne. Stages I through III
are achieved with racemi c ketami ne and i ts S(+)i somer. Wi th R(-)ketami ne, Stage II was the
maximal EEG depression produced. (Repri nted wi th permi ssi on from Shttler J, Stanski DR,
Whi te PF, et al : Pharmacodynami c model i ng of the EEG effect of ketamine and i ts
enantiomers in man. J Pharmacoki net Bi opharm 15:241, 1987.)
P.346
CLINICAL USES OF INTRAVENOUS ANESTHETICS
Use of I nt r avenous Anest het i cs As I nduct i on Agent s
The i nducti on characteri sti cs and recommended dosages of the avai l abl e IV anestheti c agents are
summarized in Tabl e 13-2. As a resul t of di fferences i n pharmacoki netic (e.g., al tered cl earance
and di stri buti on vol umes) and pharmacodynamic (altered brain sensi tivity) variabl es, the induction
dosages of al l IV anesthetics need to be adjusted to meet the needs of i ndi vi dual pati ents. For
example, advanced age, preexi sti ng diseases (e.g., hypothyroidism, hypovolemia), premedicati on
(e.g., benzodi azepi nes), and coadministration of adjuvant drugs (e.g., opioids, (-2 agoni sts)
decrease the i nducti on dose requi rements. When there i s concern regardi ng a possi bl e abnormal
response, assessing the effect of a small test dose (equal to 10 to 20% of the usual induction
dose) wil l often i dentify those pati ents for whom a dosage adjustment i s required. Before
administeri ng addi tional medi cation, adequate time shoul d be al l owed for the anestheti c to exert
its effect, especial ly when usi ng drugs wi th a slow onset of action (mi dazol am) or i n the presence
of a sl ow ci rculati on ti me i n elderly pati ents and those with congestive heart fai lure.
FIGURE 13-6. Concentrati on-response rel ati onshi p for racemic ketami ne and S(+)ketami ne
in rel ati on to speci fic cl i ni cal end poi nts. The sl owing of the median EEG frequency was used
as the effect (end point) and was related to the arterial bl ood concentrati ons of ketami ne.
(Repri nted with permi ssi on from Schttler J, Kl oos S, Ihmsen H, et al : Pharmacoki netic-
pharmacodynami c properti es of S(+)-ketami ne versus racemic ketami ne: A randomized
doubl e-bl i nd study i n volunteers. Anesthesi ol ogy 77:A330, 1992.)
TABLE 13-2 Induction Characteristics and Dosage Requirements for the Currently Available S
Hypnotic Drugs
DRUG NAME INDUCTION
DOSE
(mg/kg)
ONSET
(sec)
DURATION
(min)
EXCITATORY
ACTIVITY*
PAIN ON
INJECTION*
HEART
RATE
Thi opental 36 <30 510 + 0+

Methohexital 13 <30 510 ++ +
The cli nical uses of propofol have expanded greatl y si nce i ts introducti on i nto cli ni cal practice i n
1989.
71
Intravenous admi ni strati on of propofol resul ts i n a rapid loss of consciousness (usuall y
within one arm-to-brain circul ati on) that i s comparabl e to the barbi turates. Al though an i nducti on
dose of 2.5 mg/kg was i niti al l y recommended, the use of smal ler i nducti on doses of propofol (1 to
2 mg/kg) has mi ni mized its acute cardi ovascul ar and respi ratory depressant effects. Recovery
from propofol ' s sedati vehypnoti c effects i s rapi d wi th l ess resi dual sedati on, fati gue
(hangover), and cogni tive i mpairment than wi th other avail abl e sedati vehypnoti c drugs after
short surgi cal procedures. Consequentl y, propofol has become the IV drug of choice for
outpati ents undergoing ambulatory surgery.
Wi th benzodi azepi nes, there i s wi de vari ation in the dose-response rel ati onshi ps in
unpremedi cated elective surgery patients. Compared to mi dazol am, di azepam and l orazepam have
sl ower onset ti mes to achieve a peak effect and thei r dose-effect relationship i s l ess predictabl e.
As a resul t, diazepam and l orazepam are rarely used for induction of general anesthesi a. In
addi ti on, the sl ow hepati c cl earance of diazepam and lorazepam may contri bute to prol onged
residual effects (sedati on, amnesi a, fati gue) when they are used for premedi cati on. Mi dazol am has
a sl i ghtl y more rapi d onset and may be a useful induction agent for speci al i ndicati ons (when
ni trous oxide i s contrai ndicated, or as part of a total IV anestheti c techni que). However, when
mi dazol am i s used for i nducti on and/or mai ntenance of anesthesia, return of consci ousness takes
substantial ly l onger than wi th other sedati vehypnoti c drugs. In spi te of i ts extensive hepati c
metaboli sm, recovery of cogni ti ve functi on i s sti ll sl ower after mi dazolam compared with
thiopental , methohexi tal , etomi date, or propofol .
In an effort to opti mi ze the cl i ni cal use of mi dazol am duri ng the i nduction peri od, it i s uti li zed
increasi ngl y as a coi nducti on agent wi th other sedati vehypnoti c drugs (propofol , ketami ne).
Mi dazolam 2 to 5 mg IV can provi de for increased sedati on, amnesi a, and anxiolysis during the
prei nduction peri od. When mi dazol am i s used i n combi nati on wi th propofol, 1.5 to 2 mg/kg IV, or
ketami ne, 0.75 to 1 mg/kg IV, i t faci l itates the onset of anesthesi a wi thout del ayi ng emergence
ti mes.
72

Mi dazolam attenuates the cardi osti mul atory response to ketami ne, as wel l as i ts psychomi meti c
Propofol 1.52.5 1545 510 + ++ 0
Mi dazolam 0.20.4 3090 1030 0 0 0
Diazepam 0.30.6 4590 1530 0 +/+++ 0
Lorazepam 0.030.06 60
120
60120 0 ++ 0
Etomi date 0.20.3 1545 312 +++ +++ 0
Ketamine 12 4560 1020 + 0
*0 = none; + = mini mal ; ++ = moderate; +++ = severe.
= decrease; = increase.
P.347
emergence reactions. Use of mi dazol am, 2 to 3 mg IV wi th propofol reduces recall duri ng the
inducti on peri od; however, larger doses of mi dazol am (5 mg IV) wi ll del ay emergence after bri ef
surgi cal procedures.
As a resul t of their side effect profil es, the cl inical use of etomi date and ketami ne for i nducti on of
anesthesia i s restri cted to speci fi c si tuati ons where thei r unique pharmacologi c profi les offer
advantages over other avai l abl e IV anestheti cs. For exampl e, etomi date can faci li tate mai ntenance
of a stabl e bl ood pressure i n hi gh-ri sk pati ents wi th cri tical stenosi s of the cerebral vasculature
and in pati ents wi th severe cardiac impai rment or unstabl e angina. Ketami ne i s a useful i nducti on
agent for hypovol emi c pati ents, as wel l as i n pati ents with reacti ve ai rway disease or a
compromi sed upper ai rway.
Use of I nt r avenous Dr ugs f or Mai nt enance of Anest hesi a
The conti nued popul ari ty of volatil e anestheti cs for mai ntenance of anesthesi a is due pri maril y to
thei r rapi d reversibi l i ty and ease of admini stration when usi ng conventi onal vaporizer del i very
system for titrating to the desi red end poi nt. The avai l abi l i ty of IV drugs wi th more rapi d onset
and shorter recovery profil es, as well as user-fri endl y infusi on del ivery systems, has faci l itated
the maintenance of anesthesi a wi th conti nuous infusi ons of IV drugs, produci ng an anesthetic
state (namel y, TIVA) that compares favorabl y with the vol atil e anestheti cs. In a compari son of the
requi rement of postoperati ve anal gesics after i nhal ati on and TIVA techniques, not surprisi ngl y, the
postoperati ve pai n was reduced after TIVA.
73
For exampl e, i n morbi dly obese pati ents undergoing
bariatri c surgery, the use of TIVA techni que was associ ated wi th a superi or recovery profi l e
compared to a sevofl urane-based i nhal ati on techni que.
74
However, TIVA techni ques are more
expensive than i nhal ati on or bal anced anesthetic techni ques.
35

The traditi onal i ntermi ttent bolus admini stration of IV drugs resul ts in a depth of anesthesi a
(and anal gesi a) that osci ll ates above and below the desi red level .
75
Because of rapid di stri buti on
and redi stri buti on of the IV anestheti cs, the hi gh peak bl ood concentrati on after each bol us i s
fol l owed by a rapi d decrease, produci ng fl uctuati ng drug l evel s i n the bl ood and hence the brai n.
The magnitude of the drug l evel fl uctuati on i s dependent on the si ze of the bol us dose and the
frequency of i ts administrati on. Wi de variati on i n the pl asma drug concentrati ons can resul t in
hemodynamic and respiratory instabil i ty as a resul t of changes i n the depth of anesthesi a or
sedati on. By provi di ng more stabl e blood (and brai n) concentrati ons wi th a conti nuous IV infusi on,
i t mi ght be possi bl e to i mprove anestheti c conditi ons and hemodynami c stabil i ty, as well as
decreasing side effects and recovery ti mes wi th IV anestheti cs.
76
Admi ni strati on of IV anestheti cs
by a vari abl e-rate i nfusi on i s a l ogical extensi on of the incremental bol us method of drug titration,
as a conti nuous infusi on i s equi valent to the sequenti al admini stration of infi ni tel y smal l bolus
doses.
Although an IV anesthetic can be ti trated to achi eve and maintai n the desired cli ni cal effect, a
knowl edge of basi c pharmacoki netic princi pl es is hel pful i n more accurately predi cti ng the opti mal
dosage requi rements. The requi red pl asma concentrati on depends on the desi red pharmacol ogi cal
effect (hypnosis, sedati on), the concomitant use of other adjuncti ve drugs (opioi d anal gesics,
muscle rel axants, cardi ovascul ar drugs), the type of operati on (superfi cial , i ntra-abdomi nal,
intracranial ), and the pati ent' s sensi tivity to the drug (age, drug hi story, preexi sti ng di seases).
Preexi sti ng di seases (ci rrhosis, congesti ve heart fai l ure, renal fai l ure) can markedl y al ter the
pharmacokineti c vari ables of the hi ghl y protei n-bound, l i pophil i c IV anesthetic drugs. In general ,
chil dren have hi gher clearance rates, whi l e the el derl y have reduced cl earance values. Vari ous
intraoperative interventi ons (l aryngoscopy, tracheal i ntubation, skin i ncisi on, entry i nto body
cavi ti es) transi entl y increase the anestheti c and/or anal gesi c requi rements. Therefore, the
i nfusi on scheme shoul d be tai l ored to provi de peak drug concentrati ons during the periods of most
intense stimul ati on. For specifi c surgical interventi ons, the so-call ed therapeutic window of an IV
anestheti c i s defi ned as the bl ood concentrati on range requi red to produce a gi ven effect (Tabl e
13-3). It must be emphasi zed that the therapeuti c wi ndow for Sedati vehypnoti cs i s markedl y
infl uenced by the presence of adjuncti ve drugs (opi oi ds,
2
agoni sts, ni trous oxi de).
The use of IV anesthetic techni ques requi res conti nuous titration of the drug i nfusion rate to the
desi red pharmacodynamic end point.
72
Most anesthesi ol ogists rel y on somati c and autonomi c signs
for assessi ng depth of IV anesthesi a, anal ogous to the manner i n whi ch they titrate the vol ati le
anesthetics. The most sensi ti ve cl inical si gns of depth of anesthesi a appear to be changes i n
muscle tone (i .e., electromyography [EMG]) and venti latory rate and pattern.
77
However, if the
patient has been gi ven muscl e rel axants, the anesthesi ol ogi st must rely on signs of autonomic
hyperactivity (tachycardi a, hypertensi on, l acri mati on, di aphoresis). Unfortunately, the anestheti c
drugs (ketami ne), as well as adjunctive agents (
2
agoni sts, bl ockers, adenosi ne, cal ci um-
channel bl ockers), can di rectly infl uence the cardi ovascul ar response to surgi cal stimul ati on.
Although the cardiovascular si gns of autonomi c nervous system hyperactivity may be masked,
other autonomic signs (e.g., di aphoresi s) and purposeful movements may be more reliable
i ndi cators of depth of anesthesi a than blood pressure because the latter depends on the abi l ity of
the heart to maintai n the cardi ac output in the face of acute changes i n afterl oad. The heart rate
response to surgi cal sti mulation appears to be more useful than the blood pressure response i n
determi ni ng the need for addi tional anal gesic medicati on. Moreover, it

woul d appear that bl ood pressure and heart rate responses to surgi cal stimul ati on are a l ess
useful guide with IV techni ques than wi th vol ati l e anestheti cs.
The cli nical assessment of anestheti c depth has become more chal l engi ng because IV anestheti c
techniques invol ve a combi nation of hypnoti cs, opi oids, muscl e relaxants, and adjuvant drugs. The
interactions between these drugs can resul t in addi ti ve, supra-addi ti ve, i nfra-addi ti ve, or even
antagonisti c effects. An i deal depth of anesthesi a indicator woul d i ntegrate the physi ol ogi c and
neurol ogic i nformati on from al l aspects of the anesthetic state. In the absence of a gl obal cerebral
TABLE 13-3 Therapeutic Blood Concentrations When Intravenous Anesthetics are
Infused for Hypnosis or Sedation
DRUG NAME MAJOR
SURGERY
PROCEDURES
MINOR
SURGERY
PROCEDURES
SEDATIVE
CONCENTRATION
AWAKENING
CONCENTRATION
Thi opental 1020
g/mL
1020
g/mL
48 g/mL 48 g/mL
Methohexital 615 g/mL 510 g/mL 13 g/mL 13 g/mL
Propofol 46 g/mL 24 g/mL 12 g/mL 11.5 g/mL
Mi dazolam 100200
ng/mL
50200
ng/mL
40100 ng/mL 50150 ng/mL
Etomi date 5001000
ng/mL
300600
ng/mL
100300 ng/mL 200350 ng/mL
Ketamine 14 g/mL 0.62 g/mL 0.11 g/mL NA
NA = not avai l abl e.
P.348
functi on moni tor, the depth of anesthesi a device shoul d provide an indi cati on of one or more of
the key components of general anesthesi a (e.g., hypnosi s, anal gesia, amnesi a, suppressi on of the
stress response, or muscl e relaxati on). A si mpl e, noninvasi ve moni tor of the depth of anesthesia,
whi ch would rel iabl y predict a pati ent's response to surgical sti mulati on, would be extremel y
val uabl e when uti l izing IV anestheti c techniques.
The EMG acti vi ty of the frontali s muscl es increases significantly in pati ents who move i n response
to speci fi c surgi cal stimul i .
77
However, EMG changes occur l ate and their interpretati on i s obscured
by muscl e rel axant drugs. The EEG changes depend largel y on the type of anesthetic drugs used.
Although a common EEG pattern can be recogni zed wi th i ncreasi ng depressi on of CNS function by
sedati vehypnoti cs and opioi d anal gesics, there is no characteri sti c EEG pattern associated wi th
unconsci ous and amnesti c states.
78
Univariate descriptors of EEG activity appear to be of l i mi ted
cl i ni cal usefulness, and no meani ngful correl ati on coul d be found between EEG spectral edge
frequency and hemodynami c response to surgi cal stimul i duri ng propofol anesthesi a.
79
Al though
EEG vari abl es (spectral edge frequency, median frequency) appear to be useful i ndi cators of the
CNS effects of anestheti c and analgesic drugs i n the experi mental setti ng, thei r useful ness i n
cl i ni cal practi ce i s l i mi ted because the many confounding factors duri ng the operati on (changing
drug level s and surgi cal sti mulation). The EEG-based bi spectral i ndex (BIS), pati ent state i ndex
(PSI), state entropy (SE), and response entropy (RE) moni tors represent newer approaches to the
anal ysi s of the spontaneous EEG, have proved to be a useful i ndi cator of anestheti c (hypnoti c)
depth.
80
Recent studi es have demonstrated that the BIS i ndex can i mprove fil tration of both IV
and volatil e anestheti cs during surgery, thereby faci li tati ng the recovery process. Using EEG-based
moni tori ng can reduce the ti me requi red to achi eve fast-track el i gibi l ity after ambul atory
surgery.
81, 82

An attractive al ternative to the spontaneous EEG is the evoked response of the EEG to sensory
stimul i (e.g., audi tory evoked potenti al [AEP] moni tors). The abi l ity to quanti tatively assess the
response of the body to varyi ng l evels of stimul ati on (sensory or audi tory evoked responses) may
be useful i n improvi ng the assessment of depth of anesthesi a.
83
Although all sedativehypnotic
drugs affect the brai nstem evoked potenti al s, uncertai nty sti ll exists regardi ng the most useful
evoked response(s) to measure. The compl exity associ ated wi th recordi ng evoked responses i s
much greater than recording the spontaneous EEG because the value is criti cal ly dependent on
technical factors (e.g., sti mulus intensi ty, stimul us rate, electrode posi ti on), body temperature, as
well as the anestheti c drugs. Al though most IV anestheti cs produce dose-dependent changes i n
the somatosensory evoked potenti al s, the correlati on between the acute hemodynami c changes to
surgi cal sti mul i and the earl y audi tory evoked responses i s poor. However, the early corti cal (mi d-
latency) auditory evoked response mi ght be useful i n detecti ng awareness under anesthesi a.
Furthermore, the auditory evoked potenti al index (AEPi ) may be more di scri mi natory than BIS in
characteri zi ng the transiti on from wakefulness to unresponsi veness.
84

As a resul t of the avai l abi l ity of more rapi d and shorter acti ng sedativehypnoti cs, sophi sti cated
computer technology, and new insi ghts i nto pharmacoki neticdynami c i nteracti ons, use of TIVA
techniques has been steadil y increasi ng during the l ast decade. When uti l izing constant rate IV
infusi ons, 4 to 5 hal f-li ves may be required to achi eve a steady state anestheti c concentrati on
(Fi g. 13-7). To more rapi dly achieve a therapeutic bl ood concentration, it i s necessary to
administer a l oadi ng (pri mi ng) dose and to mai ntai n the desi red drug concentrati on usi ng a
maintenance i nfusi on. The loadi ng dose (LD) and i ni tial mai ntenance i nfusi on rate (MIR) can be
calculated from previ ously determi ned populati on kineti c values using the fol l owi ng equati ons:
LD = Cp (mg/mL) Vd (mL/kg)
MIR = Cp (mL/kg) Cl (mL/kg/min)
where Cp = plasma drug concentrati on; Vd = di stri buti on vol ume; Cl = drug cl earance.
The use of the smal l er central vol ume of distri bution (Vc) for the Vd component of the LD equati on
wil l underestimate the LD, whereas use of the larger steady-state vol ume of di stri buti on (Vd
ss
) wil l
resul t in drug level s that transientl y exceed those that are desi red. If a smal l er LD is
administered, a higher i niti al MIR wi ll be requi red to compensate for the drug that i s removed
from the brai n by both redi stributi on and el i mi nati on processes. As the redi stri bution phase
assumes l ess i mportance, the MIR wi l l decrease because i t becomes sol el y dependent on the
drug' s el imi nati on and the desi red plasma concentrati on.
An al ternati ve approach i s to begi n with a rapid loadi ng i nfusi on wi th a bol us-el i mi nation transfer
(BET) scheme that combi nes three functi ons, as shown i n the fol lowi ng equati on:
Input = V1 C
ss
+ Cl C
ss
+ V1 C
ss
(k
21
e
-k21t
)
where V1 = distri bution volume of the central compartment; C
ss
= steady-state pl asma
concentration; Cl = drug cl earance; k
21
= redistri buti on constant from the central to the
peri pheral compartment; k
21
= redi stri buti on constant from the peripheral to the central
compartment. Implementati on of the BET i nfusion scheme requires the use of a mi croprocessor-
control led pump. If a conti nuous i nfusi on i s to be used i n an opti mal manner to suppress
responses to surgi cal sti mul i, the MIR should be vari ed accordi ng to the i ndi vi dual pati ent
responses (Fi g. 13-8). Usi ng an MIR l arge enough to suppress responses to the most intense
surgi cal sti mul i wi ll l ead to excessi ve drug accumulation, postoperative si de effects, and del ayed
recovery. More gradual si gns of inadequate or excessi ve anesthesi a can be treated by maki ng 50
to 100% changes in the MIR. Abrupt increases i n autonomi c activity can be treated by gi vi ng a
smal l

bol us dose equal to 10 to 25% of the initi al l oadi ng dose and increasi ng the MIR.
FIGURE 13-7. Si mul ated drug l evel curves when a constant infusi on i s admini stered
fol l owing a ful l loadi ng dose equal to [Cp] Vd
ss
(Curve A), a smal l er l oadi ng dose equal to
[Cp] Vc (Curve B), or i n the absence of a l oading (Curve C). (Repri nted with permi ssi on
from Whi te PF: Cl i ni cal uses of intravenous anestheti c and anal gesi c i nfusi ons. Anesth Analg
68:161, 1989.)
P.349
Despi te the marked pharmacoki netic and pharmacodynami c vari abi l i ty that exists among surgi cal
patients, computer programs have been devel oped that al l ow reasonabl e predi cti ons of
concentration-ti me profil es for IV anesthetics and analgesi cs. This new technol ogy has led to the
development of target-control led i nfusi ons (TCI), whereby the anesthesi ol ogist chooses a target
bl ood or brai n (effecti ve si te) drug concentrati on and the mi cropressor-control led i nfusi on pump
infuses the drug at the rate needed to rapi dly achieve and mai ntai n the desi red concentrati on
based on popul ati on pharmacoki netic-dynami c data.
84
It i s obvious that the target concentrati on
must be al tered dependi ng on the observed pharmacodynami c effect and the anti ci pated changes
in surgical sti mulation.
Cl osed-l oop control based on plasma drug concentrati ons is not possibl e because there i s no
avai labl e methodol ogy to obtai n frequent measurements of drug concentrati ons in real time. A
more advanced form of TCI uses a feedback si gnal generated by si mul ating a mathemati cal model
of the control process. Clearl y, the preci si on of control achievabl e wi th a model -based system is
only as accurate as the model . An exampl e of a model -based drug del i very system i s the
computer-assi sted conti nuous i nfusi on (CACI) system. An ideal automatic anesthesia del ivery
device woul d ti trate anestheti c to meet the needs of the i ndi vi dual pati ent usi ng an acquired
feedback si gnal whi ch accuratel y reflects the effect si te concentrati on of the drug. The most
successful efforts at feedback control of anesthesi a have uti li zed the BIS and corti cal audi tory
evoked responses to assess the pharmacodynami c end point.
83

The rapi d, short-acti ng, sedativehypnoti cs (e.g., methohexi tal, propofol ) and opi oi ds (e.g.,
al fentani l, remifentanil ) are better sui ted for conti nuous administration techniques than the more
tradi tional anestheti c and anal gesic agents because they can be more precisely titrated to meet
the unique and changi ng needs of the i ndi vi dual pati ent. Tradi ti onall y, the el iminati on hal f-li fe of a
parti cul ar drug has been used i n attempti ng to predi ct the durati on of drug acti on and the ti me to
awakening after di sconti nuation of the anestheti c infusi on. Usi ng conceptual model i ng techni ques,
it has been shown that the concept of context-sensi ti ve half-ti me i s more appropri ate i n choosi ng
drugs for conti nuous IV admi ni stration (Fi g. 13-9). Because none of the currently avai l abl e IV
drugs can provide for a complete anestheti c state wi thout produci ng prol onged recovery ti mes and
FIGURE 13-8. The landscape of surgi cal anesthesia. The surgi cal stimul i are not constant
duri ng an operati on; therefore, the plasma concentrati on of an IV anesthetic shoul d be
ti trated to match the needs of the i ndividual pati ent. (Repri nted wi th permission from Gl ass
PSA, Shafer SL, Jacobs JR, et al : Intravenous drug deli very systems. In Mi l ler's Anesthesi a,
4th ed, p 391. New York, Churchil l Li vi ngstone, 1994.)
undesi rable si de effects, i t i s necessary to admini ster a combi nation of IV drugs that provide for
hypnosi s, amnesia, hemodynami c stabi li ty, anal gesi a, and muscl e relaxati on. Selecting a
combi nation of drugs with si mil ar pharmacoki neti cs and compatibl e pharmacodynami c profi l es
should improve the anesthetic and surgi cal conditi ons. Sedati vehypnoti cs (methohexi tal ,
mi dazol am, propofol, etomi date, ketami ne), opi oids (fentanyl , al fentani l, sufentani l, remifentanil ),
and muscl e rel axants (ci s-atracurium, mi vacuri um, rocuronium) can be successfull y admini stered
using conti nuous infusi on TIVA techni ques as al ternatives to the vol ati le anesthetics and nitrous
oxi de.
Use of I nt r avenous Anest het i cs f or Sedat i on
The use of sedati vehypnoti c drugs as part of a moni tored anesthesi a care (MAC) techni que in
combi nation with local anestheti cs is becomi ng increasi ngl y popul ar.
85, 86, 87
Duri ng l ocal or regi onal
anesthesia, subhypnoti c dosages of IV anestheti cs can be i nfused to produce sedati on, anxi ol ysi s,
and amnesi a and enhance patient comfort. The opti mum sedati on technique achieves the desi red
cl i ni cal end poi nts wi thout produci ng peri operati ve si de effects (respi ratory depressi on, nausea,
and vomi ti ng). In addi ti on, i t should provi de for ease of ti trati on to the desi red l evel of sedati on
whi l e provi ding for a rapid return to a cl ear headed state on compl eti on of the surgi cal
procedure. Sedation al so consti tutes an essenti al el ement i n the management of patients i n the
ICU. The ideal sedative agent for cri ticall y il l pati ents woul d have mi ni mal depressant effects on
the respi ratory and cardi ovascul ar systems, woul d not i nfl uence bi odegradati on of other drugs,
and woul d be i ndependent of renal and hepati c functi on for its eli mi nation. Recentl y, the BIS
moni tor has been used to moni tor the depth of sedation i n the ICU. For pati ents undergoi ng
cardi ac surgery, rapi d reversibi l ity of the sedative state may resul t i n earl i er extubati on and l ead
to a shorter stay in the ICU. Al though i ntermi ttent bolus injecti ons of sedativehypnoti c drugs
(e.g., diazepam 2.5 to

5 mg, lorazepam 0.5 to 1 mg, midazolam 1.25 to 2.5 mg) have been administered duri ng local
anesthesia, continuous i nfusion techni ques wi th propofol are becomi ng increasi ngl y popul ar for
FIGURE 13-9. Context-sensi ti ve hal f-ti me val ues as a functi on of i nfusion durati on for IV
anesthetics, including thi opental , mi dazolam, diazepam, ketami ne, etomi date, and propofol .
The context-sensi ti ve half-ti me for thi opental and di azepam i s si gnifi cantly longer compared
with etomi date, propofol , and midazol am wi th an i ncreasing i nfusi on duration increase.
(Repri nted with permi ssi on from Hughes MA, Jacobs JR, Gl ass PSA: Context-sensi ti ve half-
ti me i n multi compartment pharmacoki neti c model s for i ntravenous anesthesi a.
Anesthesi ol ogy 76: 334, 1992.)
P.350
maintai ni ng a stable l evel of sedati on i n the OR and ICU setti ngs.
Benzodi azepines, parti cul arl y midazol am, are stil l the most wi del y used for sedati on i n the ICU
and for rel ief of acute si tuati onal anxi ety duri ng local and regi onal anesthesi a. Mi dazol am has a
steeper dose-response curve than diazepam (Fi g. 13-3), and therefore, careful titrati on is
necessary to avoi d oversedati on and respiratory depressi on. Mi dazolam infusi on, 0.05 to 5
mg/kg/mi n, can be hi ghl y effecti ve i n provi di ng sedati on for hemodynami call y unstable patients i n
the ICU.
88
Use of a mi dazol am i nfusi on has been shown to control agi tati on and decrease anal gesic
requi rements wi thout produci ng cardi ovascul ar or respiratory instabil i ty. However, marked
vari abi l ity exists for midazolam in the i ndi vi dual pati ent dose-effect relationships.
88
In addition,
marked tolerance may devel op to the CNS effects of midazol am wi th prol onged admi ni strati on.
Propofol sedation offers advantages over the other sedativehypnoti cs (including midazolam)
because of i ts rapi d recovery and favorable si de effect profi l e. In addi ti on, the degree of sedati on
is readi l y changeabl e from li ght to deep level s by varyi ng the MIR. Foll owi ng a propofol LD of
0.25 to 0.5 mg/kg, a careful ly titrated subhypnoti c i nfusi on of 25 to 75 mg/kg/min produces a
stabl e l evel of sedation wi th mi nimal cardiorespi ratory depression and a short recovery peri od.
Because even l ow concentrati ons of propofol can depress the venti l atory response to hypoxi a,
supplemental oxygen should always be provi ded. Sedati ve i nfusi ons of propofol produce l ess
peri operative amnesi a than mi dazolam, and propofol -induced amnesi a appears to be di rectl y
rel ated to the infusi on rate.
A small dose of midazolam (2 mg IV) administered i mmedi atel y before a vari abl e-rate i nfusi on of
propofol has also been shown to si gni fi cantl y decrease i ntraoperati ve anxiety and recal l of
uncomfortable events without compromi si ng the rapi d recovery from propofol sedati on.
89
Propofol
sedati on can al so be suppl emented wi th potent opi oi d and nonopi oi d anal gesi cs to provi de
sedati on anal gesi a. In compari ng propofol and mi dazol am for pati ent-control led sedati on,
mi dazol am was associ ated wi th l ess i ntraoperative recal l and pai n on injecti on than propofol , whi l e
propofol was associ ated wi th l ess residual i mpai rment of cogniti ve functi on. Compared wi th
mi dazol am i n the ICU setti ng, use of propofol sedati on al l owed for more rapi d weani ng of cri ti cal l y
il l pati ents from arti fi cial venti lation.
90
It has been suggested that the more rapi d weani ng after
propofol sedation may be cost-savi ng compared with midazolam when only a l i mi ted peri od of
sedati on (<48 hour) i s required.
91
Al though a pharmacoki neti c study yi el ded no evi dence of a
change in receptor sensiti vi ty or drug accumul ation over a 4-day study peri od, prel i mi nary data
suggest that tolerance to the CNS effects of propofol may devel op wi th more prol onged
administrati on (>1 week).
Concerns have been rai sed about elevated l i pid plasma l evels i n pati ents sedated with propofol for
several days, especi al l y when hi gh infusi on rates (>6 mg/kg/h) are uti li zed. However, the
avai labi li ty of a propofol formul ati on wi th reduced lipid content (Ampofol) shoul d decrease the ri sk
of thi s problem in the future. Because of conflicti ng evi dence regardi ng increased mortali ty as a
resul t of myocardial fai lure when propofol was used for sedati on i n the neonatal ICU,
92, 93, 94
more
safety data are needed to defi ne the i ndi cations for the use of prol onged propofol i nfusions,
especi al l y i n the pedi atric popul ati on. Low-dose ketamine infusi ons (5 to 25 mg/kg/min) can al so
be used for sedati on and anal gesi a duri ng local or regi onal anestheti c procedures, as wel l as i n
the ICU setti ng.
59
Midazol am, 0.07 to 0.15 mg/kg i nfused over 3 to 5 mi n, fol l owed by ketami ne,
0.25 to 0.5 mg/kg IV over 1 to 3 mi n, produced excel l ent sedati on, amnesi a, and analgesia
without si gni fi cant cardi orespiratory depressi on.
CONCLUSION
It i s obvious that many of the goal s desi rabl e i n an i deal IV anestheti c have not been achi eved
with the currentl y avai labl e drugs. Neverthel ess, each of these sedativehypnoti c drugs possesses
characteri sti cs that may be useful in speci fi c cli ni cal si tuati ons. For exampl e, thi opental remai ns a
widel y used IV anestheti c even though i t is unstabl e i n soluti on and produces a hi gh i nci dence of
postoperati ve drowsi ness and sedati on. In si tuati ons where a rapi d recovery i s not essenti al (e.g.,
i npati ent procedures), the barbi turates may be the most cost-effecti ve IV anestheti cs. Al though
recovery from anesthesia with methohexi tal i s more rapi d than wi th thi opental (and compares
favorabl y wi th propofol ), exci tatory side effects (e.g., myoclonus, hi ccoughing) are more
promi nent than wi th the other barbiturates or propofol . Importantly, methohexital remai ns the
anestheti c of choi ce for ECT procedures.
Propofol i s the IV drug of choice when a rapi d and smooth recovery i s required (e.g.,
outpati ent [ambul atory] anesthesi a). Recovery from propofol anesthesi a i s characteri zed by
the absence of a hangover effect and less PONV. The cardi ovascul ar depressant effects produced
by propofol appear to be more pronounced than those of thiopental , but can be mi ni mi zed by
careful ti trati on and the use of a variabl e-rate i nfusi on duri ng the mai ntenance peri od. The abi li ty
to combine propofol with potent, rapi d and short-acti ng opi oid anal gesics (e.g., remi fentanil ) has
faci li tated the use of TIVA techniques. Improvements i n the abil i ty to del i ver IV anesthetics
(propofol) and anal gesi cs (remi fentani l ) wil l l ead to a greater acceptance of these techni ques i n
the future.
95

When admi nistered alone for i nducti on of anesthesi a, benzodi azepi nes are associ ated wi th a
prol onged recovery profi l e. In the usual induction doses, benzodi azepi nes are associ ated wi th
minimal cardiorespiratory depressi on and the rel i abl e amnestic effect may be valuable duri ng TIVA
(e.g., for acute sedation pri or to induction of anesthesia, for mai ntenance i n the absence of
ni trous oxide). When admi ni stered in small er doses, mi dazolam can al so be a val uabl e adjunct as
part of a coinduction and/or maintenance techni que. Other short-acti ng benzodi azepi nes may be
developed i n the future (e.g., Ro 48-6791).
Etomi date has mi ni mal cardiovascular and respi ratory depressant effects and is therefore, an
extremel y useful i nduction agent in hi gh-ri sk pati ents. It i s al so used as an al ternative to
methohexital for ECT procedures. Unfortunately, pai n on i njection, exci tatory phenomena,
adrenocorti cal suppression, and a hi gh i nci dence of PONV have l i mi ted the use of etomidate to
special situations i n whi ch i t offers si gni fi cant advantages over other avai l abl e IV anestheti cs. The
new l i pid formul ation of etomi date i s associ ated wi th i ts fewer si de effects and may al low thi s IV
anesthetic to gai n wi der cl i ni cal acceptance i n the future.
Ketamine is a uni que IV anesthetic that produces a wi de spectrum of pharmacol ogi c effects
(i ncl udi ng sedati on, hypnosis, somati c analgesia, bronchodi lation, and sympatheti c nervous
system stimul ati on). Induction of anesthesi a can be rapi dl y achi eved fol l owi ng parenteral
injecti on, maki ng it the drug of choice when IV access i s difficult to establ i sh i n an emergency
si tuati on. Ketami ne i s also i ndi cated for i nducti on of anesthesia i n the presence of hypovol emi c
shock, acute bronchospastic states, ri ght-to-left intracardi ac shunts, and cardi ac tamponade. The
adverse cardi ovascul ar, cerebro-dynami c, and psychomimeti c effects of ketami ne can be
mi ni mi zed by pri or admi ni strati on of a benzodiazepine (e.g., mi dazol am) or sedati vehypnoti c
drugs (e.g., thi opental ,

propofol ), maki ng i t useful as part of coi nducti on and mai ntenance anestheti c techni ques. The
introducti on of the more potent S(+)-ketami ne may i ncrease use of ketami ne i n smal l -doses (75
to 250 g/kg) or by continuous i nfusion (10 to 25 g/kg/mi n) as an IV adjuvant during general
anesthesia because of its anestheti c and anal gesi c-spari ng activity.
Intravenous anesthesi a has evolved from bei ng used mai nl y for induction of anesthesi a to
provi ding unconsci ousness and amnesi a for surgi cal procedures performed under l ocal , regi onal ,
and general anesthesi a. New i nsi ghts into the pharmacokineti cs and dynamics of IV anestheti cs,
as wel l as the development of computer technology to faci l i tate IV drug del i very (e.g., TCI), have
greatl y enhanced the use of TIVA techniques. The shorter context-sensi ti ve hal f-li fe val ues of the
newer sedativehypnoti c drugs make these compounds more useful as conti nuous infusi ons for
maintenance of anesthesi a or sedation. Whi le the search for the i deal IV anestheti c conti nues, the
chal l enge for the anesthesi ol ogi st is to choose the most cost-effecti ve sedati vehypnoti c that most
cl osel y matches the needs of a speci fi c cli ni cal si tuati on.
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el i gibi l ity after ambul atory anesthesi a wi th propofol and desflurane? Anesth Anal g 87:1245,
1998
82. Whi te PF, Ma H, Tang J, Wender R, Sl oninsky A, Kari ger R: Does the use of
el ectroencephal ographi c bispectral i ndex or audi tory evoked potenti al i ndex moni toring
faci li tate recovery after desfl urane anesthesi a in the ambul atory setti ng? Anesthesi ol ogy
100:811, 2004
83. Struys M, Versi chel en L, Morti er E et al : Comparison of spontaneous frontal EMG, EEG
power spectrum and bi spectral i ndex to moni tor propofol drug effect and emergence. Acta
84. Schraag S, Bothner U, Gajraj R et al : The performance of el ectroencephal ogram bi spectral
i ndex and audi tory evoked potenti al i ndex to predict l oss of consci ousness duri ng propofol
infusi on. Anesth Analg 89:1311, 1999
85. Mi l ne SE, Kenny GN: Future appl icati ons for TCI systems. Anaesthesia 53(suppl 1): 56,
1998
86. Whi te PF, Vascones LO, Mathes SA et al : Comparison of mi dazol am and di azepam for
sedaeti on duri ng pl asti c surgery. J Pl ast Reconstruct Surg 81:703, 1988
87. Tayl or E, Ghouri AF, Whi te PF: Mi dazolam i n combi nation wi th propofol for seadati on
duri ng l ocal anesthesia. J Cl i n Anesth 4:213, 1992
88. S Rgo MM, Watcha, MF, White PF: The changing role of monitored anesthesia
care in the ambulatory setting. Anesth Analg 85:1020, 1997
89. Shafer A, Doze VA, Whi te PF: Pharmacokinetic vari abi l i ty of mi dazol am i nfusi ons in
criti cal ly i ll pati ents. Cri t Care Med 18:1039, 1990
90. White PF, Negus JB: Sedative infusions during local or regional anesthesia: A
comparison of midazolam and propofol. J Clin Anesth 3:32, 1991
91. Ai tkenhead AR, Pepperman ML, Wi ll atts SM et al : Comparison of propofol and midazolam
for l ong-term sedation i n cri ti cal l y i l l pati ents. Lancet 2:704, 1989
92. Carrasco G, Molina R, Costa J et al : Propofol vs. midazolam in short-, medi um-, and l ong-
term sedati on of cri ti cal l y i l l patients: A cost-benefi t anal ysi s. Chest 103:557, 1993
93. McFarl an CS, Anderson BJ, Short TG. The use of propofol i nfusions i n paedi atric
anaesthesi a: A practi cal guide. Paedi atr Anaesth 9:209, 1999
94. Parke TJ, Steven JE, Rice ASC et al : Metabol ic acidosis and fatal myocardial fail ure after
propofol infusi on i n chil dren: fi ve case reports. BMJ 305:613, 1992
95. Marti n PH, Murphy BVS, Petros AJ: Metaboli c, biochemi cal and haemodynami c effects of
infusi on of propofol for l ong-term sedation of chil dren undergoi ng i ntensi ve care. Br J Anaesth
79:276, 1997
96. Egan T, Shafer SL: Target-controlled infusions for intravenous anesthetics.
Opi oi ds
Chapter 14
Opioids
Barbara A. Coda
KEY POINTS
The term opi oi d desi gnates al l drugs, both natural and syntheti c, including
endogenous pepti des, whi ch have morphine-li ke properti es. In i ts broadest
sense, i t refers to agoni sts, parti al agoni sts, and mixed agoni stantagonists at
one or more of the opi oid receptors.
Opi oi d receptor cl assifi cati on i s based on bi ndi ng activity of speci fic l i gands:
morphine at mu (), ketocyclazoci ne at kappa (), enkephal i ns at del ta (), and
endorphi n at epsil on () receptors, and speci fi c opi oi d receptors are responsi ble
for di fferent opi oi d effects. Most opi oi ds used i n cl i ni cal anesthesi a today (e.g.,
fentanyl and morphi ne and their derivati ves) are hi ghl y sel ecti ve for opi oi d
receptors. Naloxone, the most commonl y used opi oid antagonist, i s not sel ecti ve
for opi oi d receptor type. Very few endogenous opi oi ds exhibi t great sel ecti vi ty
for a single receptor type.
Opi oi ds are admi ni stered pri maril y for thei r anal gesic effect, whi ch results from
compl ex i nteracti ons at discrete sites in the brain, spinal cord, and under
certai n condi tions, peri pheral tissues, and i nvol ves both
1
and
2
opi oid
effects. For the mi xed agoni stantagonist opioi ds, anal gesi c effects are al so
mediated at receptors. Opioi ds act sel ecti vel y on neurons that transmit and
modul ate noci cepti on, l eavi ng other sensory modal i ti es and motor functions
intact.
Opi oi ds are used i n combi nati on wi th vol ati le anestheti cs with or wi thout ni trous
oxi de to produce balanced anesthesi a. Fentanyl and i ts derivatives reduce the
mi ni mum al veol ar concentrati on (MAC) of volati l e agents i n a dose-dependent
fashion. An apparent ceiling effect is seen at 70% MAC reduction, al though
reduction of up to 90% has been reported for sufentani l and remifentani l .
Fentanyl and its deri vatives can be combi ned with a sedativehypnoti c agent to
provi de total i ntravenous anesthesia (TIVA). Al fentani l and remi fentani l are
parti cul arl y sui ted for TIVA because of thei r rapi d onset and short durati on of
acti on.
Fentanyl and i ts deri vati ves can be given i n very hi gh doses for opi oi d

HISTORY
Opi oi ds have been used i n the treatment of pai n for thousands of years. The drug opi um, whi ch
contai ns more than 20 al kaloi ds, is obtai ned from the exudate of Papaver somniferum seed pods,
and the word opi um is derived from opos, the Greek word for jui ce. The first undi sputed
reference to poppy juice is found in the third century (BCE) wri tings of Theophrastus.
1
The German
pharmacist Sertuener isolated what he call ed the sopori fic pri ncipl e in opi um i n 1806, and in
anesthesia, but even at extremely high doses, i .e., those that produce
profound anal gesi a as well as apnea, unconsciousness i s not assured.
Muscl e hypertonus occurs wi th high-dose opi oid admini stration, and severe
chest wal l ri gidi ty can i nterfere with venti lation. It i s seen most often on
inducti on with rapid-acti ng opi oids. Opi oi d-induced muscl e ri gi dity is i ncreased
in the presence of ni trous oxi de and can be prevented or treated wi th sedati ve
hypnoti cs or low-dose muscl e rel axants.
Al l opi oi ds depress respi ratory dri ve i n a dose-dependent manner, and
ventil atory depression is seen even at doses associ ated wi th mil d anal gesi a.
Equi analgesi c opi oi d doses produce equi val ent magni tudes of respi ratory
depressi on. When gi ven in combinati on wi th benzodi azepi nes, opi oi ds can bl unt
hypoxi c dri ve to a greater extent than the hypercarbi c dri ve and produce
profound respi ratory depression.
Fentanyl or one of i ts derivati ves is often used as a component of anestheti c
inducti on. Small opioi d doses reduce the dosage requi rements of sedati ve
hypnoti cs, and bl unt airway refl exes (sympatheti c activi ty i n response to
laryngoscopy).
In l ow doses, opi oids have mi ni mal cardiovascular effects, but bradycardi a and
hypotensi on are seen wi th higher doses. A promi nent feature of fentanyl and i ts
deri vati ves i s thei r remarkable hemodynamic stabi li ty. Morphi ne and meperi di ne
cause hi stami ne rel ease, and high doses of these opioids can produce greater
hypotensi on than fentanyl and its deri vati ves.
All opioi ds can produce nausea and vomi ting through compl ex i nteracti ons at
nausea and vomi ti ng centers in the medul la. In general , equi anal gesi c doses of
opi oi ds produce si mi lar magni tude of nausea. Opi oid-induced nausea can be
exacerbated by vesti bul ar i nput, and i s parti cul arl y probl emati c in ambulatory
patients.
Opi oi ds produce smooth muscl e spasm throughout the gastrointestinal tract.
They decrease gastri c secreti ons and del ay gastri c emptyi ng. Opi oi ds i ncrease
the tone of the common bi l e duct and sphi ncter of Oddi , although meperi di ne
and the mi xed agoni st-antagonists cause l ess bi l iary spasm than morphi ne and
fentanyl.
P.354
1817 named i t morphi ne, after the Greek god of dreams, Morpheus.
2
Isolation of other opi um
al kaloi ds foll owed, and by the mi d 1800s, the medical use of pure al kal oi ds rather than crude
opi um preparati ons began to spread.
1
Morphi ne was used wi del y to treat wounded sol di ers duri ng
the American Civil War, and i n 1869, its use as a premedi cati on was descri bed by Cl aude Bernard.
However, in the absence of muscl e rel axants and control led ventil ati on, opi oi ds were associated
with a si gni fi cant ri sk of severe respiratory depressi on and death. Thus thei r use i n anesthesia
was l i mi ted at that ti me.
Wi th the advent of cardiac surgery i n the l ate 1950s came the development of opi oi d anesthesi a.
A decade l ater, Lowenstei n reported the use of progressively hi gher doses of morphi ne (0.5 to 3
mg/kg), but found li mitati ons including i ncompl ete suppressi on of the stress response,
hypotensi on, awareness duri ng anesthesi a, and i ncreased fl ui d and bl ood requi rements.
3

Fentanyl, a 4-anil i nopiperidi ne deri vati ve of phenoperi di ne, was synthesized i n 1960. The
compl etel y syntheti c opioi ds were more potent and had a better safety margi n (rati o of medi an
lethal dose to lowest effecti ve dose for surgery) than meperi dine. Advances i n surgi cal techni ques
created the need for potent opioi ds wi th a rapid onset, a bri ef, predi ctabl e durati on, and a
maxi mal safety margi n for use i n cl i ni cal anesthesi a, and l ed to devel opment of sufentani l ,
al fentani l, and other fentanyl deri vatives between 1974 and 1976. The newest potent opi oid,
remi fentani l , has an ultrashort duration of action because of rapi d metabol i sm by ester hydrol ysi s
and offers an advantage i n speci fi c cl i ni cal settings.
The search for opioid anal gesi cs wi thout potential for dependence was sti mul ated by concerns
about opi oi d addi cti on and l ed to the i dentificati on of multi ple opi oi d receptor types. In the mi d
1960s, nal orphi ne, a morphine antagoni st, was al so found to have analgesic properties. Two other
compounds, pentazoci ne and cycl azoci ne, antagonized some of morphine's effects. Pentazoci ne
al so produced anal gesi a, and both produced some psychotropi c effects that morphine di d not.
These and other observati ons l ed Martin to propose the theory of receptor dual ism. Intri nsic to
this theory were two key concepts: (1) the exi stence of mul ti pl e opi oid receptors (ori ginal l y onl y
two were proposed); and (2) the i dea of pharmacologic redundancy (i.e., more than one receptor
coul d medi ate a physi ol ogi c functi on, such as analgesi a).
4
Thus, a drug coul d be a strong agoni st,
a parti al agoni st, or a competi ti ve antagoni st at one or more of the different receptor types.
Subsequent research has reveal ed three di sti nct fami l ies of opioi d pepti des and mul ti pl e
categori es of opioid receptors. Future research may identi fy compounds that provi de potent
anal gesi a but fewer si de effects or propensi ty for abuse based on receptor sel ecti vi ty.
TERMINOLOGY
The term opi ate was ori gi nally used to refer to drugs deri ved from opium, incl uding
morphi ne, i ts semi synthetic derivati ves, and codei ne. The more general term opi oi d was
introduced to designate all drugs, both natural and syntheti c, wi th morphi ne-li ke properti es,
i ncl udi ng endogenous pepti des. The nonspeci fi c term narcoti c has been used to refer to
morphi ne and morphine-li ke anal gesi cs. However, because of i ts use in a l egal context, referri ng
to any drug (i ncl udi ng nonopioi ds, such as cocai ne) that can produce dependence, the term
narcoti c is not useful in a pharmacol ogi c or cli nical context.
In i ts broadest sense, the term opioi d can refer to agoni sts, partial agoni sts, mixed agonist
antagonists, and competi tive antagoni sts. Di fferenti ati on of these terms requi res understandi ng of
receptorl i gand i nteracti ons. Receptor theory states that drugs have two i ndependent
characteri sti cs at receptor sites: affinity, the abi l i ty to bi nd a receptor to produce a stabl e
compl ex, and intri nsic acti vi ty or effi cacy, whi ch i s descri bed by the dose-effect curve resul ting
from the drugreceptor combi nati on. Effi cacy can range from zero (i .e., no effect) to the
maximum possible effect, depi cted graphi cal l y as the plateau of the dose-effect curve (Fi g. 14-1).
Gi ven a hi gh enough dose, an agoni st will produce the maximum possibl e effect of bi ndi ng wi th
the receptor, whereas an antagonist produces no di rect effect when i t bi nds the receptor. A parti al
agoni st has a dose-effect cei li ng that i s l ower than the maxi mum possi bl e effect produced by a ful l
agoni st, as wel l as a dose-effect curve that i s l ess steep than that of a ful l agoni st. A mi xed
agoni stantagonist acts as an agoni st (or partial agoni st) at one receptor and an antagonist at
another. It i s i mportant to differenti ate the term potency from effi cacy. Whereas effi cacy
defines the range in magnitude of an effect produced by a drugreceptor combi nati on rel ati ve to
the maximum possible effect, potency refers to the rel ati ve dose required to achi eve an effect,
and is rel ated to receptor affi nity. Thus, at the lower end of the effect range, a parti al agoni st
may be more potent than a ful l agoni st (see Fi g. 14-1). However, even at very l arge doses the
effi cacy, or maxi mum effect achieved by the parti al agoni st, wil l be l ess than the maximum
possible effect of a full agonist.
ENDOGENOUS OPIOIDS AND OPIOID RECEPTORS
All of the endogenous opi oi ds are derived from three prohormones: proenkephal i n, prodynorphi n,
and pro-opi omel anocorti n (POMC). Each of these precursors is encoded by a separate gene. The
three fami l i es of pepti des di ffer in thei r distri buti on, receptor sel ecti vi ty, and neurochemical rol e,
5

but

share some features. For exampl e, al l begi n wi th the pentapepti de sequences of [Leu]- or [Met]-
enkephal in. Proenkephal in includes the pentapeptide sequences for [Met]- and [Leu]-enkephal in,
and cel l s that synthesi ze proenkephal i n are widel y di stri buted throughout the brai n, spi nal cord,
and peri pheral si tes, parti cularly the adrenal medull a.
6
Pro-opi omelanocorti n is the common
precursor of -endorphi n, adrenocorti cotropi c hormone (ACTH), and mel anocyte-stimul ati ng
hormone (MSH). The term endorphi n is reserved for pepti des of the POMC fami l y. The major si te
of POMC synthesis i s the pi tui tary, but i t i s al so found i n the pancreas and placenta. The
dynorphi n pepti des al l begi n wi th the [Leu]-enkephal in sequence and are wi del y di stri buted
throughout the brain, spi nal cord, and peri pheral sites.
Endogenous opioi ds bi nd to a number of opioi d receptors to produce thei r effects. Marti n' s
initi al cl assifi cati on of opioi d receptors i nto the three types was based on bi ndi ng acti vi ty of
the exogenous li gands morphi ne, ketocycl azoci ne, and SKF10,047 at mu (), kappa (), and si gma
() receptors, respecti vel y. Other opioid receptors identi fi ed since that ti me are del ta ()
receptors, bound by enkephali ns, and epsi l on () receptors, bound by endorphi n.
5, 6
There i s al so
FIGURE 14-1. Log dose-effect curves for two agonists (A and B) with equal efficacy but
di fferent potency, and a parti al agoni st (C). Note that the potencies of A and C are si mi lar,
but the effi cacy is l ess and the slope of the dose-response curve i s shal lower for the parti al
agoni st. Note al so that at l ower doses, the partial agoni st C i s more potent than the ful l
agoni st B.
P.355
evi dence supporti ng the exi stence of two , two , and three receptor subtypes.
8
Whi le it
appears that speci fic opi oi d receptors are responsi bl e for di fferent opi oi d effects and that
synthetic opioi ds may be highly selecti ve for a receptor type or subtype, i t i s important to note
that very few endogenous opi oi ds exhi bi t great sel ecti vi ty for a si ngl e receptor type.
7
Remember
al so, that the theory of receptor dual ism includes the concept of pharmacologi c redundancy of
receptor functi on. Thus, observed opi oid effects typi cal ly i nvol ve complex interacti ons among the
di fferent receptor systems at supraspi nal , spinal , and peri pheral si tes. Tabl e 14-1 summari zes our
current understanding of which opi oid receptors are responsi bl e for medi ating opi oi d anal gesi c and
si de effects. One caveat in i nterpreti ng this summary i s that speci es di fferences i n opi oid receptor
systems exi st, so the results of ani mal studies, from which most of this i nformation is derived,
may not al ways be di rectl y appli cabl e to humans.
Most opi oi ds used i n cl i ni cal anesthesi a today (e.g., fentanyl and morphine and thei r
deri vati ves) are hi ghl y sel ecti ve for opi oi d receptors. Nal oxone, the most commonl y used
opi oi d antagonist, i s not sel ective for opi oi d receptor type. In fact, current identi fi cati on of an
opi oi d-receptormediated drug effect requires demonstrati on of nal oxone reversi bi li ty.
Development of sel ecti ve opioi d receptor subtype antagoni sts wi l l be hel pful tool s in i mproving our
understandi ng of whi ch receptor subtypes mediate speci fi c opi oi d effects.
TABLE 14-1 Tentative Classification of Opioid Receptor Subtypes and Their Actions
RECEPTOR ANALGESIA RESPIRATORY GASTROINTESTINAL ENDOCRINE OTHER
Peri pheral Gastric secretion
GI transi t
supraspi nal and
peri pheral
Anti di arrheal
Skeletal
muscle
ri gi di ty
Pruri tus
?Urinary
retention
(and/or )
Bi l i ary spas
(probabl y >
receptor ty
1
Supraspi nal Prolacti n
rel ease
Acetyl chol i
turnover
Catal epsy
2
Spinal
Supraspinal
(synergi sm
wi th spi nal )
Respi ratory
depressi on
GI transi tspi nal and supraspi nal Most
cardi ovascu
effects
Peri pheral ADH
rel ease
Sedati on
1
Spinal
2
? (Pharmacol
unknown)
3
Supraspi nal
At the cel l ul ar l evel , endogenous and exogenous opi oi ds produce their effects by al teri ng patterns
of interneuronal communicati on. Receptor bindi ng i ni tiates a seri es of physi ologi c functi ons
resul ti ng in cell ul ar hyperpol ari zation and inhi bi ti on of neurotransmitter release, effects that are
mediated by second messengers. Al l opi oid receptors appear to be coupl ed to G-protei ns,
5
which
regul ate the activity of adenyl ate cyclase among other functi ons. G-protei n i nteractions, i n turn,
affect ion channel s; di fferent i on conductances may be i nvol ved at di fferent opi oi d receptor
types.
7

STRUCTUREACTIVITY RELATIONSHIPS
The wi de array of di fferent mol ecules that produce morphi ne-li ke anal gesi a and si de effects,
incl udi ng endogenous opi oids, al l share some common structural characteristi cs. Horn and

Rodgers
8
suggested that the tyrosine moi ety at the ami no termi nal of the enkephal i ns formed the
basis of a si gni fi cant conformati onal relationship between the enkephal i ns and opi ates. The
structure of the phenanthrene cl ass of opium al kal oi ds i s compl ex and consi sts of fi ve or si x fused
ri ngs. Morphine, one of three phenanthrenes, has a ri gi d fi ve-ri ng structure that conforms to a T
shape (Fi g. 14-2).
9
The other phenanthrenes are codei ne, a derivati ve of morphi ne, and thebai ne,
a precursor of oxycodone and naloxone. Progressi vel y reduci ng the number of fused ri ngs from the
phenanthrenes yi el ds the morphinans, wi th four rings; the benzomorphans, wi th three ri ngs; the
phenyl pi peri di nes, wi th two ri ngs; and finally, the tyramine moiety of the endogenous opi oid
pepti des, wi th a si ngle hydroxyl ated ring. Al l of these distinct cl asses of drugs possess morphi ne-
li ke activity. Thorpe' s
9
opi ate receptor model i s based on these structural si mi lariti es with two
aromati c bi nding sites and one ani onic site responsi bl e for bi ndi ng the positi vel y charged ni trogen.
In thi s model, differences i n bi nding at the aromati c or ani onic si tes coul d account for receptor
specifici ty or for agoni st versus antagonist acti vi ty. Structural modificati ons alter such i mportant
properties as opi oi d receptor affi nity, agoni st versus antagonist acti vi ty, resi stance to metabol i c
breakdown, l i pid sol ubi li ty, and pharmacoki netics.
1

Peri pheral ?Respi ratory
depressi on
GI transi tspi nal
Antidi arrhealspi nal
and supraspi nal
?Growth
hormone
rel ease
?Urinary
retention
(and /or )
1
Spinal Dopami ne
turnover
2
Supraspi nal
Unknown
(receptor
type not
identi fi ed)
Supraspi nal Pupi ll ary
constri cti on
Nausea and
vomiting
Adapted from Pasternak GW: Pharmacol ogical mechani sms of opioi d anal gesics. Cl i n Neuropharmacol
16:1, 1993.
P.356
PHARMACOKINETICS AND PHARMACODYNAMICS
Basi c Consi der at i ons
Opi oi d effects are i ni tiated by the combi nati on of an opi oi d with one or more receptors at speci fi c
ti ssue si tes. The relationshi p between opi oi d dose and effects depends on both pharmacoki neti c
and pharmacodynami c vari abl es. Pharmacoki netics determi nes the relationshi p between drug dose
and its concentrati on at the effect si te(s). Pharmacodynami c vari abl es rel ate the concentration of
a drug at i ts si te of action, in thi s case opi oid receptors i n the brai n and other ti ssues, and the
intensi ty of i ts effects. Pharmacoki neti cs general l y refers to the study of bl ood or pl asma drug
concentration versus ti me because blood is easy to sampl e, bears a defi nabl e rel ati onshi p to
ti ssue concentrati on, and i s the medi um by whi ch drugs are distri buted throughout the body.
Changes i n drug concentrati on over time in the blood, at the effect si te and at other si tes, are
determi ned by physi cochemi cal properti es of the drug as wel l as the processes of absorption,
redi stri buti on, bi otransformati on, and eli mi nation.
In cli ni cal anesthesia practice, opioi ds are typicall y administered intravenousl y. After an
i ntravenous bol us dose or bri ef i nfusi on, peak pl asma opi oi d concentrations occur withi n mi nutes.
Pl asma drug concentrati ons then fal l rapi dly as the drug i s di stri buted to extravascul ar sites,
incl udi ng si tes of action, nonel imi nati ng ti ssues, and eli minati ng organs. Compartmental model s
descri be the ti me course of change in pl asma concentrati on; typicall y, opi oids used i n anesthesia
are characteri zed by two- or three-compartment model s (see Chapter 11: Basi c Princi pl es of
Cli nical Pharmacol ogy). The earl y rapid decl i ne i n pl asma concentrati on after the peak i s cal l ed the
di stri bution phase, and the subsequent slower decl ine is the el i mi nation phase. From a
mathemati cal curve fi tted to measured pl asma concentration versus ti me data, di stri buti on and
FIGURE 14-2. T-shape conformati on of opi oid molecul es. A. Morphi ne, one of the
phenanthrene al kaloi ds, has a rigi d fi ve-ri ng structure, wi th a phenyl pi peri di ne ri ng formi ng a
crossbar and a hydroxylated aromati c ri ng in the vertical axis. B. Reducing the number of
fused rings to four yi el ds the morphinan cl ass of opi um al kal oids. C. Benzomorphans have
three fused ri ngs. D. Phenyl pi peri di nes and the 4-anil i nopiperidi nes such as fentanyl have a
fl exi bl e two-ri ng structure. E. Fi nal l y, the tyrami ne moi ety, which i s the amino termi nal
pepti de of both [Leu]- and [Met]-enkephal in, i s shown, wi th a si ngle aromatic ri ng. Another
key feature is the positively charged basi c ni trogen equi di stant (4.55) from the aromati c
ri ng. (Adapted wi th permission from Thorpe DH: Opi ate structures and activity: A gui de to
understandi ng the receptor. Anesth Anal g 63:143, 1984.)
el i mi nation half-li ves, systemic cl earance, compartment volumes, and i ntercompartmental transfer
rate constants can be cal cul ated. Tabl e 14-2 summari zes the esti mates of key pharmacokinetic
parameters and physi cochemical characteri sti cs for the most commonl y used opi oids i n cl i ni cal
anesthesia.
TABLE 14-2 Physicochemical Characteristics and Pharmacokinetics of Commonly Used Opioid
Adults
PARAMETER MORPHINE MEPERIDINE FENTANYL SUFENTANIL ALFENTANIL REM
pK
a
7.9 8.5 8.4 8.0 6.5
% noni oni zed
(pH 7.4)
23 7 8.5 20 89
ow
1.4 39 816 1757 128
Protei n
bi nding (%)
35 70 84 93 92
Clearance
(mL/min)
1050 1020 1530 900 238
Vd
ss
(L)
224 305 335 123 27
Rapi d
di stri bution
half-li fe
(T
1/2
, min)
1.21.9 1.4 1.03.5
Slow
redi stri buti on
half-li fe
(T
1/2
, min)
1.54.4 416 9.219 17.7 9.517
El iminati on
half-li fe
(T
1/2
, h)
1.73.3 35 3.16.6 2.24.6 1.41.5 0
ow
, octanol :water partiti on coeffi cient, Vd
ss
, steady-state vol ume of di stri buti on.
a
Unpubl i shed i nformation from Glaxo. JG Bovil l , personal communicati on.
b
Glass PSA et al : Anesth Anal g 89:S7, 1999.
It i s important to note that there i s tremendous variabi li ty i n the val ues publ i shed for opi oi d
pharmacokineti c parameters. Thi s i s due, i n part, to real popul ati on differences (e.g., age,
di seases), and i n part to di fferences i n study design (e.g., sampli ng si te, durati on, concomitant
events such as surgery, or other drugs that may affect di fferenti al fl ow to si tes of metabol i sm or
el i mi nation). In addi ti on, the distri buti onal and el i mi nation half-li ves are of li mited use i n
predi cti ng the onset and durati on of opi oi d acti on i n cl ini cal anesthesi a. Contri buti ons of
di stri bution processes between physi ol ogic compartments vary with ti me. In an effort to relate
pharmacokineti cs to the ti me of onset and duration of action, concepts such as effect
compartment i n pharmacodynami c model i ng
10
and context-sensi ti ve hal f-ti mes
11
have been
devel oped. The appl i cati on of these concepts are consi dered l ater in thi s chapter.
Physi cochemi cal properti es of opi oids i nfluence both pharmacoki netics and pharmacodynami cs. To
reach i ts effector sites i n the central nervous system (CNS), an opi oi d must cross bi ol ogi c
membranes from the blood to receptors on neuronal cell membranes. The abil i ty of opi oids to
cross thi s bl ood-brai n barri er depends on such properti es as mol ecular size, ioni zation, li pi d
sol ubi l i ty, and protei n bi nding (see Tabl e 14-2). Of these characteri sti cs, l i pid sol ubi li ty and
ioni zati on assume major i mportance i n determini ng the rate of penetrati on to the CNS. In the
l aboratory, l i pi d sol ubil i ty is measured as an octanol :water or octanol:buffer partition coefficient.
Drug i onization is al so an i mportant determinant of li pi d sol ubi li ty; noni oni zed drugs are 1,000 to
10,000 ti mes more l i pi d-solubl e than the i onized form.
12
The degree of i oni zati on depends on the
pK
a
of the opioi d and the pH of the environment. An opi oi d with a pK
a
much l ower than 7.4 wi ll
have a much greater noni oni zed fraction in pl asma than one wi th a pK
a
cl ose to or greater than
physi ol ogi c pH. Whi le greater lipi d sol ubi l i ty correlates with membrane permeabi li ty, the
rel ati onship is not simpl y a l inear one. Hansch
13
has shown that there is an optimal hydrophobi city
for bl ood-brai n barri er penetration, and Bernards
14
has demonstrated a si mi l ar bi phasi c
rel ati onship between the octanol:buffer distri buti on coeffi ci ent and spinal meni ngeal

permeabi l i ty. Pl asma protei n bi ndi ng al so affects opioid redi stributi on because onl y the unbound
fraction is free to diffuse across cell membranes. The major plasma proteins to which opi oids bi nd
are al bumi n and
1
-acid glycoprotein (AAG). Al terations i n AAG concentrati on occur i n a vari ety of
condi ti ons and di sease states and resul t in acute or chroni c changes i n opi oi d requi rements.
Two main mechani sms are responsi bl e for drug el i mi nation: bi otransformation and excreti on.
Opi oi ds are bi otransformed i n the l iver by two types of metabol i c processes. Phase I reactions
incl ude oxi dati ve and reducti ve reacti ons, such as those catal yzed by cytochrome P-450 system,
and hydrolyti c reacti ons. Phase II reacti ons involve conjugati on of a drug or i ts metabol i te to an
endogenous substrate, such as D-gl ucuroni c aci d.
12
Remi fentani l i s metabol i zed vi a ester
hydrol ysi s, whi ch i s uni que for an opioi d. With the excepti ons of the N-deal lylated metaboli te of
meperi di ne and the 6- and possi bl y 3-gl ucuroni des of morphine, opioi d metabol ites are general l y
inactive. Opi oid metaboli tes and, to a l esser extent, their parent compounds are excreted
Adapted from Bovi l l JG: Pharmacoki neti cs and pharmacodynami cs of opi oi d agoni sts. Anaesth Pharmac
1:122, 1993.
P.357
pri mari l y by the ki dneys. The bil i ary system and gut are other routes of opioi d excretion.
MORPHINE
Morphi ne produces i ts major effects in the CNS and the gastrointestinal system, but other systems
are al so affected. CNS effects include anal gesia, sedati on, changes i n affect, respi ratory
depressi on, nausea and vomi ting, pruritus, and changes in pupi l size. Morphine al so affects gastri c
secreti ons and gut moti l i ty, and has endocri ne, urinary, and autonomic effects. It mimi cs the
effects of endogenous opioi ds by acti ng as an agoni st at
1
and
2
opi oid receptors throughout the
body and i s consi dered the standard agonist to whi ch other agoni sts are compared.
Anal gesi a
Opi oi ds are admi ni stered pri maril y for thei r anal gesic effect. Morphi ne anal gesi a resul ts from
compl ex i nteracti ons at a number of di screte si tes in the brai n, spi nal cord, and under certai n
condi ti ons, peripheral ti ssues, and i nvol ves both
1
and
2
opi oi d effects. Morphine and rel ated
opi oi ds act sel ecti vel y on neurons that transmi t and modul ate noci ception, l eavi ng other sensory
modal iti es and motor functi ons i ntact. At the spinal cord level , morphine acts presynapti cal ly on
pri mary afferent noci ceptors to decrease the rel ease of substance P and also hyperpolari zes
postsynapti c neurons i n the substanti a gel ati nosa of the dorsal spinal cord to decrease afferent
transmi ssi on of nocicepti ve impul ses.
15
Spinal morphine analgesi a i s medi ated by
2
opi oid
receptors. Supraspinal opioi d analgesia ori gi nates i n the peri aqueductal gray matter (PAG), the
locus cerul eus (LC), and nucl ei wi thin the medul la, notably the nucleus raphe magnus (NRM), and
pri mari l y i nvol ves
1
opi oid receptors. Mi croinjecti ons of morphine into any of these regi ons
acti vates the respecti ve descending modul atory systems to produce profound anal gesi a.
6, 15
A more
detail ed descri pti on of the endogenous pai n transmi ssion and modul ati on pathways is gi ven in
Chapter 54. Morphi ne can act at a number of these discrete regi ons i n the CNS to produce
synergi sti c analgesi c effects. For example, co-administrati on at the l evel of the brai n and spinal
cord increases morphine' s anal gesi c potency nearl y 10-fol d,
16
an effect medi ated by
2
opi oid
receptors.
6
There are also synergistic i nteracti ons between supraspinal si tes of opioi d acti on (e.g.,
between the PAG and the NRM).
6
When inflammation is present, morphi ne may also produce
anal gesi a by acti vating opioid receptors on pri mary afferent neurons.
17

Al though rapi dl y changi ng plasma morphine concentrati ons, such as those that foll ow bolus
dosing, do not correl ate wel l wi th anal gesi c effects, constant or very sl owly changi ng (i .e., steady-
state) plasma concentrati ons do correl ate wi th effect i ntensi ti es. Dahl strm measured the
minimum effective analgesic concentration (MEAC) of morphine for postoperati ve pai n rel ief at 10
to 15 ng/mL.
18
For more severe pain, pl asma morphine concentrati ons of 30 to 50 ng/mL are
needed to achi eve adequate anal gesia.
19

Ef f ect on Mi ni mum Al veol ar Concentr ati on of Vol ati l e
Anestheti cs
-agoni sts are used extensi vel y i n conjunction wi th nitrous oxi de (N
2
O) wi th or wi thout vol ati l e
anesthetics to provi de bal anced anesthesi a. In ani mals, morphi ne decreases the mi ni mum
al veolar concentration (MAC) of vol ati l e anestheti cs i n a dose-dependent manner,
20, 21
but there
appears to be a cei l i ng effect to the anestheti c-spari ng abi l ity of morphine, wi th a pl ateau at 65%
MAC.
20
Measurement of the maximum effect of very hi gh morphine doses on MAC is l i mi ted by
undesi rable si de effects such as hypotension and abdomi nal wal l ri gi dity. Morphi ne 1 mg/kg
administered wi th 60% N
2
O bl ocked the adrenergic response to skin i nci si on i n 50% of pati ents, a
characteri sti c cal led MAC-BAR.
22
Neuraxi al morphi ne may al so reduce MAC. Epidural morphi ne 4
mg given 90 minutes prior

to i ncisi on reduced halothane MAC by nearl y 30%.
23
The effect of i ntrathecal morphi ne on MAC i s
uncl ear. In one study, a rel ati vel y l arge dose of intrathecal morphine (750 g) reduced hal othane
MAC approxi matel y 40%,
24
but an equal l y l arge dose (15 g/kg) fai l ed to reduce hal othane MAC i n
another.
25

P.358
Ot her Cent r al Ner vous Syst em Ef f ect s
Morphi ne can produce sedati on, as wel l as cogni ti ve and fi ne motor impai rment, even at plasma
concentrations commonl y achi eved duri ng management of moderate to severe pain.
26
Other
subjecti ve si de effects include euphoria, dysphoria, and sl eep di sturbances. Hi gh doses of
morphi ne and simil ar opi oi ds produce a sl owi ng of electroencephalogram (EEG) activity associated
with a marked shift toward i ncreased vol tage and decreased frequency.
1, 27
In routi ne anal gesi c
doses, morphine can produce sl eep di sturbances, incl uding reducti on i n REM and sl ow wave sleep,
1

as wel l as vivid dreams. In extremel y high doses, morphine can produce sei zure acti vi ty in
animal s, but thi s toxi c effect i s not seen wi th doses used cl i ni cal ly i n humans.
Morphi ne produces dose-dependent pupi l lary constriction (miosis) in humans. A near maximal
degree of mi osi s i s seen wi th 0.5 mg/kg of morphine.
28
In the absence of other drugs, miosi s
appears to correl ate wi th opi oi d-induced venti latory depressi on. However, hypoxemi a from severe
opi oi d-induced respi ratory depression wi ll cause pupi l lary dil ati on.
Systemi c and neuraxial admi ni stration of morphine can produce pruri tus, although thi s symptom i s
more common with spinal administrati on.
1
Pruri tus appears to be a receptormediated effect
produced at the level of the medul l ary dorsal horn (MDH).
29
Anti hi stami nes are often used to treat
thi s si de effect, but pruri tus i nduced by morphi ne mi croinjecti on i nto the MDH i s not hi stami ne
mediated.
29
Thus, their effectiveness i s probably rel ated to nonspeci fi c sedative effects.

Morphi ne can al so affect the rel ease of several pi tui tary hormones, both di rectl y and i ndi rectl y.
Inhi biti on of corti cotropi n-rel easing factor and gonadotropin-rel easing hormone decreases
ci rculati ng concentrati ons of ACTH, -endorphi n, foll i cl e-stimul ati ng hormone, and lutei nizing
hormone. Prol acti n and growth hormone concentrati ons may be i ncreased by opi oi ds, and
anti di ureti c hormone rel ease i s i nhi bi ted by opi oi ds.
1

Respi r at or y Depr essi on
Morphi ne and other agoni sts produce dose-dependent venti l atory depressi on pri mari ly by
decreasing the responsi vi ty of the medul lary respi ratory center to CO
2
.
28
Standard therapeutic
doses of morphine produces a shi ft to the ri ght and a decrease i n sl ope of the venti l atory response
to CO
2
curve, as well as abnormal breathi ng patterns.
30, 31
The respi ratory depressant effects of
morphi ne are si mil ar for young and el derl y pati ents,
30, 31
but normal sl eep markedl y potentiates
morphi ne-induced venti latory depressi on.
32
Frequent peri ods of oxygen desaturati on associ ated
with obstructi ve apnea, paradoxic breathi ng, and sl ow respi ratory rate have been reported i n
patients recei vi ng morphine i nfusi ons for postoperative anal gesia, but occurred only when the
patients were asl eep.
33
Such reports emphasize the need to consi der both the expected severity of
postoperative pai n as wel l as diurnal variations i n pai n and opioi d sensi tivity when i ncludi ng l ong-
acti ng opi oids such as morphi ne in an anesthetic. Sl eep apnea, seen wi th ever-increasi ng
frequency i n associ ati on wi th obesi ty, i ncreases the ri sk of morphi ne-induced respi ratory
depressi on. Wi th i ncreasing morphi ne doses, periodi c breathing resembl i ng Cheyne-Stokes
breathi ng, decreased hypoxi c venti l atory dri ve, and apnea can occur.
34
However, even wi th severe
venti l atory depressi on, pati ents are usuall y arousabl e and wi l l breathe on command.
Cough Ref l ex
Morphi ne and rel ated opi oi ds depress the cough reflex, at l east i n part by a di rect effect on the
medul l ary cough center. Doses requi red to attenuate the cough refl ex are smal l er than the usual
anal gesi c dosage, and receptors mediating thi s effect appear to be l ess stereospeci fi c and l ess
sensi ti ve to nal oxone than those responsi bl e for anal gesi a.
1
Dextroisomers of opi oi ds, which do
not produce anal gesia, are al so effecti ve cough suppressants.
1

Muscl e Ri gi di t y
Large doses of i ntravenous morphi ne (2 mg/kg i nfused at 10 mg/mi n) can produce abdomi nal
muscle ri gidi ty and decrease thoraci c compli ance; this effect plateaus 10 mi nutes after morphi ne
administrati on i s complete.
35
Subjects recei vi ng small er doses of intravenous morphine (10 to 15
mg) al so report feel ings of muscl e tensi on, most frequentl y i n the neck or l egs, but occasi onal l y i n
the chest wal l (unpubli shed observati ons). Muscl e ri gi di ty i s drasti cal l y i ncreased by the addi ti on
of 70% N
2
O.
35
Opi oid-induced muscl e ri gi dity appears to be medi ated by receptors at
supraspi nal si tes.
36
Myocl onus, sometimes resembl i ng seizures, but wi thout EEG evi dence of
sei zure acti vi ty, has also been observed wi th high-dose opi oids.
37
In cli nical practi ce, opi oid-
i nduced muscl e ri gi di ty and myocl onus are most often observed on i nducti on of anesthesi a, but
have been observed postoperativel y
38
and can be severe enough to i nterfere wi th manual or
mechani cal venti l ation. These effects are reduced or eli mi nated by nal oxone,
38
drugs that facilitate
GABA agonist activity (such as thi opental
35
and di azepam), and muscl e relaxants.
38

Nausea and Vomi t i ng
Nausea and vomi ting are among the most di stressi ng si de effects of morphine and i ts deri vati ves.
Increased postoperati ve vomiti ng i s seen wi th morphine premedicati on as wel l as wi th the use of
intraoperative opi oids.
39
The i nci dence of opioid-induced nausea appears to be simil ar i rrespecti ve
of the route of admi ni strati on, i ncl udi ng oral , intravenous, i ntramuscul ar, subcutaneous,
transmucosal, transdermal , intrathecal , and epi dural .
39
Furthermore, laboratory and cl ini cal
studi es comparing the i nci dence or severi ty of nausea and vomi ting have found no differences
among opi oids i n equi anal gesi c doses, including morphi ne, hydromorphone, meperi di ne, fentanyl ,
sufentani l, al fentani l , and remi fentani l.
39, 40, 41, 42
The physi ol ogy and neuropharmacol ogy of opioi d-
i nduced nausea and vomi ting are compl ex (Fi g. 14-3). The vomi ting center recei ves i nput from the
chemotacti c tri gger zone (CTZ) in the area postrema of the medul l a, the pharynx, gastrointestinal
tract, medi asti num, and visual center.
39, 43
The CTZ is rich in opioi d, dopamine (D
2
), serotonin (5-
HT
3
), hi stami ne, and (muscari ni c) acetyl choli ne receptors, and al so recei ves i nput from the
vesti bul ar porti on of the ei ghth cranial nerve. Morphi ne and rel ated opi oids i nduce nausea by
di rect sti mul ati on of the CTZ and can al so produce increased vesti bul ar sensiti vi ty.
1
Therefore,
vesti bul ar sti mul ati on such as ambul ati on markedl y i ncreases the nauseant and emetic effects of
morphi ne. Thi s can be especi al l y probl ematic i n outpati ent surgery, when early ambulati on i s a
cl i ni cal pri ori ty. Hi gh doses of morphi ne and other opi oi ds al so have nal oxone-reversi bl e
anti emetic effects at the level of the vomi ti ng center.
44
In vol unteer studi es, morphine-induced
nausea and vomi ti ng increase after a morphi ne infusi on i s stopped,
45
whi ch suggests that
anti emetic effects are more short-li ved than emeti c effects. Another possi bl e expl anati on for thi s
observation is that the acti ve metabol i te morphi ne-6-gl ucuroni de accumul ates and worsens
nausea. Prophyl axi s and treatment of opi oid-induced nausea and vomi ting i ncludes the use of
drugs that act as antagoni sts at the vari ous receptor

si tes i n the CTZ as wel l agents such as propofol and benzodi azepi nes, whose anti emeti c
mechanisms are unknown.
39

P.359
Gast r oi nt est i nal Mot i l i t y and Secr et i on
Morphi ne and other opi oids affect gastroi ntestinal moti li ty and propul sion, as wel l as gastri c and
pancreati c secretions via stimul ati on of opi oid receptors i n the brai n, spi nal cord, enteri c muscl e,
and smooth muscl e,
34, 46
and are medi ated by , , and opi oi d receptors at different anatomi c
si tes.
46
In rodents, agoni sts i nhibi t gastri c secreti on, decrease gastrointestinal moti li ty and
propul si on, and suppress di arrhea when admini stered by i ntracerebroventricular, intrathecal , and
peri pheral injecti on.
46
A study i n human vol unteers demonstrated that methylnal trexone, an opi oid
antagonist that does not cross the blood-brain barrier, attenuated morphi ne-induced delay in
gastri c emptying,
47
suggesti ng that thi s effect i s medi ated pri mari l y by a peripheral opi oi d
mechani sm. Morphine decreases l ower esophageal sphincter tone and produces symptoms of
gastroesophageal reflux,
34
and di amorphi ne si gni fi cantl y sl ows gastri c emptyi ng. Thus,
preoperati ve opioi d admi ni strati on shoul d be consi dered when evaluati ng the ri sk of regurgi tati on
and aspi rati on of gastri c contents i n pati ents who wi l l be anestheti zed or sedated. Li ke other
opi oi d effects, gastrointestinal effects are probabl y dose rel ated. Tone i n both the smal l and large
bowel i s i ncreased, but propul sive activity is decreased, leading to constipation. Epi dural l y
administered morphi ne can al so del ay gastri c emptyi ng. A singl e epidural dose (4 mg) of morphi ne
sl owed gastri c emptyi ng, whi l e an intramuscul ar dose did not.
48
How the effects of equi analgesic
or repeated doses woul d compare is unknown.
Bi l i ar y Tr act
Morphi ne and other opi oids i ncrease the tone of the common bil e duct and sphi ncter of Oddi .
Symptoms accompanyi ng i ncreases in bi l iary pressure can vary from epigastric di stress to typical
bi l i ary col i c, and may even mi mi c angina. When produced, bi l iary spasm can el evate plasma
amyl ase and l i pase for up to 24 hours.
1
Morphi ne and other agoni sts such as fentanyl are used
in provocative tests to evaluate sphi ncter of Oddi dysfuncti on and bi l i ary-type pai n. In vol unteers,
morphi ne caused a greater del ay i n gal l bl adder emptying
49
and an i ncrease i n contracti ons of the
sphincter of Oddi
50
than meperi dine. Nitrogl yceri ne, atropi ne, and naloxone can reverse opi oi d-
induced i ncreases i n bil i ary pressure.
1
It has been suggested that morphine causes bi li ary tract
FIGURE 14-3. Pharmacol ogy of nausea and vomi ting. The chemotacti c tri gger zone (CTZ),
located in the area postrema of the brainstem, contains dopami ne, serotoni n, hi stami ne, and
muscari ni c acetylchol ine as well as opi oid receptors. The vomi ti ng center receives input from
the CTZ as wel l as peripheral sites vi a the vagus nerve. As i l lustrated, the rol e of opioi ds is
compl ex, and they appear to have both emeti c and antiemeti c effects.
contracti on via histamine rel ease, and antagoni sm of morphine' s bi l i ary effects by
di phenhydrami ne supports thi s hypothesi s.
51

Geni t our i nar y Ef f ect s
Uri nary retenti on, seen after both systemi c and spinal morphi ne admini stration, is because of
compl ex effects on central and peri pheral neurogeni c mechani sms. It resul ts i n dyssynergi a
between the bl adder detrusor muscl e and the urethral sphi ncter because of a fail ure of sphi ncter
rel axation.
1, 52
Esti mates of the i ncidence of this bothersome side effect vary wi del y and are
confounded by the effects of anesthesia and surgery on uri nary retenti on, but i t is probabl y more
common after spinal admini stration. Spinal morphi ne appears to cause nal oxone-reversi bl e urinary
retention via and/or , but not opi oi d receptors.
52
In an ani mal study, chol i nomi metic agents
and -adrenergi c agoni sts aggravated morphi ne-induced hi gh intravesical pressures, and therefore
may be harmful agents to use for treatment of morphine-induced uri nary retention.
53

Hi st ami ne Rel ease
Opi oi ds sti mulate the rel ease of hi stami ne from ci rcul ati ng basophi ls and from ti ssue mast cel ls i n
ski n and l ung.
54, 55
Morphi ne-mediated hi stami ne rel ease i s dose dependent; i ntradermal i njection
of morphine i n a concentrati on of 1 mg/mL i nduces an urti carial wheal and fl are.
55
Morphi ne-
induced hi stami ne rel ease i s not prevented by pretreatment with naloxone,
55
suggesti ng that
hi stami ne release is not medi ated by opioi d receptors. Morphi ne-induced hi stami ne rel ease has
cl i ni cal rel evance. The decrease i n peri pheral vascul ar resi stance seen wi th hi gh-dose morphine (1
mg/kg) correl ates wel l wi th elevated pl asma histamine concentrati on.
56
Furthermore, differences
in the release of hi stami ne coul d account for most of the hemodynamic differences between
morphi ne and fentanyl (Fi g. 14-4).
56

Car di ovascul ar Ef f ect s
Opi oi ds are popul ar i n cl i ni cal anesthesi a because they rel i abl y produce analgesi a with mi ni mal
changes i n cardiovascular parameters. In doses typi cal l y used for pain management or as part of
bal anced anesthesi a, morphi ne has li ttl e effect on bl ood pressure or heart rate and rhythm i n the
supine,

normovol emi c patient. However, therapeutic doses of morphi ne can produce arteriol ar and venous
di l ati on, decreased peri pheral resi stance, and inhi bi ti on of baroreceptor reflexes,
1
whi ch can lead
to postural hypotensi on. In addi tion to histamine rel ease, morphi ne-mediated central
sympathol ytic acti vi ty and direct acti on on vascul ar smooth muscl e may al so contri bute to
peri pheral vasodi l ati on.
57
Thus, morphine's effect on vascul ar resistance is greater under
condi ti ons of high sympathetic tone.
57
The cl inical impli cati ons of thi s findi ng are important.
Patients who are cri ticall y il l (e.g., pati ents wi th severe trauma or cardiac disease) can be
FIGURE 14-4. Mean arteri al pressure (BP), systemi c vascular resistance (SVR), and plasma
hi stami ne concentrati on (mean SE) before and after morphine 1 mg/kg and fentanyl 50
g/kg (both i nfused over 10 minutes). Morphi ne, but not fentanyl , causes si gni fi cant
decrements in BP and SVR, whi ch paral l el the increase i n plasma hi stami ne concentrati on.
(Repri nted wi th permi ssion from Rosow CE, Moss J, Phi l bi n DM et al : Histamine rel ease
duri ng morphine and fentanyl anesthesi a. Anesthesi ology 56:93, 1982.)
P.360
expected to have hi gh sympatheti c tone, and thus may experi ence hypotensi on i n response to
doses of morphine that would not normal ly produce hemodynami c instabil i ty. At cli nicall y rel evant
doses, morphine does not suppress myocardi al contracti li ty.
1
However, opi oi ds do produce dose-
dependent bradycardi a, probabl y by both sympathol yti c and parasympathomi meti c mechanisms.
58

In cl i ni cal anesthesi a practi ce, opioids are often used to prevent tachycardia and reduce
myocardi al oxygen demand. Pati ents undergoi ng cardi ovascul ar surgery who received morphine 1
to 2 mg/kg experi enced mi nimal changes i n heart rate, mean arteri al pressure, cardi ac i ndex, and
systemi c vascul ar resistance. However, outcome was no di fferent from that achi eved with careful l y
administered inhal ati on-based anesthesi a.
58

Morphi ne does not di rectl y affect cerebral ci rculation, but wi th morphine-induced respi ratory
depressi on, CO
2
retention causes cerebral vasodi lation and an el evati on i n cerebrospi nal fl ui d
pressure. Thi s effect i s not seen when mechani cal venti l ati on is used to prevent hypercarbi a.
1

Thus, morphi ne and other agoni sts must be used cauti ously in spontaneousl y breathi ng pati ents
with head injury or other condi ti ons associ ated wi th el evated intracranial pressure.
Di sposi t i on Ki net i cs
Morphi ne i s rapi dly absorbed after intramuscul ar, subcutaneous, and oral admi nistrati on. Foll owi ng
intramuscul ar admi ni strati on, peak pl asma concentrati on is seen at 20 minutes and absorpti on
half-li fe i s esti mated at 7.7 mi nutes (range 2 to 15 minutes).
59
After intravenous admi ni strati on
morphi ne undergoes rapi d redi stri buti on, wi th a mean redi stri buti on hal f-ti me between 1.5 and 4.4
mi nutes i n awake and anesthetized adults.
59, 60, 61
Morphi ne has a termi nal el i mi nation half-li fe
between 1.7 and 3.3 hours.
60, 61, 62
Age affects morphi ne pharmacoki neti cs. The average el iminati on
half-li fe of morphi ne is 7 to 8 hours i n neonates l ess than 1 week of age, and 3 to 5 hours i n ol der
infants.
74
In pati ents between 61 and 80 years ol d, morphi ne' s terminal el imi nati on hal f-li fe was
4.5 hours compared to 2.9 hours in younger patients.
63

Morphi ne i s about 35% protei n bound, mostl y to albumi n.
12
Its steady-state vol ume of distri buti on
is l arge, wi th esti mates i n the range of 3 to 4 L/kg in normal adults.
59, 60, 61
Morphi ne' s major
metabol i c pathway i s hepati c phase II conjugation, to form morphine-3-gl ucuroni de (M3G) and
morphine-6-gl ucuroni de (M6G). 3-Gl ucuroni dati on i s the predomi nant pathway, and fol lowi ng a
si ngl e i ntravenous dose, 40% and 10% of the dose are excreted i n the uri ne as M3G and M6G,
respectively.
64
Unchanged morphine i n the urine accounts for onl y about 10% of the dose. The
rate of hepati c cl earance of morphi ne i s hi gh, wi th a hepati c extracti on rati o of 0.7.
59
Thus,
morphi ne eli mi nation may be sl owed by processes that decrease hepatic bl ood fl ow.
61
Extrahepatic
si tes, such as kidney, intestine, and l ung, have been suggested for morphine gl ucuroni dati on, but
thei r importance i n humans i s unknown.
Act i ve Met abol i t es
M6G possesses si gni fi cant receptor affi ni ty and potent anti noci cepti ve activity. Appreciabl e
pl asma concentrati ons of M6G and M3G have been measured in cancer pati ents recei vi ng high
doses of oral morphi ne. Duri ng chroni c oral morphi ne therapy, pl asma M6G concentrati ons can be
hi gher than those of the parent morphi ne compound.
65
Because morphi ne glucuronides are
el i mi nated by the ki dney, i t i s not surpri sing that very hi gh M6G:morphi ne rati os have been
reported in pati ents wi th renal dysfuncti on. This accumul ati on of the active metabol ite i s thought
to be responsi ble for the unusual sensi ti vi ty of renal fail ure pati ents to morphi ne. Whi le common
wisdom suggests that gl ucuroni de conjugates do not penetrate the bl ood-brai n barri er, M6G
concentration in cerebrospi nal fl uid (CSF) i s 20 to 80% that of morphine.
66
Despi te a mounti ng
vol ume of ani mal l iterature demonstrati ng the anal gesic potency of M6G, there is l i ttl e informati on
in humans concerni ng the magni tude of anal gesi a and si de effects of M6G rel ati ve to morphi ne.
Portenoy et al
66
demonstrated that i n cancer pati ents receiving chronic morphi ne therapy, pain
rel ief correl ated posi ti vel y with the M6G:morphi ne rati o, suggesti ng a contri buti ng rol e of M6G to
overal l morphi ne anal gesi a. In a study of cancer patients who received syntheti c M6G (up to 60
g/kg), 17 of 19 patients experi enced effecti ve anal gesi a and no adverse effects.
67
However,
di zzi ness, nausea, sedati on, muscle aches, and respi ratory depressi on have been reported i n
vol unteers who recei ved M6G.
65
Whi le the contributi on of M6G to morphine-induced anal gesia and
si de effects remai ns

to be determi ned, morphine shoul d be admini stered cautiousl y to pati ents wi th renal fai l ure.
Dosage and Admi ni st r at i on of Mor phi ne
In current cl inical practi ce morphine i s used mainl y as a premedi cant and for postoperative
anal gesi a, and l ess often as a component of bal anced or high-dose opi oid anesthesi a. Intravenous
anal gesi c doses of morphi ne for adul ts typicall y range from 0.01 to 0.20 mg/kg. When used i n a
bal anced anestheti c technique wi th N
2
O, morphi ne can be given i n total doses of up to 3 mg/kg
with remarkable hemodynamic stabi li ty, but awareness under anesthesi a is a risk. When combi ned
with other i nhal ati on agents, it i s unl ikel y that more than 1 to 2 mg/kg of morphine i s necessary.
Because of i ts hydrophi li city, morphine crosses the bl ood-brain barrier rel ati vel y sl owly; and whi l e
its onset can be observed withi n 5 mi nutes, peak effects may be delayed for 10 to 40 mi nutes.
Thi s del ay makes morphi ne more di ffi cul t to ti trate as an anestheti c supplement than the more
rapi dl y acti ng opi oi ds.
MEPERIDINE
Meperi di ne, a phenyl pi peri di ne derivati ve (Fi g. 14-5), was the first total ly syntheti c opi oi d. It was
initi al l y studi ed as an anti choli nergi c agent, but was found to have si gni fi cant anal gesi c activity.
1

Anal gesi a and Ef f ect on Mi ni mum Al veol ar Concent r at i on of
Vol at i l e Anest het i cs
Meperi di ne' s anal gesi c potency i s about one-tenth that of morphine' s and is most l ikel y medi ated
by opi oi d receptor activati on. However, meperi di ne al so has moderate affi ni ty for and opi oi d
receptors.
1, 68
Unli ke morphi ne, meperi di ne pl asma concentrations correl ate reasonabl y wel l wi th
anal gesi c effects.
69
Whi le there i s consi derable interpati ent vari abil i ty, the minimum effective
anal gesi a concentrati on of meperidi ne is approxi matel y 200 ng/mL. There i s very l i ttl e informati on
avai labl e on the effect of meperi dine on the MAC of i nhal ed anestheti cs, but a study i n dogs
demonstrated a dose-dependent reducti on i n the MAC of hal othane.
70

Meperi di ne al so has wel l recogni zed weak l ocal anestheti c properti es. Compared to morphi ne,
fentanyl , and buprenorphi ne i njected peri neurall y, only meperidi ne al ters nerve conduction and
produces anal gesia.
71
Thi s has l ed to some popul ari ty for epi dural and subarachnoid
administrati on, parti cul arl y i n obstetri c anesthesi a. But because of i ts l ocal anesthetic effects,
P.361
FIGURE 14-5. Chemical structures of phenylpi peri di ne, meperi di ne, and the 4-
anil i nopiperidi ne deri vati ves fentanyl , sufentanil , al fentani l, and remifentanil .
neuraxial meperidi ne may al so produce sensory and motor bl ockade as well as sympatholyti c
effects that are not seen wi th other opi oi ds.
Si de Ef f ect s
Like morphine, therapeuti c doses of meperi di ne can produce sedation, pupi l l ary constri cti on, and
euphori a, and very hi gh doses are associ ated with CNS exci tement and sei zures (see l ater). In
equi anal gesi c doses, meperi di ne produces respi ratory depressi on equal to that of morphi ne, as
well as nausea, vomi ti ng, and di zzi ness, parti cularly i n ambul atory pati ents.
1

Like other opioids, meperi di ne causes si gni fi cant del ay i n gastri c emptyi ng. Whi l e meperi di ne does
increase common bi l e duct pressure, thi s occurs to a l esser extent than wi th equianal gesi c doses
of morphine and fentanyl (Fi g. 14-6).
49, 72

Anal gesi c doses of meperi di ne i n awake patients are not associated wi th hemodynami c instabil i ty,
but 1 mg/kg i n pati ents wi th cardi ac di sease decreased heart rate, cardi ac i ndex, and rate
pressure product.
73
In an i sol ated papi ll ary muscl e preparation, hi gh concentrati ons of meperi di ne
depressed contracti li ty. This effect was not nal oxone reversi bl e and i s consi stent with a
nonspeci fi c, l ocal anesthetic effect.
74
In hi gher doses, meperi di ne causes si gnifi cantly more
hemodynamic i nstabi l ity than morphine or fentanyl and i ts deri vati ves,
75
an effect at l east
parti all y rel ated to hi stami ne rel ease. In a compari son of opi oi ds admi ni stered as part of bal anced
anesthesia, Fl acke et al
75
found that 25% pati ents in the meperi di ne group experi enced severe
hypotensi on and had abnormal ly elevated pl asma histamine concentrati ons. Interesti ngl y, only one
FIGURE 14-6. The effect of several opi oids on common bil e duct pressures in pati ents
anesthetized wi th enfl urane and N
2
OO
2
. Pati ents received either fentanyl 100 g/70 kg,
morphi ne 10 mg/70 kg, meperi di ne 75 mg/70 kg, or butorphanol 2 mg/70 kg. After 20
mi nutes, the effects were reversed wi th nal oxone. (Repri nted wi th permi ssi on from Radnay
PA, Duncalf D, Novakovik M, Lesser ML: Common bi l e duct pressure changes after fentanyl ,
morphi ne, meperidi ne, butorphanol, and nal oxone. Anesth Anal g 63:441, 1984.)
patient in the morphi ne group (0.6 mg/kg morphine given) had a si mi lar hi stami ne plasma
concentration. Thus, meperi di ne i s not recommended in hi gh doses for cl i ni cal anesthesi a.
Shi ver i ng
Meperi di ne i s effecti ve i n reducing shi vering from di verse causes, including general and epi dural
anesthesia, fever, hypothermia, transfusion reacti ons, and admi ni strati on of amphoteri cin B.
Meperidi ne reduces or eli mi nates vi si bl e shi veri ng as wel l as the accompanyi ng i ncrease i n oxygen
consumpti on
76
foll owing general and epidural anesthesi a. Equi analgesi c doses of fentanyl (25 g)
and morphi ne (2.5 mg) di d not reduce postoperative shi veri ng, suggesti ng that the antishi veri ng
effect of meperi di ne i s not medi ated by -opi oi d receptors. Thi s effect

may be medi ated by -opi oi d receptors. Butorphanol, a drug wi th significant agoni st acti vi ty,
effecti vel y reduces postoperative shi veri ng in a dose of 1 mg.
77
Furthermore, low doses of
naloxone, suffi ci ent to block receptors, di d not reverse meperidi ne' s anti shi veri ng effect, but
hi gh-dose nal oxone, desi gned to bl ock both and receptors, di d reverse the anti shi veri ng
effect.
68
The observati on that other types of drugs, such as
1
-adrenergi c agonists (cl onidi ne 1.5
g/kg), serotonin (5-HT
2
) antagonists,
78
and propofol ,
79
can reduce postoperati ve shiveri ng
suggests that a nonopi oi d mechanism may be involved. Physosti gmi ne 0.04 mg/kg can also
prevent postoperati ve shiveri ng, suggesti ng a rol e for the choli nergi c system. Perhaps
meperi di ne' s greater antishi veri ng effect, rel ati ve to other opi oi ds, i s because of addi ti ve
thermoregul atory i mpai rment by more than one mechani sm.
Foll owi ng i ntravenous admi ni stration, meperi di ne pl asma concentrati on fal l s rapi dl y. Meperi di ne' s
redi stri buti on hal f-li fe i s 4 to 16 mi nutes, and its termi nal el iminati on hal f-li fe i s between 3 and 5
hours.
81, 82
The eli mi nation hal f-li fe i s not prol onged in pati ents 60 to 80 years ol d. However, in
neonates and i nfants, a medi an el i mi nation half-li fe, 8 to 10 hours, wi th greater i ndi vi dual
vari abi l i ty (three- to fi vefol d) compared to adul ts. Absorpti on after i ntramuscul ar admi ni strati on
was compl ete i n normal vol unteers, wi th peak pl asma concentrati on at 5 to 15 mi nutes after
injecti on; but i n postoperati ve pati ents, i ntramuscul ar meperi di ne absorpti on i s qui te vari abl e,
with ti me to reach peak concentration between 5 and 110 minutes.
Meperi di ne i s moderatel y l i pi d soluble, and i s 40 to 70% protein bound, mostl y to al bumi n and
1
-
acid glycoprotein (see Tabl e 14-2).
83
Meperi di ne has a l arge steady-state vol ume of distri buti on,
with esti mates i n the range of 3.5 to 5 L/kg i n adul ts.
81, 82
The hi gh cl earance rate (10 mL/kg/mi n)
refl ects a hi gh hepati c extracti on rati o; i t is N-demethyl ated i n the li ver to form normeperidi ne,
the pri nci pal metabol i te, and al so hydrol yzed to meperi di ni c aci d. Both metabol ites may then be
conjugated
1
and excreted renal l y. Normeperidi ne is pharmacol ogi cal l y acti ve and potenti al ly toxi c
(see l ater).
Act i ve Met abol i t es
Normeperi dine has appreci abl e pharmacol ogi c acti vi ty and can produce signs of central nervous
system exci tation. In humans, mood al terati ons such as apprehensi on and restl essness, as wel l as
neurotoxi c effects such as tremors, myocl onus, and sei zures, have been reported.
84
The
el i mi nation half-li fe of the metaboli te normeperi dine (14 to 21 hours) is considerabl y longer than
the parent compound, and therefore i s li kel y to accumul ate wi th repeated or prol onged
administrati on, particul arl y i n pati ents wi th renal dysfunction.
84
Myocl onus and sei zures have been
reported in pati ents receiving meperi di ne for postoperati ve or chroni c pain. Pati ents who
devel oped sei zures had a mean pl asma normeperidi ne concentration of 0.81 g/mL,
84
and i t
appears that a total dai l y dosage of 1,000 mg is associated wi th an i ncreased ri sk of sei zures,
even i n pati ents without renal dysfuncti on.
Dosage and Admi ni st r at i on of Meper i di ne
A si ngl e dose of meperi di ne i s approxi matel y one-tenth as potent as morphine when gi ven
P.362
parenterall y, but has a shorter duration of action. Intravenous anal gesi c doses of meperi di ne for
adults typicall y range from 0.1 to 1 mg/kg. Intravenous doses of 12.5 to 50 mg are effecti ve i n
reduci ng postoperati ve shi veri ng. As di scussed earl i er, hi gh doses of meperi di ne for intraoperati ve
use are not recommended because of hemodynami c i nstabi li ty. In addi tion, very hi gh si ngl e doses
or prol onged admini stration may produce sei zures because of the metabol ite normeperi di ne; thus,
the total dail y dose shoul d not exceed 1,000 mg/24 hours.
METHADONE
Methadone, a syntheti c opi oid i ntroduced in the 1940s, is pri mari ly a agoni st with pharmacologic
properties that are si mil ar to morphine. Whi l e i ts chemical structure i s very

di fferent from that of morphi ne, steri c factors force the mol ecul e to si mulate the pseudopi peri di ne
ri ng conformati on that appears to be requi red for opi oi d acti vi ty.
1
Because of its l ong eli mi nati on
half-li fe, methadone i s most often used for l ong-term pai n management and i n treatment of opi oid
absti nence syndromes.
Anal gesi a and Use i n Anest hesi a
Foll owi ng parenteral admi nistrati on, the onset of anal gesi a i s rapi d, wi thi n 10 to 20 mi nutes. After
si ngl e doses of up to 10 mg, the duration of analgesia i s simil ar to morphi ne,
1
but wi th large or
repeated parenteral doses, prol onged anal gesi a can be obtai ned. Several i nvesti gators have
administered methadone i ntra- and postoperati vely wi th the ai m of provi di ng prol onged
postoperative anal gesia. Pati ents who received 20 mg methadone i ntraoperati vel y and up to 20 mg
addi ti onal methadone in the i mmediate postoperati ve peri od had a medi an durati on of
postoperative anal gesia of over 20 hours.
85, 86
The effect of methadone on the MAC of vol ati l e
anesthetics has not been reported.
Si de Ef f ect s
Side effects of methadone are si mi l ar i n magnitude and frequency to those of morphi ne.
1, 85

Patients who recei ved 20 mg methadone at the begi nni ng of surgery were sedated i n the
immedi ate postoperati ve peri od but di d not appear to have cl i ni cal ly significant respi ratory
depressi on. About 50% experi enced nausea or vomiti ng, whi ch was easi l y treated wi th standard
anti emetic therapy.
85
Methadone produces typical opi oi d effects on smooth muscl e. Like morphi ne,
it markedly decreases intestinal propul si ve acti vi ty and can cause consti pati on as well as bil i ary
spasm.
1

Foll owi ng an intravenous dose, the pl asma concentrati onti me data for methadone are descri bed
by a bi exponenti al equati on. The mean redi stri buti on hal f-ti me i s 6 minutes (range 1 to 24
mi nutes), and the mean termi nal eli mi nation hal f-ti me i s 34 hours (range 9 to 87 hours).
86

Methadone i s wel l absorbed after an oral dose, wi th bi oavail abil i ty approxi matel y 90%, and
reaches peak pl asma concentrati on at 4 hours after oral admini stration.
1
It i s nearl y 90% pl asma
protei n bound and undergoes extensi ve metabol i sm i n the l i ver, mostl y N-demethyl ati on and
cycl i zati on to form pyrroli di nes and pyrrol i ne.
1

Dosage and Admi ni st r at i on of Met hadone
The use of methadone in cli ni cal anesthesia has focused on attempts to achi eve prol onged
postoperative anal gesia, providi ng that an adequate i ni ti al dose i s admini stered. Because adverse
effects can also be prol onged, careful ti trati on of the dose i s necessary. In opioi d-na ve pati ents,
an i ni ti al si ngl e dose of 20 mg can provi de analgesi a without si gni fi cant postoperative respi ratory
depressi on.
85
Wangler and Rosenbl att
87
descri bed a techni que to avoi d respi ratory depression in
whi ch 8 to 12 mg methadone is admi ni stered to the awake pati ent unti l the threshol d of
respi ratory depressi on (respi ratory rate of 6 to 8/mi n) i s reached. Immedi atel y pri or to i nci si on,
an addi tional dose equal to hal f the ini ti al dose is gi ven. For admi ni steri ng suppl emental anal gesi c
P.363
doses in the i mmediate postoperative peri od, it i s essenti al to confirm that pati ents wi th ongoi ng
si gni fi cant pai n have no depressi on of respi rati on or level of consciousness, and that a 30- to 40-
mi nute i nterval shoul d el apse between 5-mg doses to al l ow ful l assessment of adverse effects. It
may be easi er and safer to use a sustai ned release opi oi d preparati on (containing oxycodone or
morphi ne) with a shorter ti me to peak effect i f a l ong-acti ng anal gesic i s desi red. Thi s i s most
easil y accompli shed by admini steri ng the oral medicati on preoperati vel y, but i t i s also i mportant
to note that these l ong-acti ng opi oids are not currentl y approved for prophyl axi s of postoperati ve
pai n.
FENTANYL
Fentanyl and its analogs sufentani l and alfentanil are the most frequentl y used opi oi ds in cli nical
anesthesia today. Fentanyl, fi rst synthesized i n 1960, i s structural ly rel ated to the
phenylpi peri di nes (see Fi g. 14-5) and has a cl i ni cal potency rati o 50 to 100 ti mes that of
morphi ne. Cl ear pl asma concentrati on-effect relationships have been demonstrated for fentanyl
(Tabl e 14-3). Scott et al
88
demonstrated progressi ve EEG changes wi th increasi ng serum fentanyl
concentration (Fi g. 14-7). Duri ng a 5-mi nute fentanyl i nfusi on, the ti me l ag between i ncreasi ng
serum fentanyl concentrati on and EEG sl owing was 3 to 5 mi nutes. After the i nfusi on was stopped,

the resol uti on of EEG changes l agged behi nd decreasi ng serum fentanyl concentrati on by 10 to 20
minutes.
P.364
TABLE 14-3 Plasma Concentration Ranges (ng/mL) for Various Therapeutic and Nontherapeutic
EFFECT MORPHINE MEPERIDINE FENTANYL SUFENTANIL ALFENTANIL
MEAC 1015 200 0.6 0.03 15
Moderate to
strong anal gesi a
2050 400600 1.55 0.050.10 4080
50% MAC
reduction
NA >500 0.52 0.145 200
Surgi cal
anal gesi a wi th
~70% N
2
O
NA NA 1525 NA 300500
Respi ratory
depressi on
threshold
25 200 1 0.020.04 50100
50%
venti l atory
response to CO
2
50 NA 1.53 0.04 120350
Apnea NA NA 722 NA 300600
Anal gesi a
Fentanyl, a -opi oi d receptor agoni st, produces profound dose-dependent analgesia, ventil atory
depressi on, and sedati on, and at hi gh doses i t can produce unconsci ousness. In postoperati ve
patients recei vi ng fentanyl by a patient-control led anal gesi a system, the mean fentanyl dose
requi rement was 55.8 g/h, and mean minimum effective anal gesi c concentrati on (MEAC) i n bl ood
was 0.63 ng/mL.
89
A l arge i nterpati ent variabi li ty i n MEAC (0.23 to 1.18 ng/mL) typi cal of opioi ds
was observed, but over the 2-day study peri od, the MEAC for any indivi dual pati ent remai ned
rel ati vely constant. In a vol unteer study, a mean plasma fentanyl concentrati on of 1.3 ng/mL
reduced experi mental pai n i ntensi ty rati ngs by 50%.
40
Thi s is consi stent with other esti mates of
pl asma fentanyl concentrati ons associ ated wi th moderate to strong anal gesi a.
90

EFFECT ON MINIMUM ALVEOLAR CONCENTRATION OF
Unconsci ousness
(not rel i abl y
achi eved wi th
opi oi ds al one)
(Sei zures) 1520 NA 5001500
Effects were generall y achi eved duri ng conti nuous infusi ons or pati ent-control led anal gesi a systems. N
pl asma concentrati ons associated wi th measurabl e depression of venti l atory dri ve are si mi lar to those
with anal gesia for al l opioids.
MEAC, mi ni mum effecti ve analgesi c concentrati on, defi ned i n most studi es as the pl asma opi oi d concen
associated wi th just perceptibl e anal gesi a; NA, informati on not avai l abl e.
FIGURE 14-7. The ti me course of EEG spectral edge and serum concentrati ons of fentanyl
(A) and alfentanil (B). Infusi on rates were 150 g/min fentanyl and 1,500 g/min alfentanil .
Increasi ng opi oi d effect i s seen as a decrease i n spectral edge. Changes i n spectral edge
fol l ow serum concentrati ons more cl osel y wi th alfentanil than with fentanyl . (Repri nted wi th
permi ssi on from Scott JC, Ponganis KV, Stanski DR: EEG quantitati on of narcotic effect: The
comparative pharmacodynami cs of fentanyl and al fentani l . Anesthesiol ogy 62:234, 1985.)
VOLATILE ANESTHETICS AND USE IN ANESTHESIA
Fentanyl reduces the MAC of vol ati l e anestheti cs i n a concentration- or dose-dependent
fashi on. A single i v bol us dose of fentanyl 3 g/kg, given 25 to 30 mi nutes prior to i nci si on,
reduced both i sofl urane and desfl urane MAC by approxi matel y 50%.
91
Fentanyl 1.5 g/kg
administered 5 minutes pri or to skin i nci si on reduces the mi ni mum al veolar concentrati on that
bl ocks adrenergi c responses to sti mul i (MAC-BAR) of isofl urane or desfl urane i n 60% N
2
O by 60 to
70%.
92
No further drop is seen with an i ncrease i n fentanyl dose to 3 g/kg. Duri ng constant
pl asma concentrati on of 0.5 to 1.7 ng/mL, fentanyl reduced i sofl urane MAC by 50%.
93
Fentanyl
produces a steep plasma concentrati on-rel ated reducti on i n sevofl urane MAC
94
; (3 ng/mL provi des
a 59% reduction), but a cei li ng effect is reached, such that a threefold increase to 10 ng/mL
reduced MAC by onl y an addi ti onal 17%.
Epi dural fentanyl al so reduces halothane MAC.
95
Epidural fentanyl 1, 2, and 4 g/kg reduced
halothane MAC by 45, 58, and 71%, respecti vel y, whi le the same doses of fentanyl gi ven iv
reduced hal othane MAC by 8, 40, and 49%, respectively.
Combini ng opioi ds wi th propofol rather than an inhal ati on agent is another common techni que
for provi di ng general anesthesi a, referred to as total i ntravenous anesthesi a or TIVA. For an
intravenous anestheti c, the potency i ndex i s descri bed as the pl asma concentrati on required to
prevent a response i n 50% (CP
50
) or 95% (CP
95
) of patients to vari ous surgi cal stimul i . Pl asma
concentrations of fentanyl and propofol that reduce hemodynami c or somati c responses to vari ous
surgi cal sti mul i in 50% of pati ents have been determi ned usi ng computer-assi sted infusi on.
96

Fentanyl pl asma concentrati ons of 1.2, 1.8, and 2.8 ng/mL were requi red for 50% reducti ons in
propofol 's CP
50
s for ski n i nci sion, peri toneal incisi on, and abdomi nal retracti on, respectivel y.
Greater fentanyl concentrati ons were required to suppress hemodynami c responses to these same
sti mul i . Thus, fentanyl reduces requi rements for both vol ati l e agents and propofol by a si mi l ar
proporti on.
Several other i nvestigators have also used computer-assi sted infusi on to admini ster fentanyl as a
component of a bal anced anesthetic techni que.
97, 98
In combinati on wi th 50 to 70% N
2
O i n oxygen,
loss of consci ousness, and absence of response to ski n i nci sion are achi eved at pl asma fentanyl
concentrations of 15 to 25 ng/mL and greater than 3.7 ng/mL, respecti vel y. Intraoperati ve
concentration requi rements vari ed between 1 and 9 ng/mL. Fi nal ly, spontaneous venti l ati on was
seen when the fentanyl concentrati on dropped to 1.5 to 2 ng/mL.
97, 98

Fentanyl has been used as the sol e agent for anesthesi a, a technique that requi res a l arge
initi al dose of 50 to 150 g/kg or stabl e plasma fentanyl concentrations i n the range of 20 to
30 ng/mL.
90
The major advantage of thi s technique is rel iable hemodynamic stabi l ity. Hi gh doses
of fentanyl si gnifi cantly blunt the stress responsethat i s, hemodynami c and hormonal
responses to surgi cal sti mul i whi l e produci ng onl y mi ni mal cardiovascular depressi on. Thus, the
technique i s sometimes referred to as stress-free anesthesi a. There are al so di sadvantages to
using hi gh-dose fentanyl as the sol e anestheti c agent. It appears that no dose of fentanyl wil l
compl etel y bl ock hemodynami c or hormonal responses i n al l patients.
99
Furthermore, al though
hi gh doses generall y resul t in unconsci ousness, there have been reports of i ntraoperati ve
awareness and recal l i n patients who received very high doses (>50 g/kg) of fentanyl . Because
opi oi ds do not produce muscl e rel axati on, and high-dose fentanyl can produce muscl e ri gi di ty, a
muscle rel axant is generall y requi red to achi eve adequate surgi cal condi tions. Thi s can potenti al l y
increase the di fficul ty i n detecti ng si gns of i ntraoperative awareness. Direct and processed EEG
moni tori ng have been used to assess the depth of anesthesi a achieved with hi gh-dose opi oids.

The effects of fentanyl on cerebral bl ood flow (CBF) and intracrani al pressure (ICP) have been
studi ed i n normal pati ents and i n those wi th neurol ogi c disease. An i nducti on dose of 16 g/kg
i ncreased mi ddl e cerebral artery flow by 25% in normal patients havi ng noncrani al
neurosurgery.
100
A small er dose (3 g/kg) resul ted i n an el evati on i n ICP i n venti lated pati ents
with head trauma.
101
However, in brai n tumor pati ents anesthetized wi th N
2
OO
2
, a dose of 5
P.365
g/kg of fentanyl di d not resul t i n el evated ICP.
102
In all cases of el evati on i n ICP and CBF, there
were decreases i n mean arterial pressure, which may have contributed to these changes.
Muscl e ri gi di ty i s often seen on i nduction wi th hi gh-dose fentanyl and its deri vatives. When
ri gidi ty i s i ntense, i t may be di ffi cul t or i mpossibl e to venti late the pati ent. In a study in
normal volunteers, 1,500 g fentanyl i nfused over 10 mi nutes produced ri gi di ty i n 50% of
subjects.
103
A si mil ar i nci dence, 35%, was seen i n patients recei vi ng 750 to 1,000 g fentanyl
duri ng i nduction of general anesthesi a, and up to 80% of patients recei vi ng 30 g/kg devel oped
moderate to severe rigi di ty.
104
Muscl e ri gi di ty seen wi th high doses of fentanyl increases wi th
age
104
and i s accompanied by unconsci ousness and apnea,
103, 104
but l ower doses, 7 to 8 g/kg,
have produced chest wall ri gidi ty wi thout unconsciousness or apnea. Strei sand et al
103

hypothesi zed that hypercarbi a from fentanyl -induced respi ratory depression may have i nfluenced
fentanyl i onizati on and cerebral bl ood fl ow and hence the del i very of fentanyl to brai n ti ssue. It
woul d fol l ow that pati ents i nstructed to deep-breathe during fentanyl inducti on may experience
less ri gi dity duri ng induction of anesthesi a. Thi s is consistent wi th observati ons by Lunn et al .
105

During hi gh-dose fentanyl i nducti on (75 g/kg), PaCO
2
was maintained at 35 to 40 torr by
assi sti ng and then control l ing respi rati ons. Al though chest wal l compl i ance was reduced i n 4 of 18
patients, no pati ent devel oped ri gi di ty suffi cient to i mpai r ventil ati on.
Fentanyl has been associ ated wi th sei zure-li ke movements during anestheti c inducti on, whi ch are
not associated wi th seizure activity on the EEG.
106
Whereas fentanyl can i nduce sei zures i n other
animal s, the doses requi red to produce EEG-documented sei zures i s general ly hi gher than that
used in humans. Such acti vi ty may represent myoclonus, a resul t of opi oid-mediated bl ockade of
inhi bitory motor pathways of corti cal ori gi n, or may represent exaggerati ons of opioi d-induced
muscl e ri gi di ty.
106
However, fentanyl can acti vate epil epti form EEG acti vi ty i n pati ents havi ng
surgery for intractable temporal lobe epi lepsy.
107

Fentanyl -induced pruri tus often presents as facial i tchi ng, but can be general i zed. Equi anal gesic
pl asma concentrati ons of fentanyl , morphi ne, and al fentani l produce equival ent i ntensi ty of
pruri tus.
40
Fentanyl has al so been reported to have a tussi ve effect. Twenty-ei ght percent of
patients coughed within 1 minute after recei vi ng a bol us dose of fentanyl (1.5 g/kg). The
mechani sm i s uncl ear, and it was not attenuated by pretreatment wi th atropi ne or mi dazol am.
108

Respiratory Depression
Fentanyl produces approxi mately the same degree of venti latory depressi on as equi anal gesi c
doses of morphine.
40
Respi ratory depressi onexpressed as an el evati on in end-ti dal CO
2
, a
decrease i n the sl ope of the CO
2
response curve, or the mi nute venti l ati on at an end-ti dal CO
2
of
50 mmHg (V
E
50)devel ops rapi dl y, reachi ng a peak i n ~5 mi nutes,
88, 109, 110
and the ti me course
cl osel y fol lows pl asma fentanyl concentrati on.
109, 111
Even at pl asma concentrati ons associated wi th
mi ld anal gesi a, venti l atory depressi on can be detected, and the magni tude of respi ratory
depressi on i s li nearly rel ated to intensity of anal gesi a (see Tabl e 14-3).
40, 112
In postoperati ve
patients, pl asma fentanyl concentrati ons of 1.5 to 3.0 ng/mL were associ ated wi th a 50%
reduction in CO
2
responsiveness.
113

The magni tude of respi ratory depressi on can be greatl y i ncreased when fentanyl is given in
combi nation with another respi ratory depressant such as midazol am. Bai ley et al
110
determi ned
that mi dazol am al one (0.05 mg/kg) di d not depress ventil ati on or cause hypoxemi a. Fentanyl
al one (2 g/kg) reduced the sl ope of the CO
2
response curve and the V
E
50 by 50%, and 6 of 12
subjects became hypoxemi c. Fentanyl and mi dazol am produced no greater depressi on of the
ventil atory response to CO
2
than fentanyl alone, but 11 of 12 subjects became hypoxemi c and 6 of
12 became apnei c wi thi n 5 minutes. These observati ons suggest that this frequentl y used
combi nation bl unts the hypoxi c venti latory drive to a greater extent than the hypercarbi c
ventil atory drive. Precautions such as suppl emental oxygen and pul se oximetry monitori ng are
recommended when such drug combi nati ons are used.
Airway Reflexes
Although obtundati on of ai rway refl exes by general inhal ati on anestheti cs i s wel l descri bed,
li ttl e i s known about the direct effects of opi oi ds on these protective refl exes. Tagai to et al
examined the dose-rel ated effects of fentanyl on ai rway responses to laryngeal irri tati on during
propofol anesthesi a in humans.
114
Al l pati ents had l aryngeal mask airways; half breathed
spontaneousl y, and hal f had venti lation control led to mai ntai n an end-ti dal CO
2
of 38 mm Hg. In
both groups, sti mulation of the l arynx (appl i cation of water to mucosa) el i cited a forced
expi rati on, fol l owed by spasmodic panti ng mi ngl ed wi th cough refl exes and brief laryngospasm.
Wi th three cumul ati ve fentanyl doses (50, 50, and 100 g), expi rati on, panti ng, and coughi ng
decreased i n a dose-dependent fashi on. After the fi rst dose of fentanyl , apnea wi th l aryngospasm
repl aced the other refl exes, and with cumulati ve fentanyl dosi ng, the durati on of l aryngospasm
shortened. These i nvestigators al so noted that cough was the airway refl ex most vulnerable to
depressi on by fentanyl . Whi l e attenuation of ai rway reflexes i s desi rabl e duri ng general
anesthesia, i t i s equall y desi rabl e that these protecti ve refl exes return to basel ine rapi dl y after
emergence, and remai n intact throughout conscious sedati on. Doses requi red to suppress cough
and other reflexes i n awake or sedated i ndi vi dual s have not been characteri zed.
Cardiovascular and Endocrine Effects
Isol ated heart muscl e models have shown concentrati on-dependent negati ve inotropi c effects
of opi oi ds, i ncl udi ng morphine, meperidi ne, and fentanyl.
58
A fentanyl concentrati on of 10
g/mL reduced contracti l i ty by 50%, but 1 g/mL had no si gni fi cant effects on papi ll ary muscl e
mechani cs. In cl i ni cal practice, high-dose fentanyl admini stration (up to 75 g/kg) produces much
lower plasma concentrati ons, that i s, i n the range of 50 ng/mL,
105
and i s associ ated wi th
remarkabl e hemodynami c stabil i ty. Pati ents who recei ved 7 g/kg fentanyl at induction of
anesthesia had a sl i ght decrease i n heart rate, but no change i n mean arterial pressure compared
to control .
75
Fentanyl -induced bradycardi a is more marked i n anestheti zed than consci ous
subjects, and usual l y resol ves wi th atropi ne. Wi th hi gher fentanyl doses, in the range of 20 to 25
g/kg, decreases in heart rate, mean arteri al pressure, systemic and pul monary vascular
resistance, and pul monary capi l l ary wedge pressure of approxi matel y 15% were seen i n pati ents
with coronary artery di sease.
105, 115
Very high fentanyl doses, up to 75 g/kg, produced no further
hemodynamic changes. Al l of these pati ents had been premedi cated wi th a di azepam or
pentobarbi tal , and scopol amine or atropi ne. In unpremedicated patients undergoi ng noncardiac
surgery, i nducti on wi th fentanyl 30 g/kg produced no changes i n heart rate or systol ic bl ood
pressure.
104
Hypertensi on i n

response to sternotomy is the most common hemodynami c di sturbance duri ng hi gh-dose fentanyl
anesthesia and occurs i n 40 and 100% i n patients recei vi ng 50 to 100 g/kg.
116
Unli ke morphi ne
and meperi di ne, whi ch i nduce hypotension, at l east i n part because of hi stami ne rel ease,
57, 117

hi gh-dose fentanyl (50 g/kg) i s not associ ated wi th si gnifi cant hi stami ne rel ease (see Fi g. 14-4).
Whil e high doses of fentanyl are associ ated with mi ni mal cardiovascular changes, combi ni ng
fentanyl wi th other drugs can compromise hemodynami c stabi l ity. The combi nati on of fentanyl and
di azepam produces si gnifi cant cardiovascular depressi on.
104, 115
Di azepam 10 mg gi ven after 20 to
50 g/kg of fentanyl decreased stroke vol ume, cardi ac output, systemi c vascular resistance, and
mean arteri al pressure, and i ncreased central venous pressure si gni fi cantl y.
115
Addi ng 60% N
2
O to
hi gh-dose fentanyl produced a significant decrease i n cardiac output and i ncreases i n systemi c and
pulmonary vascular resistance.
105

High-dose fentanyl (100 g/kg) prevented increases i n pl asma epinephrine, corti sol , gl ucose, free
fatty aci ds, and growth hormone (the stress response) duri ng surgery, but l ower dose fentanyl
(5 g/kg followed by an infusion of 3 g/kg/h) di d not.
118

Smooth Muscle and Gastrointestinal Effects

Fentanyl, li ke morphi ne and meperi di ne, si gni fi cantl y increases common bi l e duct pressure
(see Fi g. 14-6).
72
Like other opioi ds, fentanyl can cause nausea and vomi ti ng, particul arl y i n
ambul atory pati ents, and can del ay gastri c emptying and i ntesti nal transit.
P.366
Disposition Kinetics
Fentanyl' s extreme li pi d sol ubi l ity (see Tabl e 14-2) al lows rapi d crossi ng of bi ol ogi c membranes
uptake by hi ghl y perfused ti ssue groups, i ncl udi ng the brai n, heart, and l ung. Thus, after a si ngl e
bol us dose, the onset of effects i s rapid and the durati on bri ef. Hug and Murphy
119
determi ned the
rel ati onships between fentanyl effects and i ts concentrati on over time in pl asma and vari ous
ti ssues in rats gi ven fentanyl 50 g/kg (Fi g. 14-8). The onset of opi oi d effects occurred withi n 10
seconds, and correl ated wi th a rapi d i ncrease i n brai n ti ssue fentanyl concentration, whi ch
equil i brated wi th pl asma by 1.5 mi nutes. Recovery from fentanyl effects started wi thin 5 minutes
and was compl ete by 60 minutes. El imi nati on from the central ti ssues (brain, heart, and l ung)
was al so rapi d, as fentanyl was redi stri buted to other ti ssues, parti cul arl y muscl e and fat. Peak
muscle concentration was seen at 5 mi nutes, whil e fat concentrati on reached a maximum
approxi mately 30 mi nutes after the dose. The del ay i n fat uptake despi te fentanyl ' s hi gh l i pid
solubi li ty i s because of the l i mi ted bl ood suppl y to that tissue. Thus, redi stributi on to muscl e and
fat l i mi ts the duration of a bol us dose of fentanyl , and accumul ati on i n peri pheral ti ssue
compartments can be extensi ve because of the l arge mass of muscl e and hi gh affi nity of fentanyl
for fat. Wi th prol onged administration of fentanyl , fat can act as a reservoi r of drug.
Fentanyl pharmacokineti cs have been studi ed i n normal vol unteers as wel l as pati ents under
general anesthesi a. After an iv dose, pl asma fentanyl concentrati on fall s rapi dl y, and the
concentrationti me curve has been described by both two- and three-compartment models.
120

McCl ain and Hug
109
admini stered fentanyl 3.2 or 6.4 g/kg to heal thy mal e vol unteers and found
that nearl y 99% of the dose was el iminated from pl asma by 60 mi nutes. These investi gators found
both rapi d and sl ower distri buti on phases, wi th half-ti mes of 1.2 to 1.9 mi nutes and 9.2 to 19
mi nutes, respecti vel y. The termi nal eli mi nation hal f-ti me ranged from 3.1 to 6.6 hours, somewhat
longer than that for morphi ne. Simi lar values were noted i n surgi cal pati ents l ess than 50 years
ol d,
102, 121
including morbidl y obese pati ents.
102
Reports of age effects on fentanyl kineti cs are
confl i cti ng. Whi le fentanyl requirement decreases wi th i ncreasi ng age (20 to 89 years),
pharmacokineti c parameters do not change.
122
In contrast, Bentley et al
121
observed a marked
FIGURE 14-8. Fentanyl uptake and eli mi nation in various ti ssues of the rat fol l owing
intravenous i njecti on. Unchanged fentanyl ti ssue concentrations (means for 6 rats) are
expressed as percentage of dose. Central represents the combined content of brain, heart,
and lung ti ssues. The l arge mass of muscl e (50% body weight of the rat) and hi gh affini ty of
fat for fentanyl (despite slow equil i bration) serve as a drai n on the central compartment.
(Repri nted with permi ssi on from Hug CC, Murphy MR: Ti ssue redi stri buti on of fentanyl i n
terms of i ts effects i n rats. Anesthesi ol ogy 55:369, 1981.)
decrease i n cl earance and an increase i n termi nal el iminati on hal f-ti me to approximatel y 15 hours
in pati ents over 60 years ol d compared to 4.4 hours i n pati ents less than 50 years ol d.
Unl i ke i ts derivati ves, fentanyl i s significantly bound to red bl ood cel l s, approximatel y 40%, and
has a bl ood:pl asma parti ti on coeffici ent of approximatel y 1.
120
Plasma fentanyl is highly protein
bound, with estimates i n the range of 79 to 87%. It bi nds avi dl y to
1
-aci d gl ycoprotein but al so
bi nds to al bumi n.
120, 123
Fentanyl protei n bindi ng i s pH dependent, such that a decrease i n pH wi l l
increase the proporti on of fentanyl that is unbound.
120
Thus, a patient wi th respi ratory aci dosi s
wil l have a hi gher proporti on of unbound (active) fentanyl , which coul d exacerbate respi ratory
depressi on. Cl earance of fentanyl is primari ly by rapi d and extensi ve metabol ism in the l i ver.
Clearance estimates
109, 122
of 8 to 21 mL/kg/mi n approach l iver bl ood fl ow and i ndi cate a hi gh
hepati c extracti on ratio. Thus, hepatic metabol i sm of fentanyl i s expected to be dependent on l i ver
bl ood flow. Metabol i sm i s pri mari l y by N-deal kyl ati on to norfentanyl and by hydroxyl ati on of both
the parent and norfentanyl .
120
Only about 6% of the dose of fentanyl i s excreted unchanged in the
uri ne.
109

Dosage and Administration of Fentanyl
From admi ni strati on as a si ngl e bol us dose, fentanyl devel oped an earl y reputation as a short-
acti ng opi oid, but experi ence with very l arge doses and mul ti pl e doses reveal ed that prol onged
respi ratory depressi on and del ayed recovery coul d occur. These observations demonstrate that
fentanyl ' s cl i ni cal durati on i s l i mi ted by redi stri buti on, and that wi th prol onged admi ni strati on,
accumulation can occur as di scussed l ater i n thi s chapter.
Fentanyl can be useful as a sedati ve/analgesi c premedi cation when given a short ti me prior to
inducti on. For this use, incremental doses of 25 to 50 g iv can be used and ti trated unti l the
desi red effect is achi eved. It is i mportant to note that al though the onset of fentanyl ' s effects i s
rapi d, peak effect l ags behi nd peak plasma concentration by up to 5 mi nutes.
88
A

transmucosal deli very system for fentanyl i s al so avai labl e and has been shown to be an effective
premedi cant for pedi atri c and adul t pati ents as wel l as an effecti ve treatment for break-through
pai n i n chroni c pain pati ents. In chi l dren, doses of 10 to 20 g/kg, and i n adul ts, 400 to 800 g,
administered 30 minutes pri or to induction or a pai nful procedure are safe and effecti ve, but dose-
dependent side effects typical of opi oids are reported.
124, 125
Because respi ratory depressi on and
hypoxemi a can occur, transmucosal fentanyl shoul d usual ly be admi ni stered in a moni tored
envi ronment.
When fentanyl was admini stered with 50% N
2
O i n oxygen for i nducti on, the effecti ve dose for l oss
of consciousness was 8 to 23 g/kg.
98
Remember, however, that the combi nation of N
2
O and a
moderate to hi gh dose of opi oi d may cause si gni fi cant muscle ri gidi ty, whi ch can be attenuated by
a vari ety of adjuvants, i ncludi ng benzodi azepi nes, barbi turates, and muscl e rel axants.
Fentanyl i s also used frequentl y as an adjunct to i nducti on agents, such as thi opental and
propofol , to bl unt the hemodynami c response to l aryngoscopy and tracheal i ntubati on, whi ch can
be parti cul arl y severe in pati ents wi th hypertension or cardiovascular disease. Common cl i ni cal
practi ce involves ti trati on of fentanyl i n doses of 1.5 to 5 g/kg pri or to admini stration of a
barbiturate or other induction agent. Because fentanyl 's peak effect l ags behi nd peak pl asma
concentration by 3 to 5 mi nutes, fentanyl titration should be compl ete approximatel y 3 minutes
pri or to laryngoscopy to maxi mall y blunt hemodynami c responses to tracheal i ntubation. Perhaps
the most common cl i ni cal use of fentanyl and its deri vati ves i s as an anal gesic component of
bal anced general anesthesi a. Wi th this techni que, incremental doses of fentanyl 0.5 to 2.5 g/kg
are admini stered i ntermi ttentl y as dictated by the intensity of the surgi cal stimul us and may be
repeated approxi matel y every 30 mi nutes. General l y, administrati on of up to 3 to 5 g/kg/h wi ll
al low recovery of spontaneous venti lation at the end of surgery. As an al ternative to i ntermi ttent
dosing, a l oadi ng dose of 5 to 10 g/kg and conti nuous fentanyl i nfusi on at a rate between 2 and
10 g/kg/h are recommended.
98
It i s i mportant to remember, however, that anestheti c
requi rements vary wi th age, concurrent di seases, and the surgical procedure. For exampl e,
fentanyl requi rements decrease by 50% as age i ncreases from 20 to 89 years.
122
Fentanyl
P.367
requi rements can al so be expected to decrease with the duration of infusi on (see discussi on of
context-specific hal f-ti mes at the end of thi s chapter).
Fentanyl combi ned with hi gh-dose droperi dol, and ni trous oxi de, i s a technique cal l ed
neurol eptanesthesia.
126
Although used for many years, this techni que has l argel y been repl aced by
the bal anced anestheti c technique of fentanyl combi ned wi th l ow-dose i nhal ed anestheti cs.
Neuroleptanesthesi a is not l i kely to regai n popular use i n the Uni ted States because of concerns
about prol ongati on of the QT interval of the ECG by hi gh dose droperi dol .
127
Hi gh-dose (e.g., 50 to
150 g/kg) fentanyl anesthesia has been used extensi vel y for cardiac surgery. Wi th thi s
technique, a mean pl asma fentanyl concentrati on of 15 ng/mL, whi ch prevents hemodynami c
changes i n response to noxious sti mul i,
128
can be achieved wi th a loading dose of 50 g/kg,
fol l owed by a conti nuous i nfusi on of 30 g/kg/h. With hi gh-dose fentanyl , muscle rel axants and
mechani cal venti l ation are requi red. Whether opioi ds al one are sui tabl e as the sol e anesthetic
agent conti nues to be debated.
Fi nal ly, fentanyl has been used as an analgesi c in management of acute and chroni c pai n (see
Chapters 54 and 55).
Dosage recommendations are summarized in Tabl e 14-5.
SUFENTANIL
Sufentani l , a thi enyl derivati ve of fentanyl (see Fi g. 14-5) first descri bed i n the mi d 1970s, has a
cl i ni cal potency rati o 2,000 to 4,000 times that of morphi ne and 10 to 15 ti mes that of
fentanyl.
129, 130
Like fentanyl, sufentanil equi l i brates rapi dl y between bl ood and brai n, and
demonstrates cl ear pl asma concentration-effect rel ati onshi ps. In a study compari ng sufentanil and
fentanyl effects on the EEG, Scott et al
130
noted si mi l ar pharmacodynamic profi les. Duri ng a 4-
mi nute sufentanil i nfusion, the change i n spectral edge l agged behi nd the risi ng sufentanil
concentration by approxi matel y 2 to 3 mi nutes, whi le resol uti on of the EEG changes l agged behi nd
pl asma concentrati on changes by 20 to 30 mi nutes.
Anal gesi a
Sufentani l i s a hi ghl y selective -opi oi d receptor agoni st and exerts potent anal gesi c effects i n
animal s when gi ven by either systemic or spi nal routes. Whi l e the l iterature describi ng cl i ni cal
experi ence wi th sufentanil as a component of general anesthesi a is extensi ve, avai l abl e
information regardi ng the anal gesic potency of systemicall y admini stered sufentani l i n humans i s
li mi ted. Gell er et al
131
ti trated an i v i nfusion rate to adequate postoperati ve analgesi a, and noted
that a mean rate of 8 to 17 g/h was requi red during the first 48 hours. Thi s was associ ated wi th
a fivefol d range i n pl asma sufentani l concentrations, between 0.02 and 0.1 ng/mL. Si mi l ar
sufentani l requi rements (i ncl udi ng a wi de interpati ent variabil i ty) are noted in other studi es of
postoperative and cancer pati ents,
41, 132
and Lehman estimated that the minimum effective
anal gesi c concentrati on of sufentanil i s near 0.03 ng/mL,
132
and the anal gesi c EC
50
of sufentani l
concentration is approxi matel y 0.05 ng/mL.
133

EFFECT ON MINIMUM ALVEOLAR CONCENTRATION OF
VOLATILE ANESTHETICS AND USE IN ANESTHESIA
In ani mal studi es, sufentani l decreases the MAC of volatil e anestheti cs i n a dose-dependent
manner, with the maximum MAC reduction between 70 and 90%.
134
In humans, a pl asma
sufentani l concentrati on of 0.145 ng/mL is associated with a 50% reduction in i sofl urane MAC.
135

Increasi ng the plasma sufentani l concentrati on to 0.5 ng/mL reduced i sofl urane MAC by 78%, and
a cei li ng effect was approached wi th greater plasma sufentani l concentrati ons. The maximum MAC
reduction seen in humans was 89%, at a sufentani l concentrati on of 1.4 ng/mL.
In cli ni cal anesthesia practice, sufentani l i s used as a component of bal anced anesthesi a and has
been empl oyed extensively in high doses (10 to 30 g/kg) with oxygen and muscl e rel axants for
cardi ac surgery. In thi s dose range, sufentani l is at l east as effective as fentanyl i n its abil i ty to
produce and mai ntain hypnosi s. In addi ti on, hemodynami c stabi l i ty appears to be as good as or
better than that achi eved wi th fentanyl .
75, 129
Bai l ey et al
136
used a computer-assi sted conti nuous
infusi on system to determine the sufentani l pl asma concentrati on response to various noxi ous
stimul i duri ng high-dose sufentani l anesthesi a for cardiac surgery. They estimated the pl asma
concentration associated wi th a 50% probabi l ity of no response (movement, hemodynamic, or
sympatheti c) to intubati on, i nci si on, sternotomy, and medi astinal di ssection (CP
50
). The CP
50
for
intubati on, i ncisi on, and sternotomy (pool ed data) was 7.06 ng/mL, and for mediasti nal di ssecti on
CP
50
was 12.1 ng/mL. As i s typical of opi oi ds, a wi de i ntersubject vari abil i ty (3- to 10-fol d) was
noted i n sufentani l concentrati on requirements. However, when used as the sole anesthetic agent,
even high doses may not compl etel y block the hemodyami c responses to noxi ous sti muli .
99

Equi analgesi c doses of sufentani l and fentanyl produce si mil ar changes in the EEG.
129, 130
In
patients who recei ved sufentani l 15 g/kg, acti vi ty became promi nent wi thin a few seconds, and
within 3 minutes, the EEG consi sted almost enti rel y of

sl ow acti vi ty.
129
Ri gi di ty and myocl oni c acti vi ty resembl i ng seizures have been reported during
i nducti on of, and on emergence from, anesthesi a wi th sufentani l i n doses of approxi mately 1 to 2
g/kg.
37, 38

There has been consi derabl e investigation of the effects of sufentani l on cerebral hemodynami cs
and intracrani al pressure. In patients with intracrani al tumors, sufentani l 1 g/kg was associated
with an el evati on i n spi nal cerebrospinal pressure and a decrease i n cerebral perfusi on
pressure.
137
As seen wi th fentanyl, mean arterial pressure had dropped signi fi cantl y i n these
patients. In normal volunteers, a small er dose of sufentanil (0.5 g/kg) was not associated wi th
changes i n cerebral bl ood fl ow.
138
Very large doses of sufentani l (20 g/kg) i n dogs decreased
cerebral bl ood fl ow i n proportion to cerebral metabol i sm, and i ntracrani al pressure di d not
change.
139

Li ke other -opi oi d agoni sts, sufentani l causes respi ratory depression in doses associ ated with
cl i ni cal analgesia.
111, 112
Respi ratory depressi on can be especi al l y marked i n the presence of
inhalation anestheti cs. In spontaneously breathi ng patients anestheti zed with 1.5% hal othane and
N
2
O, a smal l dose of sufentani l (approximatel y 2.5 g) reduced mean mi nute ventil ati on by 50%,
and 4 g reduced mean respi ratory rate by 50%.
140
Postoperati ve respi ratory depression after
apparent recovery from anesthesia has been reported for both fentanyl and sufentanil.
141
The l ack
of exogenous sti mulation in the earl y postoperati ve peri od may be an i mportant a factor during
early recovery from anesthesi a.
In normal vol unteers who recei ved bol us doses of fentanyl and sufentani l , changes i n end-ti dal
CO
2
were the same for fentanyl and sufentani l , but the sl ope of the venti latory response to CO
2

was depressed to a greater extent by fentanyl .
111
In another vol unteer study, a fourfol d range of
equianal gesi c pl asma concentrati ons of morphine and sufentani l produced equival ent respi ratory
depressi on, measured as both i ncreased end-ti dal CO
2
and a decreased venti l atory response to
CO
2
.
133

Car di ovascul ar and Endocr i ne Ef f ect s
In ani mal studi es, sufentani l produces vasodi lation by a sympathol yti c mechani sm but may also
have a di rect smooth muscl e effect.
142
Cl ini call y, a promi nent feature of many tri als involving
sufentani l is the remarkabl e hemodynami c stabil i ty achieved during bal anced and hi gh-dose (up to
30 g/kg) opi oi d anesthesi a. Only a modest decrease in mean arterial pressure i s observed when
sufentani l (approxi matel y 15 g/kg) i s used for induction of anesthesi a.
75, 143
In general, sufentanil
and fentanyl have been found to be equival ent for use i n bal anced and hi gh-dose opi oid
anesthesia,
99, 144
but cli nical compari sons between fentanyl and sufentani l suggest that sufentani l
may be associ ated with less respi ratory depression and better anal gesia i n the immedi ate
P.368
postoperative peri od.
145

The choice of premedi cation and muscl e rel axant may si gni fi cantl y affect hemodynami cs during
inducti on and maintenance of anesthesi a with sufentani l . Combi ni ng vecuroni um and sufentani l
can cause a decrease i n mean arteri al pressure duri ng i nducti on,
146
and si gnifi cant bradycardi a
and si nus arrest
147
have been reported. Bradycardia i s not seen when pancuroni um is used during
anesthesia with sufentani l.
Sufentani l , l ike fentanyl , reduces the endocri ne and metaboli c responses to surgery.
129
However,
even a l arge induction dose (20 g/kg) di d not prevent i ncreases i n corti sol , catecholami nes,
gl ucose, and free fatty aci ds duri ng and after cardi opul monary bypass.
148

Sufentani l i s extremel y l i pophil i c and has pharmacoki netic properti es si mi l ar to that of fentanyl.
Because of a smal ler degree of ioni zation at physi ol ogi c pH and hi gher degree of pl asma protei n
bi ndi ng, i ts vol ume of di stri bution is somewhat small er and i ts el i mi nati on hal f-li fe shorter than
that of fentanyl (see Tabl e 14-2). Sufentani l pharmacoki netics has been studi ed i n anestheti zed
patients who had recei ved methohexi tal for anestheti c induction, fol l owed by the sufentani l dose
of 5 g/kg, and N
2
O i n oxygen 33%.
149
Plasma sufentani l concentrati on drops very rapi dl y after an
i v bol us dose, and 98% of the drug i s cl eared from pl asma wi thi n 30 minutes. Plasma
concentrationti me data i n thi s study were best fi tted to a three-compartment model , with rapi d
and sl ower di stri buti on hal f-ti mes of 1.4 and 17.7 minutes, respecti vel y, and an eli mi nati on hal f-
li fe of 2.7 hours. In other pharmacokineti c studies wi th anesthetized pati ents, reported mean
el i mi nation half-li ves were i n the range of 2.2 to 4.6 hours.
150, 151, 152
Obese pati ents have a l arger
total volume of distri bution and a l onger eli mi nation hal f-li fe (3.5 vs. 2.2 hours) compared to
nonobese pati ents.
150

Sufentani l i s less red cel l bound than fentanyl (22 compared to 40%) and has a whol e
bl ood:pl asma concentrati on rati o of 0.741.
120
Plasma sufentani l i s approximatel y 92% protein
bound at pH 7.4, mostl y to
1
-aci d gl ycoprotei n. Cl earance of sufentani l i s rapid, and l ike fentanyl
has a high hepati c extracti on rati o.
120
Metabol i sm i n the li ver i s by N-deal kyl ati on and O-
demethyl ati on. However, sufentani l clearance and eli mi nation hal f-li fe i n pati ents with ci rrhosi s
are si mil ar to control s.
151

Dosage and Admi ni st r at i on of Suf ent ani l
Like fentanyl , sufentanil i s most often used as a component of bal anced anesthesi a, or as a si ngl e
agent i n hi gh doses, parti cul arl y for cardiac surgery (Tabl e 14-5). Several investi gati ons have
found si mi l ar sufentani l dose requi rements for i nducti on of anesthesi a.
136, 153, 175
When sufentanil is
ti trated duri ng induction, loss of consciousness i s seen wi th total doses between 1.3 to 2.8 g/kg.
Doses in the range of 0.3 to 1.0 g/kg given 1 to 3 mi nutes pri or to l aryngoscopy can be expected
to bl unt hemodynami c responses to i ntubation, but muscl e rigi di ty can occur, parti cularly in the
el derl y, even at these l ower doses.
Bal anced anesthesi a is mai ntai ned wi th i ntermi ttent bolus doses or a conti nuous i nfusi on. Wi th
bol us doses of 0.1 to 0.5 g/kg, mean mai ntenance requi rements of 0.35 g/kg/h have been
reported.
75
Cork et al
152
admini stered an ini ti al bol us of 0.5 g/kg followed by an infusion of 0.5
g/kg/h, ti trated to pati ent need. Thi s regi men of sufentani l i n combi nati on with N
2
O 70% in
oxygen, wi th or without i soflurane, provi ded satisfactory anesthesi a wi th good hemodynami c
stabi l ity. Thus, for bal anced anesthesia, sufentanil -expected dose requi rements for bol us
administrati on and conti nuous infusi on are si mi lar, i n the range of 0.3 to 1 g/kg/h. Much hi gher
bol us doses (10 g/kg) and/or i nfusi on rates (0.15 g/kg/mi n) are required to achi eve the pl asma
sufentani l concentrati on range of 6 to 60 ng/mL requi red duri ng cardi ac anesthesi a usi ng
sufentani l as the sole agent.
ALFENTANIL
Alfentanil , a tetrazol e derivative of fentanyl (see Fi g. 14-5), was synthesi zed 2 years after
sufentani l and introduced i nto cl ini cal practi ce in the earl y 1980s. On a mil l i gram basis, i ts cl i ni cal
potency i s approxi matel y ten ti mes that of morphine and one-fourth to one-tenth that of fentanyl
when given in single doses. Alfentanil di ffers from fentanyl i n its pharmacoki netics

as wel l as i n its speed of equi li brati on between pl asma and effect si te in the brai n. In a
compari son usi ng EEG spectral edge effects to quanti fy fentanyl and alfentanil pharmacodynami cs,
Scott et al
88
demonstrated that al fentani l ' s effect followed serum drug concentrati on more closely
than fentanyl (see Fig. 14-8). Peak effect l agged behi nd peak pl asma concentration by l ess than 1
mi nute, and resol uti on of effect fol l owed decreasi ng serum al fentani l concentrati on by no more
than 10 mi nutes. Alfentani l i s a -opi oi d receptor agoni st and produces typi cal nal oxone-reversi bl e
anal gesi a and si de effects such as sedati on, nausea, and respi ratory depression.
Anal gesi a
Alfentanil has been administered i ntravenousl y for treatment of postoperati ve and cancer-rel ated
pai n, as wel l as i n l aboratory pain model s wi th normal vol unteers. Cl ear concentrati on and dose-
rel ated anal gesi c effects have been demonstrated for al fentani l , but i ndi vi dual requirements i n
terms of dosage or pl asma concentrati ons vary wi del y. For postoperati ve anal gesi a, the MEAC i s
approxi mately 10 ng/mL, wi th a range of 2 to >40 ng/mL.
154
In a l aboratory i nvesti gation, 80
ng/mL was associ ated wi th a 50% reducti on i n pai n intensi ty.
40
In cli nical studi es of pati ents
recei vi ng conti nuous iv i nfusi on of al fentani l, mean pl asma concentrations requi red for rel i ef of
moderate to severe pai n are approxi mately 40 to 80 ng/mL (see Tabl e 14-3).
155
Fol lowi ng an
adequate loading dose, average al fentani l requirements for postoperative anal gesia are
approxi mately 10 to 20 g/kg/h.
156, 157

Anest het i cs and Use i n Anest hesi a
Like other opioids, al fentani l decreases the MAC of enfl urane i n a curvil i near fashi on up to a
pl ateau.
21, 158
In dogs, an infusion rate of 8 g/kg/mi n (pl asma concentrati on 223 ng/mL) reduced
enflurane MAC by 69%, but increasing the infusion rate fourfol d di d not reduce enflurane MAC
further.
158

In humans, al fentani l pl asma concentrations requi red to suppl ement N
2
O anesthesia for vari ous
noxious stimul i have been determi ned.
159
Pati ents received a loadi ng dose of 150 g/kg, foll owed
by an i nfusi on that was ti trated between 25 and 150 g/kg/h according to the pati ents' responses
to surgical sti mul i , and steep concentration-effect curves were demonstrated. Pl asma
concentrations requi red al ong wi th 66% N
2
O to obtund somati c, autonomi c, and hemodynamic
responses to sti mul i i n 50% of patients were 475, 279, and 150 ng/mL for tracheal intubati on,
ski n i ncisi on, and ski n cl osure, respecti vel y. The plasma alfentanil concentrati on associ ated with
spontaneous venti lation after disconti nuati on of N
2
O was 223 ng/mL. Nearly identi cal resul ts were
obtai ned in a si mil ar study using computer-control led infusi ons to del i ver al fentani l (Fi g. 14-9).
160

Pl asma al fentani l concentrati ons required i n combi nation wi th propofol to obtund responses to
i ntubati on and surgi cal sti muli have al so been determi ned.
161
In contrast to combi ni ng al fentani l
and N
2
O, much lower alfentani l pl asma concentrati ons (55 to 92 ng/mL) were required to prevent
responses i n 50% of pati ents when al fentani l was combined wi th propofol at a pl asma
concentration of 3 g/mL (Fi g. 14-10).
P.369
FIGURE 14-9. The relationshi p between alfentanil pl asma concentration (wi th 66% N
2
O) and
the probabi l ity of no response for intubati on, ski n i nci sion, and ski n cl osure; and the
rel ati onship of plasma alfentani l concentrati on (wi thout N
2
O) and the recovery of adequate
spontaneous venti lation. (Reprinted with permission from Ausems ME, Vuyk J, Hug CC et al :
Compari son of a computer-assi sted infusi on versus intermi ttent bol us admi ni strati on of
al fentani l as a suppl ement to ni trous oxi de for l ower abdomi nal surgery. Anesthesi ology
68:851, 1988.)
High-dose al fentani l has been used as an inducti on agent for pati ents wi th and wi thout cardi ac
di sease
162
and for induction and mai ntenance of cardiac anesthesi a.
116, 163
Pati ents wi th cardiac
val vul ar or coronary artery disease requi red hal f as much al fentani l to i nduce unconsciousness.
162

When used as the sol e anestheti c agent, mean pl asma al fentani l concentrations required to
si gni fi cantl y blunt hemodynami c responses to intubati on and sternotomy were 700 to 830 ng/mL
and 1,200 to 1,800 ng/mL, respecti vel y.
164
These values are approxi matel y twi ce those reported
for alfentanil i n combi nation wi th 66% ni trous oxi de.
159, 160
However, even doses that produced
very hi gh plasma al fentani l concentrati ons (1,200 to >2,000 ng/mL) di d not el iminate responses
to i ntubati on and intraoperati ve sti mul i i n al l pati ents.
199
In contrast to fentanyl and sufentani l ,
the durati on of even very l arge doses of al fentani l i s short, so repeated doses or a continuous
infusion of alfentanil is required.
Alfentanil produces the typi cal general i zed sl owing of the EEG;
88, 165
a plasma concentrati on of
approxi mately 1,400 ng/mL is associ ated with the onset of -wave activity. Like fentanyl ,
al fentani l can increase epi l epti form EEG activity i n pati ents wi th i ntractabl e temporal l ope epil epsy
havi ng surgery under general anesthesi a.
132
Like fentanyl and sufentani l, al fentani l can produce
intense muscle ri gidi ty accompani ed by loss of consciousness. In 90 to 100% of pati ents, i nduction
doses of 150 to 175 g/kg were associated wi th muscl e rigi di ty, which was not li mited to the chest
wal l or trunk. Rather, el ectromyography has shown i ncreased activity of comparabl e magni tude i n
muscles of the neck, extremiti es, chest wal l , and abdomen.
137, 166

Alfentanil has been reported to i ncrease cerebrospinal fluid pressure in patients wi th brai n tumors,
whereas fentanyl does not.
102
However, Mayberg et al
167
exami ned the effect of 25 and 50 g/kg
of al fentani l on cerebral bl ood fl ow vel oci ty and i ntracrani al pressure i n neurosurgi cal and
orthopaedic patients anestheti zed wi th i sofl urane and 50% N
2
O. Venti l ati on was control l ed to
maintai n normocapnea, and bl ood pressure was mai ntai ned at basel i ne for neurosurgi cal pati ents.
No cli nicall y si gni fi cant changes i n ICP and no evidence of cerebral vasodi lation or vasoconstri cti on
were seen.
In ani mal and human studi es, antinoci ceptive effects coul d not be separated from respi ratory
depressi on i n vol unteers; mi ld ventil atory depressi on (i ncreased end-ti dal CO
2
; decreased

sl ope of the CO
2
response curve) was seen at pl asma concentrations as low as 20 ng/mL. At
pl asma concentrati ons associ ated wi th 50% reducti on i n pai n intensity, respiratory depressi on was
equival ent for al fentani l , fentanyl, and morphi ne.
10
A cli nical study exami ned postoperati ve
anal gesi a and respi ratory effects of al fentani l admi ni stered by a pati ent-control led anal gesia
system.
168
In pati ents who recei ved a conti nuous al fentani l i nfusi on at 900 g/h plus 100- to 200-
g doses as needed, 3 of 10 pati ents developed respi ratory depression (respi ratory rate <8/min).
Mean al fentani l bl ood concentrati on in thi s group of patients was 80 ng/mL.
Two cl i ni cal studies exami ned the i ntensity and durati on of respi ratory depressant effects of
al fentani l in the i mmediate postoperati ve peri od.
169, 170
Pati ents received bal anced anesthesi a 67%
N
2
O with or wi thout 0.5% hal othane and alfentani l 20 to 100 g/kg/h. At the end of surgery the
infusi on was decreased to 20 g/kg/h, which produced pl asma alfentanil concentrati ons between
106 and 120 ng/mL, and good analgesi a. Ventil atory response to CO
2
was decreased to 50% of the
FIGURE 14-10. The al fentani l pl asma concentrati on-effect relationships for intubati on, ski n
inci sion, and the opening of the peritoneum when gi ven as a suppl ement to propofol .
(Repri nted with permi ssi on from Vuyk J, Lim T, Engbers FHM et al : Pharmacodynami cs of
al fentani l as a suppl ement to propofol or ni trous oxi de for lower abdomi nal surgery in femal e
patients. Anesthesi ol ogy 78:1036, 1993.)
P.370
baseli ne value, but PaCO
2
was only moderatel y el evated (42 to 48 torr). By 2 hours after
al fentani l was disconti nued, respi ratory function was near basel i ne. Recovery of venti latory
function was faster with alfentani l compared to fentanyl .
170
Another comparison found that for
anesthetics of 1.5 to 2 hours duration, recovery of respiratory functi on was simi lar wi th al fentani l
and fentanyl .
171
Like i ts congeners, al fentani l has been associated wi th apnea and
unconsci ousness after apparent recovery from anesthesi a.
172

Car di ovascul ar Ef f ect s
The cardi ovascular effects of al fentani l are i nfl uenced by preoperati ve medicati on, muscle rel axant
used, method of admi ni strati on, and the degree of surgi cal sti mulation. In general , heart rate and
mean arteri al pressure are unchanged or sl ightly decreased duri ng i nducti on with al fentani l 40 to
120 g/kg,
162
but rapi d i nduction wi th 150 to 175 g/kg al fentani l can decrease mean arteri al
pressure by 15 to 20 torr. After induction with etomi date, al fentani l 120 g/kg decreased mean
arterial pressure by approxi mately 30 torr,
173
and fol l owi ng thi opental (3 to 5 mg/kg) i nducti on, a
smal l er dose of al fentani l (40 g/kg) decreased mean arteri al pressure by approximatel y 40
torr.
174
Al fentani l does not appear to have negative i notropic effects,
173
but severe hypotensi on
has been observed when al fentani l is gi ven after 0.125 mg/kg di azepam.
175
In combinati on wi th
l orazepam premedi cation or thi opental i nduction, moderate doses (10 to 50 g/kg) of al fentani l
bl unt the cardi ovascul ar and catechol ami ne responses to l aryngoscopy and i ntubation,
164, 174
but
for pati ents over 70 years ol d, doses i n thi s range gi ven wi th thi opental can produce signi ficant
hypotensi on after inducti on.
176
Al fentani l can al so cause bradycardi a, but thi s effect is minimi zed
by premedi cati on wi th atropi ne and by the vagolytic effect of pancuronium. Alfentanil 50 g/kg
combi ned with propofol 1 mg/kg for inducti on of anesthesia can produce si gni fi cant bradycardia
and hypotension after i ntubati on, but premedi cati on wi th gl ycopyrrol ate prevents these effects.
177

Nausea and Vomi t i ng
Earl y cl inical reports noted frequent nausea during recovery from bal anced anesthesi a using
al fentani l, but cli nical compari sons between al fentani l and sufentanil
178
or fentanyl
179
and N
2
O
revealed the same inci dence of nausea and vomi ting. In normal volunteers recei vi ng computer-
control l ed opi oi d i nfusi ons, the severi ty of nausea at equi analgesic pl asma concentrations was
equival ent for al fentani l , fentanyl, and morphi ne,
40
but alfentanil -induced nausea and

vomiti ng resol ved more qui ckl y (Coda BA, unpubl i shed observati ons).
Al fentani l pharmacoki neti cs di ffers from fentanyl and sufentani l in several respects (see Tabl e 14-
3). A unique characteristic is that alfentanil i s a weaker base than other opi oi ds. Whereas other
opi oi ds have pK
a
above 7.4, the pK
a
of al fentani l i s 6.8; consequentl y, nearl y 90% of unbound
pl asma al fentani l i s noni onized at pH 7.4.
120
Thi s property, together wi th i ts moderate l i pi d
solubi li ty, enabl es al fentani l to cross the bl ood-brai n barri er rapi dl y and accounts for its rapi d
onset of acti on. Compared to fentanyl and sufentani l , which have mean plasma-brain equi l ibrati on
half-ti mes of 6.4 and 6.2 mi nutes, respectivel y,
88, 130
al fentani l has a blood-brain equi l ibrati on
half-ti me of 1.1 mi nutes.
110
Al fentanil al so has a smal l er vol ume of distribution than fentanyl,
whi ch i s a resul t of l ower li pi d sol ubi l ity and hi gh protei n bindi ng.
180
Approxi matel y 92% of
al fentani l is protei n bound, mostl y to
1
-aci d gl ycoprotei n.
120, 123

After i v admi nistrati on, pl asma al fentani l concentrati on fall s rapi dly; 90% of the admini stered
dose has l eft the plasma by 30 mi nutes,
181
mostl y because of di stri buti on to hi ghl y perfused
ti ssues. Pl asma concentrati on decay curves i n pati ents most often fi t a three-compartment
model .
19, 181
Like fentanyl, alfentanil is qui ckl y di stri buted, wi th rapi d and sl ow di stri buti on hal f-
ti mes of 1.0 to 3.5 mi nutes and 9.5 to 17 mi nutes, respectivel y. However, al fentani l has a
termi nal eli mi nation half-li fe of 84 to 90 minutes, which is considerabl y shorter than those of
fentanyl and sufentanil. Clearance of alfentanil, 6.4 mL/kg/min, is just half that of fentanyl, but
because alfentani l ' s vol ume of di stributi on i s 4 ti mes smal l er than fentanyl' s, relativel y more of
the dose i s avai l abl e to the li ver for metabol ism.
182
Chauvi n et al
183
found that alfentanil has an
P.371
intermedi ate hepatic extracti on coeffici ent (32 to 53%) in humans, and that i ts el i mi nation is
dependent on hepatic pl asma flow.
In ani mals, al fentani l undergoes N-deal kyl ati on and O-demethyl ati on in the l i ver to form i nacti ve
metabolites.
120
Liver di sease can signi ficantl y prol ong the el i mi nati on hal f-li fe of al fentani l.
Patients with moderate hepati c insuffi ciency as a resul t of ci rrhosis have reduced bi ndi ng to
1
-
aci d gl ycoprotei n and a pl asma clearance one-half that of control pati ents. These changes resul t i n
a marked increase i n the el iminati on hal f-li fe, 219 minutes versus 90 mi nutes i n control s.
184
Renal
di sease also decreases al fentani l protein bi ndi ng, but does not resul t i n decreased pl asma
cl earance or a prolonged termi nal eli mi nation half-li fe.
185
Al fentanil ' s eli minati on hal f-li fe i s
prolonged by about 30% i n the el derl y and appears to be much shorter (about 40 mi nutes) i n
chil dren 5 to 8 years old.
186
Obesi ty is al so associ ated with a 50% decrease i n al fentani l clearance
and a prolonged (172 minutes) el imi nati on hal f-li fe.
186

The combinati on of moderate l ipi d sol ubil i ty and short el imi nati on hal f-li fe suggests that both
redi stri buti on and el i mi nati on are important i n the termi nation of al fentani l 's effects.
182
After a
si ngl e bol us dose, redi stri buti on wi l l be the most i mportant mechanism, but after a very l arge
dose, repeated smal l doses, or a continuous i nfusion, eli mi nation wi ll be a more i mportant
determi nant of the durati on of al fentani l ' s effects.
Dosage and Admi ni st r at i on of Al f ent ani l
Because of i ts rapid onset, al fentanil has been used as an induction agent al one or i n combi nation
with other drugs. In heal thy pati ents, doses of about 120 g/kg produce unconsci ousness i n 2 to
2.5 mi nutes, but may also produce muscl e ri gi di ty. Premedi cati on with a benzodi azepi ne (e.g.,
lorazepam 0.08 mg/kg) is associ ated with a lower dose requirement, 40 to 50 g/kg, and a faster
onset of unconsciousness, wi thi n 1.5 mi nutes,
162
but may al so produce hypotension.

Because of i ts bri ef durati on of acti on, al fentani l can be a useful component of general anesthesi a
in short surgical procedures, especi al l y those associ ated wi th mini mal postoperative pai n,
parti cul arl y i n the outpatient surgery. In thi s setti ng, loading doses of 5 to 10 g/kg provi de good
anal gesi a wi th rapi d recovery.
180
For l onger procedures, al fentani l can be admini stered as needed
i n repeated smal l bol us doses, but i ts pharmacoki neti c properti es make i t i deal for admi ni strati on
as a conti nuous infusi on. After induction of anesthesi a, a l oadi ng dose of alfentanil 10 to 50 g/kg
is fol lowed with supplemental bolus doses of 3 to 5 g/kg as needed or a conti nuous infusi on
starting at 0.4 to 1.7 g/kg/mi n wi th 60 to 70% N
2
O or a propofol i nfusion.
159, 160, 180, 187, 188
A
pedi atric study reported use of si mi lar doses of alfentanil and propofol ,
189
whi l e another used
hi gher al fentani l doses (100 g/kg l oadi ng dose fol l owed by 2.5 g/kg/mi n) combi ned with 70%
N
2
O without propofol .
190

When hi gh-dose al fentani l i s used as the sol e anestheti c agent, a conti nuous infusi on of up to 150
to 600 g/kg/h is adjusted accordi ng to the patient' s responses to sti mul i, but much l ower doses
can be effecti ve for cardiac surgery if adequate premedicati on i s gi ven.
163
See Tabl e 14-5 for a
summary of dosage recommendati ons.
REMIFENTANIL
Remifentanil , a 4-anil i dopi peri di ne wi th a methyl ester si de chai n (see Fi g. 14-5) first descri bed i n
1990 and approved for cl i ni cal use i n 1996, was developed to meet the need for an ul trashort-
acti ng opi oid. Because i ts ester si de chain i s susceptibl e to metaboli sm by bl ood and ti ssue
esterases, remi fentani l is rapi dl y metabol i zed to a substantial ly l ess active compound. Thus,
because i ts ultrashort acti on i s due to metaboli sm rather than to redi stributi on, i t does not
accumulate wi th repeated dosi ng or prol onged i nfusi on. Remi fentani l demonstrates potent,
naloxone-reversi bl e -sel ecti ve opioi d agoni st activity i n ani mal assays.
191

Anal gesi a
In ani mals and humans, remifentanil produces dose-dependent anal gesic effects. Human
laboratory studies have examined analgesic effects of bol us i v doses (0.0625 to 2.0 g/kg)
192
as
well as computer-control led i nfusi ons wi th targeted pl asma concentrations (0.75 to 3.0 ng/mL).
193

Bol us doses produced a peak anal gesic effect between 1 and 3 mi nutes and a durati on of
approxi mately 10 mi nutes. In volunteers, MEAC i s approximately 0.75 ng/mL, and anal gesi c EC
50

i s approxi matel y 3 ng/mL.
193
Both studies found remi fentani l to be about 40 ti mes as potent as
al fentani l.
Cli nical i nvesti gati ons have eval uated earl y postoperative anal gesia. One study reported that after
remi fentani l propofol anesthesi a, nearl y 80% of patients were titrated to sati sfactory anal gesi a
with remifentanil infusi on of 0.05 to 0.15 g/kg/mi n.
194
Another early postoperati ve eval uati on
demonstrated effective anal gesia wi th patient-controlled infusion of remifentanil to a mean target
bl ood concentration of 2 ng/mL, but noted a fai rly hi gh inci dence of nausea (26%) with thi s
regi men.
195
Cl ini cal evaluati ons of remi fentani l for labor anal gesia have produced confl icting
resul ts, and some have found prohi bi ti ve rates of unacceptabl e si de effects such as nausea and
respi ratory depressi on. However, a dose-rangi ng study that used remi fentani l vi a PCA reported a
medi an effecti ve bol us dose of 0.4 g/kg (range 0.2 to 0.8 g/kg) and consumpti on of 0.066
g/kg/mi n (range 0.027 to 0.207 g/kg/mi n).
196

Anest het i cs and Use i n Anest hesi a
The effect of remifentanil on the MAC of volatile anestheti cs i s characteri zed by steep dose-effect
or concentrati on-effect curves typi cal of other -opi oi d agoni sts. In ani mal s, remifentani l
decreases enfl urane and i sofl urane MAC i n a dose-dependent fashi on up to a maximum near 65%,
si mi l ar to fentanyl .
197, 198
In humans, remi fentani l reduces i sofl urane MAC l ogari thmi cal l y i n a
bl ood concentrati ondependent fashi on.
199
A whol e blood remifentanil concentrati on of 1.3 ng/mL
reduced i sofl urane MAC by 50%, wi th a maxi mum MAC reducti on (91%) at 32 ng/mL.
Remifentanil ' s effect on the MAC-BAR (requi rement for bl unti ng the sympatheti c response to ski n
inci sion) of sevofl urane i n 60% N
2
O i s simil ar.
200
A remi fentani l pl asma concentrati on of 1ng/mL
sevofl urane reduced MAC-BAR by 60%, whi l e 3 ng/mL decreased MAC-BAR another 30%.
The rapi d onset and bri ef durati on of remifentanil suggest that i t is sui tabl e for i nduction of
anesthesia. Al though a medi an ED
50
of 12 g/kg for l oss of consci ousness has been reported,
cl i ni cal i nvestigati ons have al so found that, as wi th other opi oi ds, l oss of consciousness i s not
rel iabl y achi eved with remifentanil al one, even in doses of 20 g/kg or more.
201, 202
Furthermore, a
hi gh i nci dence of muscl e rigi di ty and purposel ess movement was seen. Even at 2 g/kg
remifentanil, moderate muscle rigidity was seen i n 40% of pati ents, and at the 20 g/kg, 60% of
patients had severe muscl e ri gi di ty.
201

Drover and Lemmens
203
used computer-assi sted infusi ons to determine the bl ood concentrati ons of
remi fentani l required to supplement 66% N
2
O i n pati ents havi ng abdomi nal surgery. A range of
0.5 to 7.8 ng/mL target remi fentani l concentrati ons was used, and other than premedi cati on wi th
1 to 2 mg midazolam, no sedatives or hypnoti cs were gi ven. Duri ng surgery, the remi fentani l
bl ood concentrati on associ ated wi th a 50% probabi li ty of adequate anesthesia (EC
50
) was 4.1
ng/mL for men and 7.5 ng/mL for women. The reason for gender differences i n these resul ts was
not cl ear, but coul d have been rel ated to di fferent types of surgeri es. A pedi atri c study of
remi fentani l and N
2
O i n O
2
reported an i nfusi on rate twice that used for adults, and qual i ty of
anesthesia si mi lar to al fentani l, propofol , and isofl urane, but noted that this regimen may have
been an overestimate of remifentanil requi rement.
190

Investi gati ons of remifentanil for bal anced anesthesi a, including combi nation wi th i sofl urane,
204, 205

sevofl urane,
206
and desfl urane,
207
report si mi lar fi ndi ngs of hemodynamic stability and easy
ti tratabi li ty. A cl i ni cal tri al of remi fentani l and desfluraneN
2
O i denti fi ed blood remifentanil
concentrations that provi de an opti mal balance between hemodynamic stabi li ty and blunting
responses to noxious sti mul ati on whil e permi tti ng rapi d recovery.
207
In the presence of 2.2 to
2.7% end-ti dal desfl urane and N
2
O, optimal remi fentani l plasma concentrati ons were 5 to 7 ng/mL
for l aryngoscopy and ski n cl osure and 10 ng/mL duri ng abdomi nal surgery. It i s interesti ng to note
that adjustments i n remi fentani l blunted the sympatheti c response to noxious stimul ati on but di d
P.372
not al ter desflurane' s effect on the bi spectral index anal ysis of the EEG.
Remifentanil is frequently admini stered wi th propofol, to provi de total i ntravenous anesthesi a
(TIVA). Both can be admini stered at fi xed i nfusion rates or by computer-control led systems that
provi de target pl asma concentrations, commonl y referred to as target-control led i nfusi ons or TCI.
The combinati on of remifentanil and propofol for TIVA has been used successful l y for a vari ety of
i npati ent procedures, i ncl udi ng coronary artery bypass graft (CABG); other major thoraci c,
neurosurgi cal , abdomi nal , and orthopaedi c procedures; as wel l as ambul atory surgery and other
pai nful procedures i n adults and chi l dren. Two studi es demonstrated that a fairl y l ow pl asma
concentration of remi fentani l , TCI at 3.4 to 4 ng/mL, reduces propofol EC
50
for intubation by 66%,
from approximatel y 6 ng/mL to 2 ng/mL.
202, 208
However, further i ncreases i n remi fentani l dosage
onl y modestl y reduced propofol dose requi rements, an apparent cei l ing effect.
208
An early cl i ni cal
study
209
evaluated vari ous combinati ons of remifentanil and propofol concentrations (EC
50
) to
prevent responses to laryngoscopy and surgi cal sti mul i i n 50% of pati ents. Remi fentani l EC
50
for
laryngoscopy was 14.3 ng/mL and 1.4 ng/mL wi th propofol infusi ons of 44 and 200 g/kg/mi n,
respectively. Response to i ntubati on was prevented i n 80% of pati ents by approxi matel y doubl i ng
the remifentanil .
Barvai s and Sutcli ffe revi ewed the use of remifentanil for cardiac anesthesi a.
210
Whi le hi gh-dose
remi fentani l (1 to 2 g/kg/mi n) has been used as a si ngl e agent, i t is more commonly
administered wi th propofol or i sofl urane for fast-track cardi ac anesthesi a. Target remi fentani l
and propofol concentrati ons for cardi ac surgery
210, 211
are very si mi l ar to those for other
procedures wi th l ow-dose propofol . In a study comparing remi fentani l, sufentani l, and fentanyl for
fast-track cardi ac anesthesia, Engoren
212
found that remi fentani l pati ents were more likely to
requi re treatment for bl ood pressure fl uctuations duri ng and after surgery, but otherwi se, the
three regimens produced si mi lar outcomes wi th respect to extubati on, ICU stay, and cost.
One drawback of remi fentanil use for general anesthesi a i s that pati ents requi re anal gesics very
soon after an infusi on i s stopped. A conti nuati on of remifentanil to transiti on to postoperative
anal gesi a can avoi d early pain and accompanying detri mental sympatho-adrenal sti mul ati on and is
essential for patients undergoi ng cardi ac or other major surgery.
Remifentani l admi ni stered by i nfusi on al so appears to be useful during monitored anesthesi a care
(MAC) for consci ous sedati on i n procedures such as extracorporeal shock wave li thotri psy and
colonoscopy,
213, 214
or i n conjunction with regi onal anesthesia.
215, 216, 217
When compared to
propofol , remi fentanil provides better analgesi a, but more nausea and respi ratory depression,
whereas propofol causes more oversedati on. Times requi red for readi ness for discharge are
cl i ni cal ly simil ar. For MAC, the ideal admi ni stration regi men appears to be small bol us doses of
remi fentani l wi th a conti nuous infusi on combi ned wi th l ow-dose propofol or mi dazol am.
Remifentanil produces cl assic -opi oi d agoni st effects on the EEG, that i s, a concentration-
dependent slowi ng. The plasma concentrati on associ ated with 50% maxi mal EEG changes (EC
50
) is
15 to 20 ng/mL.
218, 219
Remi fentani l ' s rapi d onset and very short durati on resul ts in extremely
cl ose tracki ng of changes i n EEG spectral edge wi th pl asma remi fentani l concentrati on.
218, 219
Li ke
other opi oids, remi fentani l can produce muscl e rigi di ty, especi al l y with bol us doses. Thi s can be
avoi ded wi th usi ng smal l er doses and injecti ng over 60 seconds or more.
Several cl i ni cal reports have descri bed cerebral hemodynami cs in humans. When bolus doses of
remi fentani l (0.5 or 1.0 g/kg) or al fentani l (10 or 20 g/kg) were gi ven during i sofl urane/N
2
O
anesthesia with control led ventil ati on, neither opioi d affected i ntracranial pressure and both
produced modest, dose-dependent decreases i n mean arteri al pressure.
220
In another study,
patients received hi gher remi fentani l doses, fol l owed by continuous i nfusion, whi l e isocapnea and
mean arteri al pressure were mai ntained. Cerebral bl ood fl ow vel oci ty decreased signi fi cantl y i n
patients recei vi ng 5 g/kg, fol l owed by 3 g/kg/mi n, but not i n those wi th 2 g/kg, fol l owed by 1
g/kg/mi n remifentanil . A multi center cli ni cal tri al comparing remifentanil /N
2
O to fentanyl /N
2
O
anesthesia found that i ntracrani al pressure (remi fentani l 13 10; fentanyl 14
P.373
13 mm Hg) and cerebral perfusi on pressure (remi fentani l 78 14; fentanyl 76 19 mm Hg) were
si mi l ar wi th the two regi mens.
221
In a study compari ng cerebrovascular autoregulation in the
awake and anestheti zed states, remifentanil 0.5g/kg/mi n pl us propofol preserved cerebral
autoregulation, whereas i sofl urane 1.8% di d not.
222

In many crani al and spi nal neurosurgical procedures, the abil i ty to monitor motor evoked
potential s (MEPs) i s important; opioi ds, sedati ve hypnoti c drugs, and i nhal ati on agents used i n
general anesthesi a are known to suppress MEPs. A human and ani mal study compared the effects
of phenyl pi peradi ne opi oi ds and hypnoti cs i ncl udi ng thi opental , mi dazol am, and propofol on
MEPs.
223
Whi le al l opi oids and propofol suppressed MEPs i n a dose-dependent fashion, remifentanil
exerted l ess suppressi on than the other opi oids and propofol . A target pl asma concentrati on of 9
ng/mL reduced ampl i tude by 50%, but the qual i ty and reproduci bi l i ty of MEPs was preserved even
at pl asma concentrati on of 15 ng/mL, wel l wi thin the pl asma concentration range that provi des
surgi cal anesthesi a.
Although remi fentani l has not been shown to produce seizure activity, it can be used to reduce
methohexi tal requirement in pati ents havi ng electroconvul si ve therapy. Remi fentani l 1 g/kg
al lowed a 50% reducti on i n methohexi tal dose, whi ch resul ts i n sei zure prol ongation by 50%.
224

Remifentanil produces dose-dependent respi ratory depressi on as measured by i ncreases i n end-
ti dal CO
2
and decreased oxygen saturati on. In a dose-escal ati on study in normal vol unteers, the
respi ratory depressant effects of remifentanil and al fentani l were compared.
192
Peak respi ratory
depressi on occurred at 5 minutes after each dose of remi fentani l and alfentanil , and the maxi mal
respiratory depressant effect seen after 2 g/kg remi fentani l was si mil ar to that caused by 32
g/kg al fentani l . The durati on of respi ratory depression, measured as time to return of blood
gases to wi thin 10% of basel i ne val ues, was 10 minutes after 1.5 g/kg and 20 mi nutes after 2
g/kg remifentanil compared to 30 mi nutes after 32 g/kg al fentani l . Duri ng conti nuous opi oi d
infusi on, the ventil atory response to CO
2
decreased by approximatel y 30, 45, and 60% in response
to 4-hour remifentanil i nfusions of 0.025, 0.050, and 0.075 g/kg/mi n, respecti vel y.
225
Recovery
from remi fentani l -induced respi ratory depressi on was rapi d, and mi nute venti lation returned to
baseli ne by 8 (range 5 to 15) mi nutes after the infusi on was stopped for all i nfusi on rates. In
contrast, a 50% decrease i n minute venti lation produced by a 4-hour infusi on of al fentani l at 0.5
g/kg/mi n required 61 (range 5 to 90) mi nutes to return to basel ine.
225
In a vol unteer study,
Gl ass et al reported that the blood remifentanil concentrati on needed to depress venti l atory
response to i nspi red 8% CO
2
by 50% (EC
50
) was 1.17 ng/mL.
226
Boui l l on et al
227
reported a simil ar
EC
50
(0.92 ng/mL) determi ned by an i ndi rect response model and also noted that remi fentani l
concentrations wel l tol erated at steady state wi l l produce cli nicall y si gnifi cant respi ratory
depressi on when achi eved wi th bol us dosi ng. In general , cl i ni cal compari sons report that
respiratory parameters (respi ratory rate, O
2
saturati on and end-ti dal CO
2
) recover more rapi dl y
after remifentani l compared to other opi oi ds gi ven i n equi potent dosage.
An ani mal model suggested that in combinati on wi th sevofl urane, remi fentani l depressed
ventil ati on more than responses to noxious stimul ati on. Therefore, mai ntenance of spontaneous
respirati on duri ng general anesthesi a with remifentanil and vol ati l e agents or propofol may not be
feasi ble unl ess l ow doses of remifentanil are used.
228
Clinical experience in spontaneously
breathing humans recei vi ng remi fentani l combined wi th ei ther i soflurane or propofol demonstrates
respiratory depressi on i n 10 to 35% of pati ents receiving remifentanil at 0.025 g/kg/mi n. It
increases to nearly 50% i n patients recei vi ng 0.05 g/kg/mi n and to >90% i n pati ents recei vi ng
remi fentani l at 0.075 g/kg/mi n.
229
A simi lar rate of respiratory depressi on (20%) wi th need for
assi sted venti lati on i s seen i n pedi atri c patients recei vi ng remifentanil /propofol i nfusi ons for
general anesthesi a during bone marrow aspi rati on.
230
As discussed earli er, remifentanil alone or
combi ned with low-dose propofol or mi dazol am can be used for consci ous sedati on and to
suppl ement regi onal or l ocal anesthesia duri ng moni tored anesthesi a care. Cl inical reports
descri bi ng these regi mens report respi ratory depression (respi ratory rate <8 or SpO2 <90%) in 2
to 30% of pati ents; but in all cases, recovery from respi ratory depression wi th remifentanil i s
more rapi d than other agents.
213, 214, 215, 216
As wi th other opi oi ds, hi gher rates of respi ratory
depressi on are seen when propofol i s combi ned wi th remi fentanil (15 to 50% of pati ents) and
careful moni toring and ti trati on are requi red to mi ni mize thi s si de effect.
Hemodynami c Ef f ect s
In healthy vol unteers, remi fentani l i n bol us doses greater than 1.0 g/kg produces bri ef i ncreases
in systoli c bl ood pressure (5 to 20 torr) and heart rate (10 to 25 beats/min).
192
In pati ents
anesthetized wi th i sofl urane and 66% N
2
O i n oxygen, remi fentani l (up to 5 g/kg) produces dose-
dependent decreases i n systol i c bl ood pressure and heart rate. These effects are attenuated by
premedi cation wi th gl ycopyrrol ate 0.3 to 0.4 mg and are readi l y reversed wi th ephedri ne or
phenylephri ne.
231
Sebel et al
232
eval uated hemodynami c responses i n pati ents recei vi ng
remi fentani l 2 to 30 g/kg (escal ati ng doses) gi ven duri ng general anesthesia and found that
systol i c heart rate decreased more than 20% for doses greater than 2 g/kg. These hemodynami c
effects were not medi ated by hi stami ne rel ease. Cl i ni cal reports of experi ence wi th pati ents
recei vi ng opi oid-based anestheti cs have characteri zed hemodynamic changes duri ng bal anced
anesthesia with remi fentani l combined wi th i sofl urane N
2
O/O
2
or propofol. During a comparison
of remi fentani l - versus al fentani l -based TIVA, a 20% drop i n mean arteri al pressure, wi th mi ni mal
change in heart rate, was noted after i nducti on, with 35 to 50% of pati ents experi enci ng at l east
one episode of mean arteri al pressure less than 70 mmHg.
188
Decreases i n bl ood pressure were
transi ent and easil y treated wi th fl ui ds and downward ti trati on of propofol . In a compari son of
remi fentani l - and fentanyl -based general anestheti cs in more than 2,400 pati ents (80% ASA I and
II), hypotension (systol i c BP <80 or treated pharmacol ogi cal l y) occurred i n 12% of pati ents
recei vi ng remifentanil compared to 4% with fentanyl.
204
Bradycardi a was less common, 2% and
1% of pati ents i n the remi fentani l and fentanyl groups, respecti vel y.
Greater hemodynamic changes can be seen in pati ents wi th coronary disease. In a comparison of
hi gh-dose remifentanil (2g/kg/mi n) and remifentanil 0.5g/kg/mi n pl us propofol targeted to 2
g/mL plasma concentrati on, both techni ques produced si mi l ar changes: 30% drop in mean
arteri al pressure, and 25% drop in cardiac i ndex. Myocardi al bl ood fl ow and oxygen consumpti on
decreased by about 30 and 40%, respecti vel y. More moderate hemodynami c changes were
reported wi th l ower doses (remi fentani l target-control led i nfusi on [TCI] 4 to -8 ng/mL and
propofol 1.2 ng/mL).
211
Heart rate and cardi ac i ndex dropped 20 and 6%, respecti vel y, and no
hypotensi on was seen. In an earl y cl ini cal report, DeSouza reported a series of si x cases
233
of
severe bradycardi a (HR <30 beats/min) and hypotension (systol ic BP <80 mmHg) i n si x pati ents
who recei ved a rapi d injecti on of remi fentani l 1 g/kg fol l owed by a conti nuous infusi on at 0.1 to
0.2 g/kg/mi n on induction for cardi ac surgery.

Hypotensi on was effectivel y treated by ephedri ne and temporary disconti nuati on of remi fentani l .
These severe effects can often be avoi ded by sl ower admi ni stration (more than 60 seconds or
longer) of the l oadi ng dose, as smal ler bolus doses of remifentanil (0.3 to 0.5 g/kg) are
apparentl y not associated wi th severe bradycardi a and hypotensi on.
Gast r oi nt est i nal Ef f ect s
Li ke other agoni sts, remi fentani l can cause nausea and vomi ti ng, but the occurrence of these
adverse effects i s i nfl uenced to a large extent by surgery, adjuvant anesthetic agents, and
anti emetic prophyl axis. In a volunteer study, hi gh i nfusi on rates (1 to 8 g/kg/mi n) produced
nausea i n 70% of subjects.
218
However, much l ower doses are typi cal l y used for general
anesthesia. Phi li p et al
187
compared nausea and vomi ting at mul tipl e time points i n outpatient
adults for laparoscopic surgery who recei ved remi fentani l or al fentani l combi ned with N
2
O and
propofol . In thi s study remi fentani l was infused at 0.25 to 0.5 g/kg/mi n and alfentanil was
infused at 1 to 2 g/kg/mi n after i nducti on. Overal l, the incidence of nausea was 44 and 53% for
remi fentani l and al fentanil , respectively; the incidence of vomiti ng was 21 and 29% for
remi fentani l and al fentanil , respecti vel y. In outpati ents wi th si mi lar opi oid infusi ons combi ned wi th
0.8% isofl urane, nausea occurred i n 18 and 20% of pati ents wi th remi fentani l and al fentani l ,
respectively.
234
In contrast, a report summari zi ng adverse events i n over 2,400 pati ents who
recei ved remifentanil (range 0.25 to 2 g/kg/mi n) or fentanyl wi th i sofl urane or propofol for a
P.374
vari ety of surgeri es, nausea and vomi ti ng were rare.
204
Another compari son of l ow-dose
remi fentani l (0.5 g/kg and 0.1 g/kg/mi n) pl us propofol to al fentani l pl us propofol reported very
low i nci dence of nausea and vomi ting (6 to 12%, mostly at home).
235
A study i n 100
otorhi nol aryngeal surgery patients who received either remi fentani l or alfentani l and propofol
reported an i ntermediate inci dence that was equi valent for both opi oids.
42
Nausea occurred in 16
and 22% of pati ents wi th remifentanil and al fentani l, respecti vel y, and vomi ti ng in 14 and 12% of
patients recei vi ng remi fentani l and al fentani l, respecti vel y. In a pedi atri c study, the addi ti on of
remi fentani l 0.2 g/kg/mi n to desflurane anesthesia produced no increase i n the i nci dence of
postoperative nausea or vomi ting after dental surgery; nausea and vomi ting occurred in <5% of
patients who recei ved remifentanil . For strabi smus surgery in chi l dren, vomi ti ng occurred with
equal frequency (26 to 31%) wi th remi fentani l, al fentani l , i sofl urane, and propofol .
236
Thus,
remi fentani l appears to produce dose-dependent nausea and vomi ting simi lar to other short-acti ng
-agoni st opi oi ds that can be attenuated by propofol. Taken together, remi fentani l studi es confirm
the wi de vari abi l i ty in occurrence of nausea and vomi ting i n the cl i ni cal setting.
Like other opioids, remi fentani l delays gastric emptying
237
and bi l i ary drai nage.
238
As expected,
bi l i ary effects resol ve more quickl y than bi l iary drai nage delay from morphine of meperidi ne.
Other Si de Ef f ects
Postoperative shiveri ng occurred i n about 40% of pati ents undergoing otorhinol aryngeal surgery
despi te acti ve warmi ng, and i ndependent of temperature,
42
whi l e another noted shi vering i n 10%
of outpati ents.
234
In both of these studi es, shi vering was less common with al fentani l . One
pedi atric i nvesti gati on reported pruritus i n 12% of pati ents.
236

In volunteers, remi fentani l produced concentrati on-rel ated subjecti ve and psychomotor si de
effects typi cal of -opi oi ds.
193
Subjecti ve si de effects i nduced by remi fentani l included dry mouth,
itchi ng, flushi ng, sweati ng, and turning of the stomach. Remifentanil al so i mpaired performance
of psychomotor tests and caused mi osi s and respi ratory depressi on. Some of these effects l asted
an hour or more after remifentanil admi ni strati on was stopped.
The key structural feature of remi fentani l i s an ester functional group that i s susceptibl e to
hydrol ysi s by bl ood and ti ssue nonspeci fi c esterases and resul ts in very rapi d metabol i sm. Because
butyrocholi nesterase (pseudocholi nesterase) does not appear to metaboli ze remi fentani l , pl asma
chol i nesterase defi ciency and antichol inergi c admi ni strati on do not affect remifentanil
cl earance.
237
Unli ke other opi oids, remi fentani l cl earance i s mainly because of enzymati c
hydrol ysi s, wi th redi stri buti on pl ayi ng onl y a mi nor rol e. This property reduces i ts pharmacoki netic
vari abi l ity compared to other opioi ds. Remifentanil has a smal l volume of di stri bution,
approxi mately 0.3 to 0.5 L/kg,
192, 240
or about 25 li ters i n an average adult.
241
Remi fentanil' s
cl earance, 3 to 5 L/min, i s approximatel y 3 to 4 times normal hepati c bl ood fl ow.
192, 240, 241
Both
two- and three-compartment model s have been used to descri be the pl asma concentrati on decay
curve of remifentani l . A rapid di stri buti on phase of 0.9 mi nutes and a very short termi nal
el i mi nation half-li fe of 9.5 mi nutes characteri zed a two-compartment model i n adults.
192
In
pedi atrics, el imi nati on hal f-li fe i s about 3.5 to 6 minutes.
242
In the three-compartment model,
rapi d and sl ow di stri bution half-ti mes were 0.4 to 0.9 and 2 to 6 mi nutes, respectivel y, and the
el i mi nation half-ti me was about 10 to 30 mi nutes.
219, 240

As for other fentanyl congeners, gender does not affect remifentanil pharmacoki neti cs, but
advanced age i s associated wi th a decrease i n cl earance and vol ume of di stri buti on, as wel l as an
apparent i ncrease i n potency.
243
Remi fentani l pharmacokineti cs are si mil ar i n lean (withi n 20%
ideal body wei ght) and obese (at l east 80% over i deal body wei ght) pati ents, indicati ng that
remi fentani l dosi ng shoul d be based on l ean body mass.
244
Al though pharmacoki neti c parameters
of remi fentani l are unchanged i n pati ents wi th severe l i ver disease
245
or renal fai l ure,
246
pati ents
wi th hepati c di sease appear to be more sensi ti ve to remi fentani l -induced respi ratory depressi on.
Dosage and Admi ni st r at i on of Remi f ent ani l
Because of i ts extremel y short duration of action, remifentani l i s best admi ni stered as a
conti nuous i nfusi on, although admi ni strati on as repeated bol us doses has al so been reported to be
effecti ve. Outside the Uni ted States, remifentanil is often admi nistered by TCI, a pump system
desi gned to i nfuse the drug based on popul ati on kineti cs to achi eve desi red target pl asma
concentrations. Theoreti cal l y, thi s makes sense especi al l y for remifentanil , because i ts
pharmacodynami c effects track pl asma concentrations very cl osel y. However, two studi es have
found that si mpl e manual l y control l ed i nfusi on i s as effecti ve
247, 248
and i s more economi cal than
computer-control led infusi ons.
Numerous reports have described dosi ng regi mens for remi fentani l al one or in combinati on wi th
intravenous and i nhal ed agents for i nducti on and maintenance of general anesthesi a, and as a
component of sedati on and moni tored anesthesi a care.
Induction Dosage, Intubation, LMA Placement. As descri bed earl i er, remi fentani l alone has
not been found to be a satisfactory single agent for i nduction of anesthesi a because of
unreli abil i ty i n l oss of consci ousness as wel l as si gni fi cant muscl e ri gi dity.
201
However, induction
of anesthesi a wi th high-dose remifentanil 4 to 5 g/kg, or an i nfusi on of 2 g/kg/mi n has been
reported.
210
It i s i mportant to note that bol us doses of >2 g/kg can drop arteri al pressure 20 to
30%, whi l e hemodynami c changes in cardi ac pati ents recei vi ng high-dose i nfusi on are si mi l ar to
remi fentani l pl us propofol .
249
Combi ned with a potent i nhal ati on agent, a l oadi ng dose of 1 g/kg
gi ven over 60 seconds can provi de

adequate intubati ng condi tions wi th hemodynami c stabi l ity. By far the most commonl y reported
remi fentani l -based regi men for anesthetic i nducti on and l aryngoscopy consi sts of remi fentani l 0.5
to 1 g/kg given over 60 seconds pl us propofol 1 to 2 mg/kg, followed by remifentanil infusion of
0.25 to 0.5 g/kg/mi n.
204, 205, 250, 251
Thi s may be gi ven wi th or wi thout a mi dazol am 1- to 2-mg i v
premedi cation. Si mi lar regi mens are recommended for pedi atri c pati ents, wi th substi tuti on of oral
mi dazol am premedicati on 0.5 mg/kg. In the el derl y, dose reducti on i s i ndi cated, with remi fentanil
0.05 g/kg over 60 seconds pl us propofol ti trated to l oss of consci ousness i n 10-mg i ncrements,
followed by remifentanil infusion of 0.1 g/kg/mi n. If TCI i s used for induction of anesthesi a, an
initi al remifentanil target of 5 to 7 ng/mL accompani ed by 0.5 to 1 MAC i nhal ed anestheti c or
propofol TCI of 2 ng/mL i s recommended.
203, 241

Maintenance of General Anesthesia. In combination with 70% N
2
O i n O
2
, remifentanil 0.6
g/kg/mi n is generall y adequate, but at l east one study reported a wi de range of i nfusion rates
(0.025 to 2 g/kg/mi n).
252
A si mi l ar i nfusi on rate for remifentani l wi th N
2
O is recommended for
pedi atric pati ents. A l ower i nfusion rate (0.2 to 0.25 g/kg/mi n) i s needed when remifentanil i s
combi ned with sevofl urane (1 to 2%),
206
desflurane (3 to 3.6%),
207, 253
or i sofl urane (0.2 to
0.8%).
204, 205, 234
For TIVA, mai ntenance i nfusion rates for remi fentani l and propofol are 0.25 to 0.5
g/kg/mi n and 75 to 100 g/kg/mi n, respecti vel y.
188, 204, 250, 254, 255
If N
2
O i s added, remi fentani l
infusion rates as low as 0.125 g/kg/min and propofol infusi on of 50 to 75 g/kg/mi n can be
used.
254
For elderl y pati ents or those wi th cardiac disease, a reduction i n propofol by about 25% i s
recommended. For pedi atri c patients, reported i nfusi on rates are si mi lar to adul ts, wi th
remi fentani l at 0.25 g/kg/mi n and propofol about 100 g/kg/mi n. For hi gh-dose opi oid anesthesi a
for cardi ac surgery, the remi fentani l infusi on i s maintai ned at 1 to 3 g/kg/mi n and shoul d be
adjusted downward for hypothermi a as di scussed earl i er.
210
Adding a l ow-dose propofol i nfusion of
50 g/kg/mi n to thi s hi gh-infusi on rate effecti vel y suppressed responses to skin i nci si on,
sternotomy, and aorti c cannul ati on.
256

If TCI is used, a target range for remi fentani l i s 4 to 10 ng/mL for bal anced anesthesia and TIVA,
and a starting rate of 25 to 30 ng/mL i s recommended for high-dose opi oid anesthesi a.
210, 241

A di sadvantage of remi fentani l , rel ated to i ts short duration of action, is that pati ents may
experi ence substanti al pai n on emergence from anesthesi a. Thus, if moderate to severe
postoperative pai n is anti ci pated, conti nuing the remi fentani l infusi on between 0.05 and 0.15
g/kg/mi n ensures adequate analgesi a i n most patients.
194
The use of local and regi onal
anesthetic techni ques are also effecti ve. When only mi l d postoperati ve pai n i s anti ci pated,
intraoperative admini stration of a nonsteroi dal anti -infl ammatory drug 30 to 60 mi nutes before the
P.375
end of surgery may provide effecti ve anal gesi a wi thout addi ti onal opi oi ds.
Monitored Anesthesia Care (MAC). Remi fentani l can al so be used for consci ous
sedati on/anal gesia and as an adjunct for sedati on or anal gesi a duri ng regional anesthesi a, or for
block placement, as part of MAC. When l ocal or regional anesthesi a is not used, and the procedure
i s expected to be pai nful , remi fentani l and propofol can be benefi ci al. During col onoscopy, a
conti nuous remi fentani l infusi on of 0.2 to 0.25 g/kg/mi n, suppl emented wi th smal l (10-mg) doses
of propofol , provided good anal gesia but mi ld respiratory depressi on was common.
214
In another
cl i ni cal evaluati on, pati ents havi ng extracorporeal shock wave li thotri psy recei ved l ow-dose
propofol (50 g/kg/mi n) as wel l as remi fentani l . Pati ents who received l ow-dose (12.5 to 25 g)
intermi ttent bol us i njecti on of remi fentani l wi th or without i nfusi on at 0.05 g/kg/mi n reported
better anal gesi a than conti nuous i nfusi on of 0.1 g/kg/mi n al one.
213
Remi fentanil 1 g/kg wi th or
without a subsequent infusi on of 0.2 g/kg/mi n admi ni stered 90 seconds pri or to placement of
ophthal mol ogi c block resulted i n excel l ent analgesia,
257
but 14% of pati ents who recei ved an
infusi on experi enced respi ratory depressi on.
When used as an adjunct to l ocal or regi onal anesthesi a, a much lower mai ntenance i nfusi on rate,
0.05 to 0.1 g/kg/mi n, provi des adequate sedati on and anal gesi a.
216, 217
Fi nal l y, the dose
requi rement of remi fentani l for sedati on/anal gesi a i s reduced approxi matel y 50% when combi ned
with midazolam or propofol. When 1 to 2 mg of mi dazol am premedi cation is gi ven, 0.01 to 0.07
g/kg/mi n remifentanil provides good sedati on/anal gesi a for procedures performed under l ocal or
regi onal anesthesi a.
215, 216

Dosage recommendations are summarized in Tabl e 14-5.
PARTIAL AGONISTS AND MIXED AGONISTANTAGONISTS
The parti al agoni st and mi xed agoni stantagonist opioi ds are synthetic or semisyntheti c
compounds that are structurall y rel ated to morphi ne. They are characteri zed by bi ndi ng acti vi ty at
mul tipl e opioi d receptors and their di fferential effects (agonist, parti al agonist, or antagonist) at
each receptor type. The cl ini cal effect of a parti al agoni st at the -opi oi d receptor i s compl ex (Fi g.
14-11). Admi ni stered al one, a partial agonist has a fl atter dose-response curve and a l ower
maximal effect than a full agonist (see Fi g. 14-1 and the l owermost curve i n Fi g. 14-11).
Combi ned wi th a l ow concentrati on (compare the curve i ndi cated by [Ag] = 0.25 i n Fi g. 14-11) of
a ful l agoni st, the effects of the parti al agoni st are addi tive up to the maximum effect of the
parti al agoni st. Combined wi th i ncreasing concentrati ons ([Ag] = 0.67 to 256) of ful l agoni st, the
parti al

agoni st wil l act as an antagoni st. These drugs medi ate thei r cl ini cal effects via - and -opi oi d
receptors, as summari zed i n Tabl e 14-4. The classificati on scheme presented may change as our
understandi ng of these drugs and of opi oid receptors continues to grow. Bowdl e extensi vely
revi ewed the pharmacol ogy and cl ini cal uses of these and other drugs i n thi s cl ass.
258
Only
nalbuphi ne, butorphanol, and buprenorphine are consi dered in thi s chapter.
P.376
TABLE 14-4 Actions of the Nalbuphine, Butorphanol, and Buprenorphine at Opioid
Receptors
DRUG RECEPTOR RECEPTOR
Nal buphi ne Parti al agoni st Parti al agoni st
Butorphanol Parti al agoni st Parti al agoni st
Buprenorphi ne Parti al agoni st ?Antagonist
Although nal buphine and butorphanol have been reported to be antagoni sts at the -
opi oi d receptor, they do cause respi ratory depressi on, whi ch i s not a function of
agoni sts. Thus, they appear to have at l east parti al agonist acti vi ty at the -opi oi d
receptor.
Adapted from Bowdl e TA: Partial agoni st and agoni stantagonist opioi ds: Basic
pharmacol ogy and cl ini cal appl i cations. Anesth Pharmacol Rev 1:135, 1993.
TABLE 14-5 Dosage for Fentanyl, Sufentanil, Alfentanil, and Remifentanil during
Elective Surgery in Adults Doses are guidelines for hemodynamically stable adults.
They should be adjusted downward for elderly patients and those with cardiac
dysfunction and hemodynamic instability
ANESTHETIC
PHASE
FENTANYL SUFENTANIL ALFENTANIL REMIFENTANIL
Premedication
(g)
2550 25 250500
Induction
Wi th hypnotic
(g/kg)
1.55 0.11 1050 0.51.0
+/or 0.250.5
g/kg/mi n
Wi th 6070% N
2
O
(g/kg)
823 1.32.8
Hi gh dose opi oi d
(g/kg)
50 1030 120 25
+/or 2
g/kg/mi n
Maintenance
Bal anced anesthesi a
Intermi ttent bolus
(g)
25100 520 250500 2550
Infusi on
(g/kg/mi n)
0.033 0.0050.015 0.51.5 0.250.05
Hi gh dose opi oi d
(g/kg/mi n)
0.5 2.510 1.03.0
Transiotion to
PACU (g/kg/mi n)
0.050.15
Monitored Anesthesia Care
Intermi ttent bolus
(g)
12.550 2.510 125250 12.525
Infusi on
(g/kg/mi n)
0.010.2
The major role of the opi oid agoni stantagonist and parti al agoni st drugs conti nues to be i n the
provi si on of postoperati ve anal gesi a, but they have al so been used for i ntraoperati ve sedati on, as
adjuncts duri ng general anesthesi a, and to antagonize some effects of ful l -opi oi d agoni sts.
Nal buphi ne
Nal buphi ne is a phenanthrene opioi d deri vati ve. Although it is often classified as a agoni st and
antagonist, i t is more accuratel y descri bed as a parti al agoni st at both and receptors.
258
Whi le
MAC reducti on studi es have not been done i n humans, Murphy and Hug
20
reported that a 0.5
mg/kg dose reduced enfl urane MAC by 8% in dogs. However, increasi ng the dose ei ghtfold
produced no further reducti on i n enflurane MAC. This modest MAC reduction, compared to 65% for
morphi ne, suggests that nal buphi ne may not be a useful adjunct for general anesthesi a. However,
several investi gators have exami ned i ts effecti veness as a component of bal anced anesthesi a for
cardi ac
259
and l ower abdomi nal surgery.
20, 260
Combi ned with diazepam 0.4 mg/kg and 50% N
2
O i n
oxygen, a l oadi ng dose of 3 mg/kg was fol l owed by addi ti onal doses of 0.25 mg/kg as needed
throughout surgery. No si gni fi cant increases i n blood pressure, stress hormones, or histamine
were seen, and emergence from anesthesi a was uncompl icated.
259
Nal buphine 0.2 mg/kg was
compared to meperidine 0.5 mg/kg as an adjuvant to general anesthesi a wi th 1% hal othane and
70% N
2
O i n oxygen i n spontaneously breathi ng pati ents undergoi ng ingui nal herni a repai r.
261
Both
drugs produced a si mi l ar degree of respi ratory depressi on, postoperati ve anal gesi a, and si de
effects. The most common si de effect was drowsiness. In a double-bl i nd compari son wi th fentanyl
for gynecol ogi c surgery, fentanyl was found to better attenuate hypertensive responses to
intubati on and surgi cal sti mulation.
260
However, si gnificant respi ratory depression was seen i n 8 of
30 patients who recei ved fentanyl, and 4 required nal oxone, compared to no respiratory
FIGURE 14-11. Hypotheti cal l og dose-effect curves for the combinati on of a partial agoni st,
B (intri nsi c effi cacy of 0.4), with a range of concentrati ons of a full agoni st, A. The observed
effect of the combi nation of A and B i s expressed as a fracti on of the maxi mal effect of the
ful l agoni st. As the concentrati on of the partial agoni st increases, the effect of the
combination converges on the maximum effect of the parti al agoni st. When added to a l ow
concentration (e.g., [A] = 0.25) of agoni st, the partial agoni st increases the response; but
when added to a l arge concentrati on of the agonist, the response decreasesthat i s, B acts
li ke an antagoni st. (Modi fi ed wi th permi ssi on from Bowdl e TA: Parti al agoni st and agoni st
antagonist opioi ds: Basic pharmacology and cl i ni cal appli cati ons. Anaesth Pharmacol Rev
1:135, 1993.)
depressi on i n the nalbuphi ne group. Analgesi a was si mi l ar, and as i n other studi es, postoperati ve
sedati on was common i n the nalbuphi ne group.
The respi ratory depressi on produced by nalbuphi ne, most l i kely medi ated by -opi oi d receptors,
has a cei li ng effect equi valent to that produced by ~0.4 mg/kg morphi ne.
258
Anal gesi a i s medi ated
by both and receptors. Because of these effects, nal buphine has been used to antagoni ze the
respiratory depressant effects of ful l agoni sts whi le stil l provi di ng anal gesi c effects. In a double-
bl i nd compari son, nal buphine and nal oxone both effecti vel y antagoni zed fentanyl -induced
postoperative respiratory depression, but pati ents who recei ved nal buphi ne had l ess reversal of
anal gesi a.
262
Nal buphine has also been effective i n antagonizing fentanyl -induced respi ratory
depressi on fol lowi ng hi gh-dose (100 to 120 g/kg) fentanyl anesthesia for cardi ac surgery.
263
Only
3 of 21 pati ents experi enced pai n after nal buphine admi ni strati on, and thi s was adequately treated
with addi tional nal buphine. However, i n a vol unteer study, nal buphine 0.21 mg/kg did not
antagoni ze the respi ratory depressant effects of 0.21 mg/kg morphi ne.
264
Whi le nal buphi ne and
other agoni stantagonists have ceil i ng

anal gesi c and respi ratory depressant effects, they can be as effecti ve as ful l agoni sts in
provi di ng postoperati ve anal gesi a. Nal buphine 5 to 10 mg has also been used to antagonize
pruri tus induced by epi dural and i ntrathecal morphi ne. The usual adult dose of nal buphi ne is 10
mg as often as every 3 hours. It i s important to be aware that nalbuphi ne can precipi tate
withdrawal symptoms i n pati ents who are physi cal l y dependent on opi oi ds.
But or phanol
Butorphanol , a morphi nan congener, has parti al agonist acti vi ty at and opi oi d receptors,
si mi l ar to those of nal buphine. Compared to nal buphine and si mi lar drugs, however, butorphanol
has a pronounced sedati ve effect, whi ch i s probabl y medi ated by receptors. In a l aboratory
study as wel l as i n cl i ni cal use as a premedi cant, butorphanol produced dose-dependent sedation
comparabl e to that of mi dazol am.
265
Like nal buphi ne, butorphanol decreases enflurane MAC, i n
dogs, by a modest amount, 11%, at 0.1 mg/kg.
25
Increasi ng the butorphanol dose 40-fol d does
not produce a further reduction. However, l ike nal buphi ne, butorphanol has al so been reported to
be an effective component of bal anced general anesthesi a. Combi ned wi th di azepam and ni trous
oxi de, butorphanol and morphi ne provi ded equall y sati sfactory anesthesia.
258

Gi ven alone, butorphanol produces respi ratory depressi on with a cei l i ng effect bel ow that of ful l
agoni sts. In postoperati ve pati ents a parenteral dose of 3 mg produces respi ratory depression
approxi mately equal to that of 10 mg morphine. In a cl inical study exami ni ng its effecti veness i n
reversi ng fentanyl -i nduced respi ratory depression,
266
pati ents anesthetized wi th i sofl urane, nitrous
oxi de, and fentanyl 5 g/kg followed by an infusion of 3 g/kg/h received three sequenti al doses
of butorphanol 1 mg at 10- to 15-mi nute i nterval s. After the fi rst 1-mg dose, respi ratory rate and
ventil atory response to CO
2
i ncreased, whi l e end-ti dal CO
2
decreased si gni fi cantl y. Further
progressi ve changes were not si gni fi cantl y di fferent from the initi al response to butorphanol , and
anal gesi a was not si gni fi cantl y affected i n 21 of 22 pati ents.
In contrast to morphi ne, fentanyl , and even meperi dine, butorphanol does not produce si gni fi cant
el evati on i n i ntrabil i ary pressure
72
(see Fi g. 14-6). Butorphanol has al so been effective in the
treatment of postoperative shiveri ng,
77
but the mechanism for this effect i s unknown.

Butorphanol i s indicated for use as a sedative and i n treatment of moderate postoperati ve pai n.
Prel iminary cl i ni cal experience suggests that butorphanol admi ni stered as pati ent-control led
anal gesi a i s associated wi th a lower i ncidence of opi oi d-induced i leus compared to -sel ecti ve
opi oi ds (Dunbar PJ, personal communicati on). A dose as low as 0.5 mg can provi de cli ni cal l y
useful sedati on, whil e si ngl e anal gesic doses range from 0.5 to 2 mg. Butorphanol has also been
administered epidurally and transnasal l y.
Bupr enor phi ne
Buprenorphine i s a hi ghl y l i pophil i c thebai ne derivati ve, whi ch at smal l to moderate doses i s 25 to
50 ti mes more potent than morphi ne.
1
Unli ke nal buphi ne and butorphanol , buprenorphi ne does not
P.377
appear to have agoni st, and may have antagoni st, acti vi ty at the -opi oi d receptor (see Tabl e 14-
4).
258
Another uni que characteri sti c of buprenorphine i s its sl ow di ssociati on from receptors,
whi ch can l ead to prol onged effects not easil y antagoni zed by nal oxone. Buprenorphi ne al so
appears to have an unusual bel l -shaped dose-response curve such that, at very hi gh doses, i t
produces progressi vel y less analgesi a.
258
In a cli ni cal study, pati ents who recei ved 10 or 20 g/kg
buprenorphi ne duri ng surgery were pai n-free postoperati vel y, but hal f of the patients who
recei ved 30 or 40 g/kg had si gni fi cant postoperati ve pai n.
267
Thi s observati on i s consi stent wi th
buprenorphi ne' s bel l -shaped dose-effect curve, and pati ents who recei ved very hi gh buprenorphi ne
doses probabl y had pl asma drug concentrati ons i n the range at whi ch decl ini ng anal gesi a is seen.
Buprenorphine also appears to have a ceil i ng effect to its respi ratory depressant dose-response
curve. However, al though buprenorphi ne-i nduced respi ratory depressi on can be prevented by pri or
naloxone admini stration, it i s not easi ly reversed by nal oxone once the effects have been
produced.
1
A dose of 0.3 mg buprenorphi ne reduces CO
2
responsiveness to about 50% of control
values.
268
Large doses of nal oxone (5 to 10 mg) were required to antagonize buprenorphi ne
respiratory depressi on i n volunteers, whil e 1-mg doses were not effecti ve. In addi ti on, the
maxi mum antagoni st effect di d not occur unti l 3 hours after nal oxone admi ni strati on, an
observation consi stent wi th buprenorphi ne' s sl ow di ssoci ati on from receptors. Buprenorphi ne has
been compared to nal oxone i n i ts abi l ity to antagoni ze fentanyl -induced respi ratory depression,
and appears to increase respi ratory rate wi thout antagoni zi ng anal gesi c effects in slowl y
administered doses up to 0.5 mg.
269

Buprenorphine can be effective in treatment of moderate to severe pai n. Its onset can be sl ow,
but anal gesic duration can be more than 6 hours. A si ngle dose of 0.3 to 0.4 mg appears to
produce anal gesia equival ent to 10 mg morphine.
1

Opi oi d Ant agoni st s ( Nal oxone and Nal t r exone)
Under normal condi ti ons, opioi d antagoni sts produce few effects. They are competi ti ve i nhi bitors
of the opi oid agoni sts, so the effect profi le depends on the type and dose of agoni st admi ni stered
as wel l as the degree to whi ch physi cal dependence on the opi oi d agoni st has devel oped. The most
widel y used opioid antagoni st i s nal oxone, whi ch is structural l y related to morphi ne and
oxymorphone, and i s a pure antagoni st at -, -, and -opi oi d receptors.
1
Nal trexone i s a long-
acti ng oral agent, whi ch also has rel ati vel y pure antagonist activity. In some circumstances,
naloxone can antagoni ze effects that appear to be medi ated by endogenous opi oi ds. For exampl e,
naloxone can reverse stress analgesia in ani mals and man, i t can antagoni ze anal gesi a produced
by l ow-frequency sti mul ati on wi th acupuncture needl es, and i t can al so reverse analgesi a
produced by pl acebo medi cati ons.
1

In cli ni cal anesthesia practice, nal oxone i s admi nistered to antagoni ze opioi d-induced respi ratory
depressi on and sedati on. Because opioid antagoni sts wi l l reverse al l opi oid effects, i ncl udi ng
anal gesi a, nal oxone shoul d be careful l y ti trated to avoi d produci ng sudden, severe pai n i n
postoperative pati ents. Sudden, compl ete antagoni sm of opioi d effects with nal oxone has been
reported to cause severe hypertensi on, tachycardi a, ventricul ar dysrhythmi as, and acute,
sometimes fatal, pul monary edema.
270
Nal oxone-induced pul monary edema can occur even in
heal thy young pati ents who have received rel ati vel y smal l doses (80 to 500 g) of naloxone.
271, 272

The mechanism for thi s phenomenon i s thought to be centrall y mediated catechol ami ne release,
whi ch causes acute pul monary hypertensi on. Because most pati ents wi th opi oid-induced
respiratory depressi on wil l often breathe on command, i t is i mportant to sti mulate them i n
addi ti on to admi ni steri ng careful l y titrated nal oxone doses i n the i mmediate postoperati ve peri od.
It i s al so essential to moni tor vi tal si gns and oxygenati on cl osel y after nal oxone i s admini stered to
detect occurrence of any of these potential ly seri ous compl i cations.
Nal oxone wi ll preci pi tate opi oi d withdrawal symptoms i n opi oid-dependent i ndi vi duals. Cli ni ci ans
tend to be aware of

this risk when treati ng pati ents with known opi oid addi cti on, but i t i s important to consi der the
potential for opi oi d wi thdrawal syndrome when treati ng nonaddi cts who use opi oi ds chronicall y,
P.378
such as cancer patients and severe burn and trauma pati ents wi th protracted recovery courses.
Nal oxone has a very fast onset of action, and thus i s easi l y ti trated. Peak effects occur withi n 1 to
2 mi nutes, and durati on i s dose dependent, but total doses of 0.4 to 0.8 mg generall y last 1 to 4
hours.
1
Suggested incremental doses for i ntravenous ti trati on are 20 to 40 g given every few
mi nutes unti l the pati ent' s venti lation improves, but anal gesi a is not compl etel y reversed. Because
naloxone has a short durati on of acti on, respiratory depressi on may recur i f l arge doses and/or
long-acti ng opi oid agoni sts have been admini stered. When prol onged venti l atory depressi on i s
anti cipated, an i ni ti al loading dose followed by a naloxone infusion can be used. Infusion rates
between 3 and 10 g/h have been effecti ve i n antagoni zi ng respi ratory depressi on from systemi c
as wel l as epi dural opi oi ds.
273

USE OF OPIOIDS IN CLINICAL ANESTHESIA
Opi oi ds are used al one or i n combi nation wi th other agents, such as sedatives or anti choli nergi c
agents, as premedi cations. For this purpose, longer acti ng opi oi ds such as morphine are
administered as si ngle doses that are general ly withi n the anal gesi c range. The goal of opioi d
premedi cation is to provi de moderate sedati on, anxi ol ysis, and anal gesia whi le maintai ni ng
hemodynamic stabi li ty. Potential ri sks of opioid premedi cati on i nclude oversedati on, respi ratory
depressi on, and nausea and vomi ti ng. For i nduction of anesthesi a, opi oi ds are often used to bl unt
or prevent the hemodynami c responses to tracheal intubati on. Opioi ds with rapi d onset of acti on,
such as fentanyl and its deri vatives, are appropri ate for this use.
Intraoperativel y, opi oids are admi nistered as components of bal anced anesthesi a, or alone in hi gh-
dose opi oid anesthesi a. During mai ntenance of general anesthesi a, opioid dosage is ti trated to the
desi red effect based on the surgical sti mul us as wel l as i ndi vi dual pati ent characteri sti cs, such as
age, vol ume status, neurologi c status, li ver dysfuncti on, or other systemic disease states. Pl asma
opi oi d concentrati ons required to blunt hemodynami c responses to laryngoscopy, tracheal
intubati on, and various surgi cal sti muli , as wel l as pl asma opi oi d concentrati on associ ated with
awakening from anesthesi a, have been determi ned for several opi oids. Ti trati on to achi eve these
pl asma concentrati ons (see Tabl e 14-3), whi ch refl ect brai n (effect si te) concentrati ons, can be
accompl i shed by admi ni steri ng repeated smal l bolus doses or by manual - or target-control led
infusi on. Fentanyl and i ts deri vati ves sufentanil and al fentani l are the opioi ds most wi del y used as
supplements to general anesthesi a; remi fentani l i s a useful al ternati ve when ul trashort durati on i s
desi rabl e. Al l of these opi oi ds are more easi ly titrated than morphi ne because of thei r rapi d onset
of acti on. However, Shafer and Varvel
10
have emphasi zed that maki ng a rati onal choi ce among
these opi oi ds requires an understanding of the relationshi ps between thei r pharmacokineti cs and
pharmacodynami cs. They have used el egant computer model s to simul ate the rate of decrease i n
pl asma and effect site (brain) concentrations after vari ous administrati on methods, i ncl udi ng bol us
doses, bri ef i nfusi on, and prol onged i nfusi on. Decreases i n effect site concentrati on wi ll determine
ti me to recovery from vari ous opi oid effects. Comparable si mulations have al so been done for the
newer opi oid remifentanil .
218
Important pharmacokineti c differences among these opioi ds incl ude
vol umes of distri buti on and intercompartmental (di stri buti onal) and central (eli mi nation)
cl earances. A smal l er di stri bution volume tends to shorten recovery time, and a reducti on i n
cl earance tends to i ncrease recovery ti me.
10
The major pharmacodynamic di fferences among these
opi oi ds are potency and the equi librati on ti mes between the pl asma and the si te of drug effect.
Equi l ibrati on hal f-ti mes between pl asma and effect si te are 5 to 6 mi nutes for fentanyl and
sufentani l and 1.3 to 1.5 mi nutes for al fentani l and remifentanil .
10, 192
Computer si mul ati ons
demonstrate that si mpl y comparing eli minati on hal f-li ves wi l l not predi ct the relative rate of
decl ine in drug concentrati on at the effect site after ei ther bol us doses or conti nuous infusi on of
fentanyl , sufentani l , and al fentani l . The rate of recovery after a conti nuous infusi on wi l l depend on
the durati on of the i nfusion as wel l as the magni tude of decli ne that i s required. Fi gure 14-12
demonstrates how the ti mes requi red for 20, 50, and 80% decrements in effect si te (i.e., brain)

concentrations vary with each opi oi d dependi ng on infusion duration. If only a 20% drop in effect
si te concentrati on i s requi red (upper panel ), recovery from al l three opi oids wi l l be rapi d, al though
recovery ti me i ncreases for fentanyl after 3 hours of drug i nfusion. However, if a 50% decrease i s
P.379
requi red, recovery from sufentani l wi ll be fastest for i nfusi ons less than 6 to 8 hours in durati on,
but more rapid for alfentanil if i nfusi ons are continued for more than 8 hours.
Cont ext - Sensi t i ve Hal f - Ti me
Hughes et al
11
expanded the concepts of Shafer and Varvel to defi ne the relative contributi ons of
di stri bution compartments to central compartment (pl asma) drug di stri bution. These rel ati ve
FIGURE 14-12. Recovery curves for fentanyl, sufentanil , and al fentani l showi ng the ti me
requi red for decreases of 20% (A), 50% (B), and 80% (C) from maintained i ntraoperative
effect si te (brai n) concentrati ons after termi nation of the i nfusi on. (Repri nted wi th
permi ssi on from Shafer SL, Varvel JR: Pharmacokineti cs, pharmacodynami cs, and rational
opi oi d sel ecti on. Anesthesi ol ogy 74:53, 1991.)
contri buti ons vary according to i nfusi on durati on. Hughes devi sed the concept of context-
sensi ti ve half-ti me, whi ch i s defi ned as the time required for the drug concentrati on i n the central
compartment to decrease by 50%, and demonstrated how thi s hal f-ti me changes as drug i nfusion
duration increases. Duri ng an i nfusi on, the peri pheral (fast and sl ow) compartments begi n to fil l
up. After the i nfusi on i s stopped, drug wi ll be el i mi nated, but wi l l al so conti nue to be
redi stri buted as l ong as the concentration in a peri pheral compartment i s l ower than that in the
central compartment. This l eads to a rapi d drop i n central compartment drug concentration. When
central compartment (pl asma) concentrati on drops bel ow that of the peripheral compartment(s),
the di recti on of drug redistri buti on wi l l reverse and wi l l sl ow the decli ne in plasma concentrati on.
The degree to whi ch redi stribution will affect the rate of drug el iminati on depends on the rati o of
the distri buti onal to eli mi nation ti me constants. Thus, a drug that can rapi dl y redi stri bute wi l l
have a correspondi ngl y l arger contri buti on from the peripheral compartment(s), and plasma
concentration wi ll drop progressi vel y more slowl y as i nfusion duration conti nues. Fi gure 14-13
il l ustrates the context-sensi ti ve hal f-ti mes for fentanyl , al fentani l, sufentani l, and remi fentanil .
Thi s model predi cts the ti me to a 50% concentration decrease i n the pl asma, which wi ll refl ect,
but not be equal to, effect site concentrati ons depi cted i n Fi gure 14-12.
Some testing of these computer model s in humans has been done. Kapil a et al
274
compared
model ed context-sensi ti ve half-ti mes wi th measured decreases i n drug concentration and drug
effect (respi ratory depression) i n volunteers recei vi ng remi fentani l and al fentani l . After 3-hour
opi oi d i nfusions, measured whol e bl ood opi oi d concentrati ons and recovery of venti latory dri ve
corresponded cl osel y to model ed values for both drugs. Al though the concept of a context-
sensi ti ve half-ti me appears to be useful , Hughes et al
11
noted that it i s unknown whether a
decrement of 50% provides the most cl i ni cal l y useful description of the rate of offset of opi oi d
effects. If one cl osel y titrates infusi ons so that mi nimum effecti ve concentrations are achi eved,
perhaps much smal l er decrements wi ll be necessary. For example, it can be seen in the upper
panel of Fi gure 14-12 that i f only a 20% decl i ne i n effect si te concentrati on i s needed, fentanyl,
sufentani l, and alfentani l concentrati ons al l drop rapidly if the infusion durati on i s 2 hours or l ess.
Thi s rapid resol uti on i s seen for sufentanil and al fentani l even wi th prol onged (5- to 10-hour)
administrati on i f only a 20% decrement i s required. In practi ce, it i s rel ati vel y easy to administer
hi gher than necessary doses of opioi ds, particul arl y to mechani cal l y venti l ated pati ents, because
FIGURE 14-13. Context-sensi ti ve hal f-ti mes for fentanyl , sufentanil , al fentani l, and
remi fentani l . Thi s computer si mul ati on depi cts the ti me necessary to achi eve a 50%
reduction in pl asma opi oi d concentrati on as a functi on of i nfusion duration. (Reprinted with
permi ssi on from Egan TD, Lemmens HJM, Fi set P et al : The pharmacoki neti cs of the new
short-acti ng opi oid remi fentani l (GI87084B) in heal thy adul t mal e volunteers. Anesthesi ology
79:881, 1993.)
hemodynamic consequences are mi ni mal. Titrati ng agai nst a quanti fi abl e parameter, such as
mi nute ventil ati on i n a spontaneousl y breathing pati ent, may al l ow a ti ghter dose titrati on, but
this may not be practi cal for many surgeri es, for exampl e, those requi ri ng the use of muscl e
rel axants. It does seem cl ear, however, that some context-sensi ti ve index i s more useful than the
el i mi nation half-li fe. Understandi ng these concepts can be useful when decidi ng which opi oi d to
use, as wel l as i n adapti ng gui deli nes for opi oid dosage and i nfusi on rates dependi ng on the
duration of anesthesi a.
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237. Wal ldn J, Thrn SE, Wattwil M: The del ay of gastri c emptyi ng i nduced by remi fentani l i s
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238. Fragen RJ, Vi li ch F, Spi es SM, Erwi n WD: The effect of remifentanil on bi l i ary tract
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239. Manul lang J, Egan TD: Remi fentani l ' s effect i s not prol onged i n a pati ent wi th
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255. Phi ll i p BK, Scuderi PE, Chung F et al : Remifentani l compared to al fentani l for ambulatory
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257. Ahmad S, Leavel l ME, Fragen RJ et al : Remi fentanil versus al fentani l as anal gesi c
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1999
258. Bowdle TA: Parti al agoni st and agoni stantagonist opi oids: Basi c pharmacol ogy and
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260. Rawal N, Wennhager M: Infl uence of peri operati ve nal buphi ne and fentanyl on
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261. O' Connor SA, Wi l ki nson DJ: A doubl e-bl i nd study of the respi ratory effects of nalbuphi ne
hydrochl ori de i n spontaneousl y breathing anestheti zed pati ents. Anesth Analg 67:324, 1988
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263. Mol denhauer CC, Roach GW, Fi nl ayson DC et al : Nal buphine antagoni sm of ventil atory
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265. Dershwi tz M, Rosow CE, Di Bi ase PM et al : Compari son of the sedati ve effects of
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266. Bowdle TA, Grei chen SL, Bjurstrom RI et al : Butorphanol i mproves CO
2
response and
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267. Pedersen JE: Peri operati ve buprenorphi ne: Do hi gh doses shorten anal gesi a
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269. Boysen K, Hertel S, Chraemmer-Jorgansen B et al : Buprenorphi ne antagonism of
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270. Pal lasch TJ, Gi ll CJ: Naloxone-associated morbi di ty and mortal ity. Oral Surg Oral Med
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271. Partri dge BL, Ward CF: Pul monary edema foll owing low-dose nal oxone administration.
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fol l owing conservati ve doses of i ntravenous nal oxone. Anesthesi ol ogy 60:485, 1984
273. Rawal N, Schtt U, Dahl strm B et al : Influence of naloxone infusion on analgesia and
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274. Kapila A, Glass PSA, Jacobs JR et al : Measured context-sensitive half-times of
remifentanil and alfentanil. Anesthesiology 83:968, 1995
Inhal ati on Anesthesi a
Chapter 15
Inhalation Anesthesia
Thomas J. Ebert
KEY POINTS
Vol ati le anesthetics are relatively inexpensi ve, easi ly admi ni stered vi a
inhalation, readil y ti trated, and have a hi gh safety rati o i n terms of preventi ng
recal l . Depth of anesthesia can be qui ckl y adjusted i n a predi ctabl e way whi le
moni tori ng ti ssue level s vi a end-ti dal concentrati ons. In addi ti on they cause
rel axation of skeletal muscle.
The i nhal ed anestheti cs are among the most rapi dl y acting drugs i n exi stence,
and thei r pharmacoki neti cs are descri bed i n four phases: absorpti on,
di stri bution, metabol ism, and excreti on. Anestheti c uptake i s assessed wi th the
rati o of the fractional concentrati on of alveol ar anestheti c to i nspi red anesthetic
(F
A
/F
I
), fol l owed over ti me. The most important factor i n the rate of ri se of F
A
/F
I

is F
A
because of the avi d uptake of anestheti c from the alveol i i nto the
bl oodstream. The i nhal ed anestheti cs with the l owest sol ubi l iti es i n blood show
the fastest ri se i n F
A
/F
I
, and are el i mi nated most rapi dl y.
The pharmacodynami c effects of i nhal ed anestheti cs i s rel ated to dose,
descri bed as the mi ni mum al veol ar concentrati on or MAC. MAC i s the al veol ar
concentration of an anestheti c at one atmosphere that prevents movement in
response to a surgi cal stimul us i n 50% of pati ents.
All of the potent, vol atil e anestheti cs depress cerebral metabol ic rate and
increase cerebral bl ood fl ow, varyi ng as a functi on of dose. Increases i n
intracerebral pressure with sevofl urane, i sofl urane, and possibl y desfl urane are
mi ni mal and far less than with halothane.
Sevoflurane has been associ ated wi th a l ower heart rate compared to desfl urane
and does not i ncrease sympatheti c nervous system activity as does desfl urane.
Cardi ac output i s wel l preserved wi th sevoflurane, desfl urane, and isofl urane,
and al l three have been associated wi th cel l ul ar protecti on from ischemia-
i nduced myocardi al i njury.
In dehydrated carbon di oxi de absorbents, degradati on of desflurane, enfl urane,
isoflurane, and sevoflurane resul ts i n carbon monoxi de formati on. In rare
instances, sevofl urane destructi on has l ed to hi gh heat and fires.
INTRODUCTION
Inhalation anesthetics are the most common drugs used for the provi sion of general
anesthesia. Addi ng as l i ttl e as 1% of a volatil e anestheti c to the inspi red oxygen resul ts i n a
state of unconsci ousness and amnesi a, whi ch are essenti al components of general anesthesi a.
When combi ned wi th i ntravenous adjuvants, such as opi oids or benzodiazepi nes, a balanced
technique i s achi eved that resul ts in further sedation/hypnosi s and anal gesi a. The popul ari ty of the
inhaled anesthetics for establ i shi ng general anesthesia i s based on thei r ease of admi ni strati on
(i .e., via i nhal ati on) and the abi li ty to rel i abl y moni tor thei r effects with both cl i ni cal signs and
end-ti dal concentrati ons. In additi on, the vol ati le anesthetic gases are rel ati vely inexpensi ve i n
terms of the overal l cost of the anesthesi a care of the pati ent.
The most popul ar potent i nhal ed anestheti cs used in adul t surgi cal procedures are sevofl urane,
desfl urane, and isoflurane (Fi g. 15-1). In pediatri c cases, halothane and sevofl urane are most
commonly empl oyed. Al though there are many si mi lariti es i n terms of the overal l effects of the
vol ati l e anestheti cs (e.g., they al l have a dose-dependent effect to decrease bl ood pressure), there
are some uni que differences that affect the cl i ni cian' s selection for use. These differences are
weighted against the pati ent's heal th and wi th the parti cular effects of the planned surgical
procedure. Di scussi on of the four most popul ar i nhal ed anestheti cs provi des the major emphasi s of
this chapter. For the sake of compl eteness and for hi storical purposes rel ated to metaboli sm and
renal toxi city, comments on both enfl urane and methoxyfl urane al so are included.
Hal othane i s 20% metaboli zed and an i mmune response to the metaboli te
trifluoroacetyl (TFA) has resul ted in hepatiti s. Based on % metabol ized,
halothane>enflurane>

isoflurane>desfl urane i n anti geni c potenti al . Sevoflurane i s not metabol ized to a
TFA hal i de; rather i t i s metabol i zed to hexafluoroisopropanol that does not
serve as a neoanti gen. Immunol ogic memory resul ti ng in hepatiti s has been
reported years after an initi al hal othane exposure. In addi tion, cross-sensi ti vi ty
has been reported i n whi ch exposure to one anestheti c can sensi tize pati ents to
a second but di fferent anestheti c.
P.385
HISTORY
The vol ati le anesthetics i n earl y cl i ni cal use consisted of fl ammable gases, including di ethyl ether,
cycl opropane, and di vi nyl ether. Several nonflammabl e compounds were avail able, incl udi ng
chloroform and tri chloroethyl ene, but these were associated wi th hepatic toxici ty and
neurotoxi ci ty, and were onl y bri efl y i n cl i ni cal use. In the early 1930s, studi es on derivati ves of
the halogenated compound, chl oroform, i ndi cated that noncombustibl e anestheti c gases mi ght be
deri ved usi ng organic fluoride compounds. Advances in fl uorine chemi stry i n the 1940s al lowed
safe incorporation of fluorine into mol ecul es at a reasonabl e expense. These advances proved to
be pi votal to the devel opment of modern-day anestheti cs. Fl uorine i s the hal ogen wi th the l owest
atomic weight (18.998; chlori ne = 35.45; bromi ne = 79.90; i odine = 126.9). Fluori ne
substi tuti ons for other hal ogens on the ether molecul e l owered the boi li ng poi nt, i ncreased
stabi l ity, and general l y decreased toxi city. The fl uori de i on al so dampened the fl ammabl e
hydrocarbon of the ether anestheti c framework.
In 1951, hal othane was synthesi zed and extensi vel y tested i n ani mals by Suckl i ng, worki ng at ICI
Laboratory i n Engl and. Hal othane was introduced i nto cl ini cal practi ce in 1956 and was rapi dl y
embraced, owing i n part to i ts nonfl ammabi li ty and i n part to i ts lower ti ssue sol ubi l ity. Halothane
al so had a rel ati vely l ow pungency and a hi gh potency; thus, i t coul d be admi ni stered in hi gh-
inspi red concentrations (rel ati ve to i ts potency) to induce anesthesi a vi a inhal ati on. Halothane was
associated wi th a l ower incidence of nausea and vomi ti ng.
Despi te these desi rable properties of hal othane, some concerns and drawbacks remai ned. Most
notable were the effects of hal othane on sensiti zi ng the myocardi um to catecholamines and the
later descri bed role of its intermedi ate metabol i te in hepati c necrosi s. Thus, the search for better
agents conti nued. Between the years of 1959 and 1966, Terrell and col leagues at Ohio Medical
Products (subsequentl y cal l ed Anaquest, Ohmeda, and most currentl y, Baxter) synthesi zed more
FIGURE 15-1. Chemical structure of inhal ed anestheti cs. Hal othane is an al kane, a hal ogen-
substi tuted ethane derivative. Isoflurane and enfl urane are isomers that are methyl ethyl
ethers. Desflurane differs from i sofl urane i n the substi tution of a fl uori ne for a chl ori ne atom
and sevofl urane i s a methyl i sopropyl ether.
than 700 compounds. The 347th and 469th compounds in the seri es were methyl ethyl ethers,
enfl urane and i sofl urane, whi ch were hal ogenated wi th fl uorine and chl ori ne. Cli ni cal trial s of
enfl urane and isofl urane proceeded nearl y i n paral l el, involving both human vol unteer and pati ent
studi es. Years later, several compounds i n Terrel l 's series were reexami ned. One of these (the
653rd) was probl ematic because the compound had a vapor pressure close to 1 atmosphere,
maki ng i t i mpossi bl e to del i ver wi th a standard wicked vaporizer. However, thi s particular
compound was compl etel y hal ogenated wi th fl uorine and hence was predi cted to have a very l ow
solubi li ty in bl ood. As synthesi s and del i very probl ems were resol ved, thi s compound, now known
as desfl urane, was introduced into cl inical practi ce in 1993.
TABLE 15-1 Physiochemical Properties of Volatile Anesthetics
SEVO DES ISO ENFLUR HALO
N
2
O
Boi l ing point (C) 59 24 49 57 50 -88
Vapor pressure at 20C
(mm Hg)
157 669 238 172 243 38,770
Mol ecular wei ght (g) 200 168 184 184 197 44
Oil:gas partition coeffi ci ent 47 19 91 97 224 1.4
Bl ood:gas parti ti on
coeffi ci ent
0.65 0.42 1.46 1.9 2.50 0.46
Brai n:blood sol ubi l ity 1.7 1.3 1.6 1.4 1.9 1.1
Fat:bl ood sol ubi l i ty 47.5 27.2 44.9 36 51.1 2.3
Muscl e:bl ood solubi li ty 3.1 2.0 2.9 1.7 3.4 1.2
MAC in O
2
3060 yr,

at 37C P
B
760 (%)
1.8 6.6 1.17 1.63 0.75 104
MAC i n 6070% N
2
O (%)
0.66 2.38 0.56 0.57 0.29
MAC, >65 yr (%) 1.45 5.17 1.0 1.55 0.64 -
Preservative No No No No Thymol No
Stable in moi st CO
2

absorber
No Yes Yes Yes No Yes
Wal li n and col l eagues at Travenol Laboratori es descri bed other new compounds in the earl y 1970s,
duri ng the course of eval uati ng fl uori nated isopropyl ethers. One of these proved to be a potent
anesthetic agent and became known as sevofl urane. Li ke desfl urane, i t had a l ow sol ubi li ty owi ng
to fl uori nation of the ether molecul e. It was noted that sevofl urane released organi c and i norgani c
fluori des i n both animals and humans; thus, the drug was not aggressi vel y devel oped and
marketed. When the patent ri ghts were transferred to Ohi o Medi cal Products, further testi ng
revealed si gni fi cant

breakdown of sevoflurane in the presence of soda l ime, rai si ng safety concerns that limi ted further
eval uation. Marui shi Pharmaceuti cal i n Japan undertook testi ng and devel opment of sevoflurane,
rel easing the drug for general use in Japan in Jul y 1990. Because of the rapid acceptance and
safety record of sevofl urane i n Japan, Abbott Laboratori es began pursui ng l aboratory and cl i ni cal
trial s wi th sevoflurane i n the United States. After i ts safety was establ ished, sevofl urane was
introduced in U.S. cl i ni cal practi ce in 1995.
The new i nhal ed anestheti cs sevofl urane and desfl urane di ffer from isofl urane most i mportantl y i n
thei r ki neti c behavior. They both have si gnifi cantly lower sol ubi l ity in bl ood, whi ch i ncreases thei r
speed for washin and washout and thei r speed i n adjustment of anestheti c depth (Tabl e 15-1).
These characteri sti cs mesh wel l wi th the ambul atory anesthesi a envi ronment of modern day
practi ce.
PHARMACOKINETIC PRINCIPLES
Pharmacokineti cs as a di sci pli ne began wi th the study of noni nhal ed drugs before the concepts
were appl i ed to the i nhal ed anestheti cs. Kety i n 1950 was the fi rst to examine the
pharmacokineti cs of inhal ed agents i n a systemati c fashion.
1
Eger and col l eagues accompl i shed
much of the earl y research i n the fiel d l eadi ng to his l andmark text on the subject in 1974.
2
The
inhaled anesthetics di ffer substanti al l y from nearly al l other drugs because they are gases gi ven
via inhal ati on. Thi s makes thei r pharmacokineti cs unique as wel l , and most major textbooks of
anesthesia continue to devote considerabl e space to pharmacoki neti c pri nci ples of currentl y used
agents.
Drug pharmacol ogy i s cl assi cal l y di vi ded i nto two di sci pl i nes, pharmacodynami cs and
pharmacokineti cs. Pharmacodynami cs can be defi ned as what drugs do to the body. It descri bes
the desi red and undesi red effects of drugs, as wel l as the cel l ul ar and molecul ar changes l eadi ng
to these effects. Pharmacoki netics can be defi ned as what the body does to drugs. It descri bes
where drugs go, how they are transformed, and the cel l ul ar and mol ecular mechani sms underl yi ng
these processes.
Systemi c drug pharmacoki neti cs have four phases: absorpti on, di stri buti on, metabol i sm, and
excreti on. Absorption is the phase i n whi ch drug i s transferred from the admi ni strati on si te (e.g.,
di gesti ve tract, l ung, muscl e) i nto the bl oodstream. Intravenous drugs have no absorption phase
Fl ammabi li ty (%) (i n 70%
N
2
O/30% O
2
)
10 17 7 5.8 4.8
Recovered as metabol i tes
(%)
25 0.02 0.2 2.4 20
P.386
because they are del i vered di rectl y i nto the bl oodstream. Distribution is the phase i n which drug i s
transferred to ti ssue sites throughout the body. Metabol ism refers to the physi ochemi cal processes
by which substances in a l iving organi sm are synthesized (anaboli sm) or al tered (cataboli sm); but
in the context of anestheti c drugs onl y drug alteration i s perti nent. Fi nal ly, excreti on is the phase
in which changed or unchanged drug i s transferred from ti ssues or bl ood i nto some vehi cl e (e.g.,
bi l e, exhal ed air, urine) for removal from the body.
Ti ssues are often grouped i nto hypotheti cal compartments based on perfusi on. An i mportant
impli cati on of different compartments and perfusi on rates i s the concept of redi stri buti on. After a
gi ven amount of drug is admini stered, it reaches highly perfused ti ssue compartments fi rst where
i t can equi l i brate rapi dl y and exert i ts effects. With ti me, however, compartments with lower
perfusi on rates receive the drug and addi ti onal equi l i bri a are establ i shed between bl ood and these
ti ssues. As the ti ssues wi th l ower perfusi on absorb drug, mai ntenance of equi l i bri a throughout the
body requi res drug transfer from hi ghl y perfused compartments back i nto the bloodstream. Thi s
loweri ng of drug concentrati on in one compartment by deli very i nto another compartment i s cal l ed
redi stri buti on.
In di scussions of the inhaled anesthetics, the termi nology just described i s subject to some mi nor
di fferences. The absorption phase i s usual l y cal led uptake, the metabol i c phase i s usual ly cal l ed
bi otransformation, and the excreti on phase i s usual ly cal led el i mi nation. The terms are completely
interchangeabl e.
Uni que Feat ur es of I nhal ed Anest het i cs
Speed, Gas State, and Route of Administration
The i nhal ed anestheti cs are among the most rapi dl y acti ng drugs i n exi stence, and when
administeri ng a general anesthetic, this speed provides a margin of safety. The abi li ty to
qui ckly i ncrease or decrease anestheti c level s as necessary can mean the di fference between an
anesthetic state and an anestheti c mi sadventure. Speed al so means effi ciency. Rapi d induction
and recovery may l ead to faster operati ng room turnover

ti mes, shorter recovery room stays, and earli er di scharges to home.
Techni cal ly, ni trous oxi de is the only true gas, whi le the potent anestheti cs are the vapors of
vol ati l e li quids. But for si mpl i ci ty, al l of them are cal l ed gases because they are all i n the gas
phase when administered via the lungs. As gases, none devi ate si gni fi cantl y from i deal gas
behavior. These agents are al l noni oni zed and have l ow molecul ar weights. This al lows them to
di ffuse rapi dly wi thout the need for facil i tated diffusi on or acti ve transport from bloodstream to
ti ssues. The other advantage of gases i s that they can be del i vered to the bl oodstream vi a a
uni que route avai l abl e i n al l pati ents: the lungs.
The l ung route of admi ni strati on i s unique to the inhaled anestheti cs, except for bronchodil ators or
endotracheal admini stration of cardiac resuscitati on drugs. These exceptions are, however, a
one-way street because thei r route of delivery is different from their el imi nati on route. Inhal ed
anesthetics have a two-way street in the l ungs; they are del ivered and pri maril y el i mi nated vi a
this route.
Speed, gaseous state, and the l ung route of admi ni strati on combine to form the major benefi ci al
feature of the i nhal ed anestheticsthe abi l ity to decrease pl asma concentrati ons as easi ly and as
rapidl y as they are increased.
P hysi cal Char act er i st i cs of I nhal ed Anest het i cs
The goal of del i veri ng i nhal ed anesthetics i s to produce the anestheti c state by establi shi ng a
specific concentrati on of anesthetic molecul es i n the central nervous system (CNS). Thi s i s done
by establi shi ng the speci fi c parti al pressure of the agent in the l ungs, whi ch ul ti matel y
equil i brates with the brai n and spi nal cord. Equi li brati on is a resul t of three factors:
P.387
1. Inhaled anesthetics are gases rapi dl y transferred bidi rectional ly vi a the l ungs to and from
the bl oodstream and subsequentl y to and from CNS tissues as parti al pressures equi l i brate.
2. Pl asma and tissues have a l ow capacity to absorb the i nhal ed anestheti cs relative to the
amount we can del i ver to the l ungs, al l owing us to qui ckl y establ ish or abol i sh anestheti zi ng
concentrations of anesthetic i n the bloodstream and ul timatel y the CNS.
3. Metabol ism, excreti on, and redistri buti on of the i nhal ed anestheti cs are mi ni mal rel ati ve to
the rate at whi ch they are deli vered or removed from the l ungs. Thi s permi ts easy
maintenance of blood and CNS concentrati ons.
At equil i bri um, CNS parti al pressure equal s bl ood partial pressure, whi ch in turn equal s al veol ar
parti al pressure:

where P is parti al pressure. The physi cal characteri sti cs of inhal ed anestheti cs are shown i n Tabl e
15-1.
Inhaled anesthetics are del ivered to the l ung as gases and foll ow the i deal gas law, PV = nRT,
where P is pressure, V is volume, n i s number of mol es of gas, R is the gas constant, and T is
absol ute temperature. If a gas is heated i n a fi xed vol ume, pressure wi l l increase. If a gas i s
heated or i f mol ecul es of gas are added whi l e keeping i ts pressure constant, its volume must
increase. If the number of molecul es of gas is i ncreased i nto a fixed volume, pressure wil l
increase.
The so-call ed permanent gases, such as oxygen and ni trogen, exi st only as gases at ambi ent
temperatures. Gases such as ni trous oxi de can be compressed i nto l iquids under hi gh pressure at
ambient temperature. Most potent volatil e anestheti cs are li quids at ambient temperature and
pressure. Some molecul es wi th suffici ent energy escape the l i qui d and enter a gas phase above
the surface of the l i qui d as a vapor. Pure gases al ways diffuse from an area of hi gh pressure to an
area of l ow pressure, because of thei r chemi cal potenti al , . Chemical potential, also called the
escapi ng tendency, i s a thermodynami c concept. It i s simil ar to an el ectrical potential . In thi s
case, however, i t is gases that conti nue to seek equil i brati on unti l is equal throughout the
system. Chemi cal potenti al depends on the substance and characteri sti cs of the system in whi ch i t
exists, such as temperature, pressure, and presence of other substances.
If the system in whi ch the vol ati le l i qui d resi des is a cl osed container, molecul es of the substance
wil l equi l ibrate between the l iquid and gas phases (to equal ize ). At equil i bri um the pressure
exerted by mol ecul ar col li sions of the gas agai nst the contai ner wal ls i s the vapor pressure. One
i mportant property of vapor pressure i s that as l ong as any li quid remai ns i n the container, the
vapor pressure is independent of the vol ume of that l i qui d. As wi th any gas, however, vapor
pressure i s proportional to temperature.
For al l of the potent agents at 20C the vapor pressure i s bel ow atmospheric pressure. If the
temperature i s rai sed the vapor pressure increases. The boi li ng poi nt of a li quid i s the
temperature at whi ch its vapor pressure exceeds atmospheri c pressure in an open contai ner.
Desfl urane i s bottled in a speci al contai ner because i ts boi l ing poi nt of 23.5C makes i t boi l at
typi cal room temperatures. Boi li ng does not occur wi thi n the bottle because i t i s countered by
bui l dup of vapor pressure wi thi n the bottle; but once opened to ai r, the desflurane would qui ckly
boi l away. The bottl e i s desi gned to all ow transfer of desflurane from bottle to vaporizer without
exposure to the atmosphere.
Gases i n Mi xt ur es
For any mixture of gases in a cl osed contai ner, each gas exerts a pressure proporti onal to i ts
fracti onal mass (or fracti onal vol ume according to PV = nRT, si nce vol ume i s a more fami l i ar
term when deal i ng wi th gases). This i s i ts parti al pressure. The sum of the parti al pressures of
each gas i n a mixture of gases equals the total pressure of the enti re mi xture (Dal ton' s l aw).

The enti re mixture behaves just as i f i t were a si ngle gas according to the i deal gas l aw.
Gases i n Sol ut i on
Parti al pressures of gases i n sol ution are more compl i cated. Any gas/vapor di ssol ved i n a l i qui d
exerts a force to drive molecul es out of sol ution and i nto the gas phase. Molecul es i n the gas
phase counter thi s by exerti ng a force that dri ves them i nto the li quid phase. Onl y at a gi ven
concentration of molecul es in the gas phase wi ll the forces (hence chemi cal potenti al s) be equal
and the system i n equil i bri um. Thi s force i s cal l ed the tensi on, and the concentrati on of mol ecul es
in the gas phase at equi l ibri um will determine the pressure of that phase according to the ideal
gas l aw. Tensi on i s convenientl y descri bed by the parti al pressure of the gas i n equi l i bri um wi th
the li quid phase. The terms tensi on and parti al pressure are used synonymousl y i n this
chapter.
The concentration of gas mol ecul es in sol ution is more compli cated sti l l, owing to i ntermolecul ar
interaction. Gas molecul es wi thi n a l i qui d i nteract with sol vent mol ecules to a much larger extent
than do molecul es i n the gas phase. The gas mol ecules wi l l be present i n the l iquid only to the
extent that thi s equali zes the chemi cal potenti al between the l i qui d and gas phases. The chemi cal
potential of the gas in a l iquid

depends dramati cal l y on the li quid i tsel f and the energy-state of that l iquid. Sol ubi l ity is the
term used to describe the tendency of a gas to equil i brate wi th a sol uti on, hence determini ng i ts
concentration in sol uti on. The solubi li ty coeffici ent, i s an expressi on of thi s tendency:

where V = volume.
The pri nci pl es of parti al pressures and sol ubi l i ty apply i n mi xtures of gases in sol uti on. That i s,
the concentration of any one gas i n a mi xture of gases i n soluti on depends on two factors: (1) its
parti al pressure i n the gas phase i n equi li brium with the sol uti on, and (2) its sol ubi l ity wi thin that
sol uti on. Thus, the parti al pressure of a parti cul ar gas is proporti onal to its fractional vol ume in
the gas phase, not the l i qui d phase.
The i mpl i cati ons of these properti es are that anesthetic gases admini stered via the lungs di ffuse
i nto bl ood unti l the parti al pressures i n al veoli and blood are equal . The concentration of
anestheti c i n the bl ood depends on the parti al pressure at equil i bri um and the bl ood sol ubi l i ty.
Likewise, transfer of anestheti c from bl ood to target tissues also proceeds toward equali zi ng
parti al pressures. The concentration of anestheti c in target ti ssue depends on the parti al pressure
at equi l ibri um and the target ti ssue sol ubi li ty. Because i nhal ed anestheti cs are gases, and because
parti al pressures of gases equi l ibrate throughout a system, moni toring the al veol ar concentration
of inhaled anesthetics provi des an i ndex of thei r effects i n the brain.
In summary:
1. Inhaled anesthetics equi l ibrate based on thei r parti al pressures in each tissue (or ti ssue
compartment), not based on thei r concentrati ons.
2. The parti al pressure of a gas i n sol uti on i s al ways defi ned by the parti al pressure i n the gas
phase with whi ch i t i s in equi l ibri um.
3. The concentrati on of anestheti c i n a ti ssue depends on i ts partial pressure and tissue
solubi li ty.
Fi nal ly, the parti cular termi nol ogy used when referri ng to gases i n the gas phase or absorbed i n
pl asma or tissues i s important. Inspi red concentrati ons or fractional volumes of i nhal ed anestheti c
are typicall y used rather than parti al pressure. For most drugs, concentration is expressed as
mass (mg) per vol ume (mL), but i t can al so be expressed i n percent by wei ght or volume. Si nce
P.388
vol ume of a gas i n the gas phase i s di rectly proportional to mass according to the i deal gas l aw, i t
is easi er to express thi s fractional concentrati on as a percent by vol ume. Tension and partial
pressure, on the other hand, are expressed i n mmHg, or torr (1 torr = 1 mmHg), or kPa
(ki l opascal s). In the gas phase, fracti onal concentration i s equal to the parti al pressure (or
tensi on) di vi ded by ambi ent pressure, usual ly atmospheric, or:

Anest het i c Tr ansf er : Machi ne t o Cent r al Ner vous Syst em
Anestheti cs fol l ow a mul tistep route from anesthesia machi ne to pati ent (and back). Each of these
steps represents a transfer poi nt or i nterface between hypotheti cal compartments. The
compartments are organi zed by l ocation or pharmacoki netic properti es i n an effort to si mpl i fy the
concept of anestheti c fl ow. For exampl e, one-way fl ow occurs from the fresh gas outl et to the
anesthesia ci rcui t and to the waste gas scavenging system. Equi l ibri um flow occurs between the
anesthesia ci rcui t and the ai rways (and al veol i ) and between the al veoli and pul monary bl ood.
Bul k flow of blood accounts for anesthetic transfer to systemi c bl ood and equi li bri um flow occurs
between systemi c bl ood and tissues. The fl ow of anestheti c from compartment to compartment can
be characteri zed by pharmacoki neti cs. Technicall y, the flow from fresh gas outl et (FGO) to circui t
is not a pharmacoki netic concern because i t does not characteri ze what the body does to the drug.
But i t is typi cal l y di scussed as a pharmacoki neti c parameter because i t has i mportant cl inical
impli cati ons.
When the fresh gas fl ow and the vaporizer are turned on, fresh gas wi th a fi xed fracti onal
concentration of anestheti c l eaves the FGO and mixes wi th the gas in the ci rcui tthe bag, tubi ng,
absorbent canister, and pi ping. It i s i mmedi atel y di l uted to a l ower fractional concentrati on, then
sl owly ri ses as thi s compartment equi li brates with the fresh gas fl ow. With spontaneous pati ent
ventil ati on by mask, the anesthetic gas passes from ci rcuit to ai rways. The fracti onal
concentration of anestheti c l eavi ng the ci rcui t i s desi gnated as F
I
(fracti on i nspi red). In the lungs
the gas compri si ng the dead space i n the ai rways (trachea, bronchi) and the alveol i further dil utes
the ci rcuit gas. The fracti onal concentration of anesthetic present i n the al veoli i s F
A
(fracti on
al veolar). The anestheti c then passes across the al veol arcapil l ary membrane and dissol ves i n
pul monary blood accordi ng to the parti al pressure of the gas and i ts sol ubi l i ty. It i s further di l uted
and travel s vi a bul k bl ood fl ow throughout the vascular tree. The anesthetic then passes vi a
si mpl e di ffusi on from bl ood to ti ssues as wel l as between ti ssues.
The vascular system deli vers bl ood to three physi ol ogi c ti ssue groups; the vessel -ri ch group
(VRG), the muscl e group, and the fat group. The VRG includes the brai n, heart, ki dney, l i ver,
di gesti ve tract, and gl andul ar ti ssues. The percent body mass and perfusi on of each are shown i n
Tabl e 15-2. The CNS ti ssues of the VRG are referred to as ti ssues of desi red effect. The other
TABLE 15-2
% BODY MASS % CARDIAC OUTPUT PERFUSION mL/min/100 g
Vessel ri ch 10 75 75
Muscl e 50 19 3
Fat 20 6 3
ti ssues of the VRG compri se the compartment frequently referred to as ti ssues of undesi red
effects. The ti ssues of the muscl e and fat groups compri se the ti ssues of accumul ation.
Anestheti c is del i vered most rapi dl y to the VRG because of hi gh bl ood fl ow. Here i t di ffuses
according to parti al pressure gradi ents. CNS ti ssue takes i n the anestheti c according to the ti ssue
solubi li ty, and at a hi gh enough ti ssue concentrati on unconsci ousness i s achieved. Increasi ng CNS
ti ssue concentrati ons causes progressivel y deeper stages of anesthesi a. As this i s occurri ng,
anesthetic i s also distri buti ng to other VRG tissues. Al so coinci dent wi th del ivery to the CNS,
anestheti c i s bei ng del i veredal beit more slowl y because of l ower perfusi onto muscl e and fat
where it accumulates and may affect the speed of emergence from the anestheti c. In real ity, the
fat sol ubil i ti es provi de l ittle i nfluence on emergence i n cases l asti ng <4 hours si nce the deli very of
anesthetic to fat ti ssue is extremel y sl ow as a result of l ow bl ood fl ow. The concentration of
inhaled anesthetic i n a given tissue at a particul ar ti me during the

administrati on depends not onl y on tissue blood fl ow, but al so on ti ssue solubi li ty, whi ch governs
how the i nhal ed anestheti cs parti ti on themsel ves between bl ood and ti ssue. Parti ti oni ng depends
on the rel ati ve solubil i ti es of the anestheti c for each compartment. These rel ati ve sol ubil i ti es are
expressed by a partiti on coeffici ent, , whi ch i s the ratio of di ssolved gas (by vol ume) in two-
ti ssue compartments at equi l ibri um. Al ternati vel y i t i s the ratio of tissue:gas solubil i ti es i n the two
compartments. For a pure gas i n the gas phase, equal s 1, that i s, V
di ssol ved gas
/V
gas
= 1. Thus
bl ood:gas parti ti on coeffi ci ent i s the same as bl ood sol ubi l i ty:

where
b/g
i s the bl ood:gas partition coefficient.
For other partiti on coeffici ents such as brain:bl ood (
br /bl
), the volume of anesthetic di ssolved i n
brai n i s di vi ded by the vol ume of anesthetic di ssol ved i n bl ood:

Some of the partiti on coefficients for the i nhaled anesthetics are shown i n Tabl e 15-1.
As explai ned earl i er, one of the reasons why inhal ed anestheti cs are rapi dl y titratabl e i s that thei r
ti ssue sol ubi li ties are low relative to deli very rate; thus del i very of a desi red parti al pressure to
the CNS i s possi bl e despi te redi stri bution and accumul ati on of anestheti c i n other ti ssues.
Upt ake and Di st r i but i on
F
A
/F
I

A si mple, common way to assess anestheti c uptake i s to fol l ow the ratio of fracti onal
concentration of al veolar anestheti c to i nspi red anestheti c (F
A
/F
I
) over time. Experi mentall y
deri ved data for F
A
/F
I
versus ti me duri ng induction are shown in Fi gure 15-2.
P.389
The i nhal ed anestheti cs with the l owest sol ubi l iti es in bl ood show the fastest ri se in F
A
/F
I
. The
shape of these curves has several regi ons wi th di fferent ori gins. As fresh gas carryi ng anesthetic
begi ns to fl ow i nto the ai r-fil l ed circui t (assumi ng compl ete mixing), the concentrati on i n the
ci rcuit (F
I
) wil l rise accordi ng to fi rst-order ki netics:

F
FGO
is the fracti on of inspired anestheti c in the gas l eavi ng the fresh gas outl et (i .e., the
vapori zer setting), T is ti me, and is a time constant. Because al l anestheti cs i n the circui t are i n
the gas phase, F (fracti onal vol ume or concentrati on) i s al so P (parti al pressure) di vi ded by P
B

(barometri c pressure), and i nspired anestheti c can be expressed as ei ther F
I
or P
I
. The ti me
constant i s simpl y the vol ume or capaci ty of the ci rcui t (V
C
) di vi ded by the fresh gas fl ow (FGF)
or = V
C
/FGF. For exampl e, i f the bag, tubi ng, absorbent cani ster, and pi pi ng compri se 8 L, and
the fresh gas flow i s 2 L, the ti me constant = 8/2 = 4. One of the characteri sti cs of first-order
kineti cs is that 95% of maximum i s reached after 3 time constantsin thi s case, 3 4 = 12
minutes.
Because 12 minutes is relatively l ong, starti ng with a hi gher F
FGO
can increase the rate of ri se of
F
I
. Usi ng the earl i er example with = 4, by fi rst-order ki neti cs 63% of maximum is reached after
one ti me constant, or 4 mi nutes. To attain an F
I
of 2% at 4 instead of 12 mi nutes, the F
FGO
can be
set to 3.2% (2% di vi ded by 0.63) and then l owered to 2% at the 4-mi nute mark.
FIGURE 15-2. The ri se i n al veol ar (F
A
) anesthetic concentrati on toward the i nspired (F
I
)
concentration is most rapi d with the l east sol ubl e anestheti cs, ni trous oxi de, desfl urane, and
sevofl urane. It ri ses most slowl y with the more solubl e anestheti cs, for example, halothane.
All data are from human studi es. (Adapted from Yasuda N, Lockhart SH, Eger EI II et al :
Compari son of ki netics of sevoflurane and isofl urane in humans. Anesth Anal g 72:316, 1991;
and Yasuda N, Lockhart SH, Eger EI II et al : Ki neti cs of desflurane, isoflurane, and hal othane
in humans. Anesthesi ol ogy 74:489, 1991.)
Other ways to speed the i ncrease i n F
I
include i ncreasi ng the fresh gas flow, thus decreasi ng .
Furthermore, the rebreathi ng bag can be coll apsed pri or to starti ng the fresh gas fl ow, such that
the capaci ty i n the ci rcuit (V
C
) i s l ess, whi ch also decreases . Fi nal ly, at hi gh fl ows (>4 L/mi n)
there i s far l ess mi xi ng because fresh gas pushes ol d gas out of the ci rcui t vi a the pop-off valve
before complete mi xi ng occurs, causi ng F
I
to i ncrease at a greater rate.
One factor that delays the rate of ri se of F
I
arises from the fact that CO
2
absorbent can adsorb and
decompose the inhaled anesthetics. From a practi cal standpoint, thi s does not affect the rate of
ri se in F
I
to a signi fi cant extent compared to other factors. Another factor that del ays the rate of
ri se of F
I
is solubil i ty of the i nhal ed anestheti cs in some of the pl asti c and rubber parts of the
anesthesia ci rcui t. Thi s absorpti on has been quanti fi ed, but pl ays onl y a small role i n decreasi ng
the rate of ri se of F
I
.
Rise in F
A
in the Absence of Uptake

The rate of rise i n F
I
discussed earli er assumes that no anestheti c i s mi xi ng with gas i n the
patient' s lungs. In reali ty, ci rcui t gas mi xes wi th exhal ed gases from the l ung wi th each breath. If
extremel y high fresh gas fl ows (produci ng a hi gh vol ume of gas at the desi red concentration) are
used, l ittl e mixing wi th exhaled ai r occurs and F
I
is relatively fi xed. In this si tuati on, ci rcuit gas
enters the l ungs where it mixes wi th alveol ar gas. If there were no blood flow to the lungs, F
A

would ri se in a fashion anal ogous to F
I
; that i s:

In thi s equati on, i s the ti me constant for al veolar ri se i n anestheti c concentration and equal s the
functional residual capacity (FRC) of the pati ent' s l ungs di vi ded by minute venti l ati on,

A
. There are two ways to speed the equi li brati on of F
A
with F
I
, that i s, to decrease . One way is to
increase minute venti l ation, and the other is to decrease FRC. Both of these methods can be used
to speed i nducti on by mask: the pati ent can exhal e deepl y before applying the mask (to decrease
the ini ti al FRC), and the pati ent can breathe deeply and rapi dl y (to i ncrease
TABLE 15-3 Factors That Increase or Decrease the Rate of Rise of F
A
/ F
I

INCREASE DECREASE
Low
B
High
B
The l ower the bl ood:gas solubil i ty, the faster the ri se in
F
A
/F
I
Low Q High Q
The l ower the cardi ac output, the faster the ri se i n F
A
/F
I
High
A
Low
A
The hi gher the mi nute ventil ati on, the faster the ri se in
F
A
/F
I
Hi gh (P
A
-
P
v
)
Low (P
A
-
P
v
)
At the begi nni ng of inducti on, P
v
i s zero but ri ses rapi dl y
(thus [P
A
-P
v
] fal l s rapi dl y) and F
A
/F
I
increases rapi dl y.
Later, duri ng induction and mai ntenance, P
v
ri ses more
sl owly so F
A
/F
I
ri ses more slowl y.
Parameters as descri bed in Equati on 1516:
B
, bl ood sol ubi l i ty; Q, cardiac output; ,
mi nute ventil ati on; P
A
, P
v
, pul monary arteri al and venous bl ood parti al pressure.
P.390

A
) after the mask i s appl i ed. One of the reasons that pedi atri c i nductions by spontaneous
breathing of i nhal ed anestheti cs are so much quicker than adul t i nducti ons is that the l ow FRC
rel ati ve to

A
of children makes for a low time constant, and hence a rapid increase i n F
A
/F
I
. One i mportant
caveat about the relationshi p of F
A
to FRC i s that FRC i ncl udes ai rway dead space; thus, in real i ty,
F
A
by Equation 15-8 is not just the concentration of inhal ed anestheti c in the alveol i but also the
concentration in the enti re l ung. However, i t i s si mpl y cal led the al veolar concentrati on because
the dead space in the airways i s rel ati vel y insignificant and onl y the al veolar gas i s exchangi ng
anesthetic with the blood.
Rise in F
A
in the Presence of Uptake

Because i n reali ty there is pul monary blood fl ow, the most important factor i n the rate of ri se of
F
A
/F
I
is uptake of anesthetic from the alveoli i nto the bl oodstream. The rate of ri se of F
A
/F
I
(the
sl ope of the curves seen in Fi g. 15-2) refl ects the speed at which al veolar anestheti c (F
A
)
equil i brates with that bei ng del i vered to the l ungs (F
I
). F
A
is not solely a function of F
I
and time.
Inhaled anesthetics so avi dl y transfer i nto and are di l uted by the bl oodstream that uptake i nto
bl ood i s a pri mary determinant of F
A
; that i s, the greater the uptake, the slower the rate of rise of
F
A
/F
I
. Uptake i s proporti onal to tissue sol ubil i ty. The l ess solubl e the anestheti c (such as
desfl urane), the l esser its uptake and the faster i t reaches equil i bri um.
Consi der a hypothetical example. Suppose that hal othane and desfl urane are sol ubl e i n bl ood, but
insol ubl e in al l other ti ssues. Suppose further that total lung capaci ty and bl ood vol ume were both
5 li ters. If a fi xed volume of anesthetic i s deli vered to the lungs (by aski ng the patient to take one
deep breath and hol d i t), accordi ng to parti ti on coeffi ci ents, 70.6% of the deli vered hal othane wil l
be transferred to the bl ood whi l e 29.4% remai ns i n the al veoli (70.6/29.4 = 2.4). In contrast
29.6% of the desfl urane wi l l be transferred to the blood whi l e 70.4% remai ns i n the alveol i
(29.6/70.4 = 0.42). Therefore, 2.4 times (70.6/29.6) more hal othane than desfl urane (by volume
or number of molecul es) wi ll be transferred from al veoli to bloodstream before parti al pressures
equil i brate. At equi li brium, the partial pressures of hal othane and desfl urane are 29.4% and
70.4% of thei r i nhal ed val ues, respecti vel y.
But anestheti cs are sol ubl e i n ti ssues, and they are del i vered conti nuousl y rather than in a one-
shot fashi on; thus they are again characterized by fi rst-order ki netics:

where P
A
= F
A
P
B
(barometric)
Here, P
B
is the barometric pressure, and the ti me constant, , equal s capaci ty (vol ume of
anesthetic dissolved in blood at the desi red al veol ar parti al pressure) di vi ded by flow (vol ume of
anesthetic del i vered per uni t ti me). For any given flow of anesthetic into the system, this capacity
for the more sol ubl e hal othane is greater than the capacity for the l ess soluble desfl urane; thus,
for hal othane is greater than that for desfl urane. The more soluble an inhal ed anestheti c, the
larger the capaci ty of the bl ood and ti ssues for that anestheti c, and the l onger it takes to saturate
at any gi ven del i very rate.
Anesthetic flow can be described by a seri es of first-order rate equati ons: F
I
as a functi on of F
FGO
,
F
A
as a function of F
I
, bl ood uptake as a functi on of F
A
, and so on. These differenti al equati ons can
then be solved to determi ne any val ue as a functi on of ti me. Relati vel y strai ghtforward equati ons
hel p descri be whi ch parameters determi ne the rate of ri se of F
A
/F
I
.
During any given period of time, the al veolar anestheti c fracti on, F
A
, as a proportion of the
inspi red anestheti c fracti on, F
I
, wi l l equal the rati o of

expi r ed
to

i nspi r ed
; that i s:

If F
A
/F
I
is zero and starts to increase as i nhal ed anestheti c reaches the al veoli from the ci rcuit but
uptake of anestheti c in the pul monary bl ood nearly equals i ts del i very to the al veoli , then F
A
/F
I

wil l not ri se. Al l of the anestheti c arri vi ng at the al veol i i s transferred immedi atel y to the bl ood.
Since bl ood capacity to absorb anestheti c i s fini te, F
A
wi l l eventual l y begi n to rise relative to F
I
. If,
on the other hand, bl ood uptake is very smal l , F
A
and F
I
qui ckl y become nearl y equal .
Bl ood uptake of anestheti c i s expressed by the equati on:

Where

B
i s bl ood uptake,
b/g
i s the bl ood:gas parti ti on coeffi ci ent, Q is cardi ac output, P
A
is al veol ar
parti al pressure of anestheti c, P
v
i s mi xed venous parti al pressure of anestheti c, and P
B
is
barometric pressure. This i s the Fi ck equati on appl i ed to bl ood uptake of inhal ed anestheti cs. The
parameters that i ncrease or decrease the rate of ri se in F
A
/F
I
during i nducti on can be cl earl y
defi ned and these i mportant factors have been substanti ated i n experi mental models (Tabl e 15-3).

Before i nducti on, P
v
is zero because no anesthetic i s present i n the bloodstream. P
A
is establ i shed
with the fi rst i nspi rati on of anestheti c, and the alveol ar to pul monary bl ood parti al pressure
gradient, P
A
-P
v
, determi nes the rate of i ncrease i n F
A
/F
I
. Ini ti all y, P
A
cl i mbs at a much greater rate
than P
v
because ci rcul ati on and di l ution as wel l as ti ssue uptake together keep P
v
low. As
si gni fi cant ti ssue concentrati ons of anesthetic start to accumul ate, P
v
rapi dl y cl i mbs as the
pul monary blood, ori ginal l y carryi ng no anesthetic, becomes saturated wi th anesthetic. This earl y
rapi d ri se i n F
A
/F
I
foll owed by sl owing i s seen in Fi gure 15-2.
Distribution (Tissue Uptake)
Until P
v
starts to increase, the maximum F
A
/F
I
at a gi ven inspi red concentrati on of anestheti c,
cardi ac output, and mi nute venti lation are entirel y dependent on the sol ubi l i ty of that drug i n the
bl ood as characteri zed by the bl ood:gas parti tion coefficient
b/g
. Thi s can be seen i n the ti me
curves for the rise i n F
A
/F
I
during i nducti on for the vari ous i nhal ati on anestheti cs shown i n Fi gure
15-2. The first knee in each curve i n Fi gure 15-2 represents the poi nt at whi ch the rapi d ri se i n
P
v
begi ns to taper off, that i s, when si gni fi cant i nhal ed anestheti c concentrations begi n to bui l d up
in the bloodstream because of di stri buti on to and equi l ibrati on wi th the vari ous ti ssue
compartments.
Each of the three perfusion compartmentsVRG, muscle, and fattakes up anesthetic based on
the Fi ck equati on:

where P
aCompar t .
and P
vCompar t .
are arteri al and venous parti al pressures i n the tissue compartment.
Mi xed venous parti al pressure of anestheti c in the pulmonary outflow, P
v
, depends on the rel ati ve
uptake in each of these perfusi on compartments. To the extent that the mass and bl ood fl ow to
each of these compartments di ffers, anesthetic uptake will differ.
As bl ood is equi l i brati ng wi th alveol ar gas, it al so begi ns to equi li brate wi th the VRG, muscl e, and,
more gradual l y, the fat compartments based on perfusi on. Muscl e i s not that di fferent from the
VRG, havi ng parti ti on coeffi cients that range from 1.2 (ni trous oxide) to 3.4 (hal othane), just
under a 3-fold difference; and for each anesthetic except ni trous oxi de, the muscl e partiti on
coeffi ci ent i s approxi matel y doubl e that for the VRG. Although both VRG and muscl e are l ean
ti ssues, the muscl e compartment equi l ibrates far more sl owl y than the VRG. The explanation
comes from Equati on 15-12 and the mass of the compartments rel ati ve to perfusi on. The perfusion
of the VRG is about 75 mL/mi n/100 g of ti ssue, whereas i t is onl y 3 mL/mi n/100 g of ti ssue in the
muscle (see Tabl e 15-2). Thi s 25-fol d di fference i n perfusi on between VRG (especi al l y brai n) and
P.391
muscle means that even i f the partiti on coeffi cients were equal , the muscle would sti ll take 25
ti mes l onger to equil i brate with blood.
Fat is perfused to a lesser extent than muscle and i ts time for equi librati on wi th bl ood i s
consi derably sl ower because the parti ti on coeffi cients are so much greater. Al l of the potent
agents are highl y l ipi d sol ubl e. Partiti on coeffici ents range from 27 (desfl urane) to 51 (halothane).
On average, the sol ubi l i ty for these agents is about 25 ti mes greater in fat than in the VRG group.
Thus, fat equi l ibrates far more sl owl y wi th the bl ood and does not pl ay a si gni fi cant role i n
determi ni ng speed of i nducti on. After long anestheti c exposures (>4 hours), the hi gh saturation of
fat ti ssue may pl ay a rol e in del aying emergence.
Ni trous oxi de represents an exception. Its partiti on coeffici ents are fai rl y si mi l ar i n each ti ssue, it
does not accumul ate to any great extent and i s not a very potent anestheti c. Its uti l ity li es as an
adjunct to the potent agents, and as a vehi cl e to speed i nducti on.
Met abol i sm
Data suggest that enzymes responsibl e for bi otransformati on of inhal ed anestheti cs become
saturated at l ess than anestheti zi ng doses of these drugs, such that metabol ism plays l i ttle role in
opposi ng induction. It may, however, have some si gni fi cance to recovery from anesthesi a as
di scussed later.
Over pr essur i zat i on and t he Concent r at i on Ef f ect
There are several ways to speed uptake and i nducti on of anesthesi a wi th the i nhal ed anestheti cs.
The fi rst i s overpressuri zation, which is anal ogous to an i ntravenous (IV) bolus. Thi s is the
administrati on of a higher parti al pressure of anestheti c (F
I
) than the alveol ar concentrati on (F
A
)
actual l y desi red for the pati ent.
Inspi red anesthetic concentration (F
I
) can i nfluence both F
A
and the rate of ri se of F
A
/F
I
. The
greater the i nspi red concentrati on of an inhal ed anestheti c, the greater the rate of ri se. Thi s
concentration effect has two components. The fi rst is a concentrati ng effect, and the second is an
augmented gas i nfl ow effect.
For example, consi der the administration of 10% anesthetic (10 parts anesthetic and 90 parts
other gas) to a pati ent i n which 50% of the anestheti c in the alveol i i s absorbed by the bl ood. In
this case 5 parts (0.5 10) anestheti c remai n i n the al veol i , 5 parts enter the bl ood, and 90 parts
remai n as other al veol ar gas. The al veolar concentration is now 5/(90 + 5) = 5.3%. Consi der next
administeri ng 50% anesthetic with the same 50% uptake. Now 25 parts anesthetic remain i n
al veol i , 25 parts pass i nto bl ood, and 50 parts remai n as other al veolar gas. The al veolar
concentration becomes 25/(50 + 25) = 33%. Giving fi ve ti mes as much anestheti c has led to a
33%/5.3% = 6.2 ti mes greater alveolar concentrati on. The hi gher the F
I
, the greater the effect.
Thus nitrous oxi de, typicall y given i n concentrations of 50 to 70%, has the greatest concentrati ng
effect. Thi s i s why the F
A
/F
I
versus ti me curve i n Fi gure 15-2 ri ses the most quickl y wi th ni trous
oxi de, even though desflurane has a sl i ghtly l ower bl ood:gas sol ubi l i ty. The concentrati ng effect
becomes most promi nent wi th the most sol ubl e anestheti c. Therefore, hal othane and i sofl urane
should benefi t most at any particular concentrati on of anestheti c, F
I
. But because equi potent
concentrations for hal othane and isofl urane are l ower than those of the l ess sol ubl e anestheti cs,
sevofl urane and desfl urane, these agents benefit from the concentrati on effect less than
expectedthat i s, concentration outwei ghs sol ubil i ty. The typi cal i nspi red concentrati ons of N
2
O
are so much greater than the potent anestheti cs that i ts low ti ssue sol ubi li ty i s of no consequence.
Thi s isn' t the compl ete pi cture; there is yet another factor to consi der. As gas i s leavi ng the
al veol i for the bl ood, new gas at the ori gi nal F
I
is entering to repl ace that whi ch i s lost. Thi s other
aspect of the concentration effect has been cal led augmented gas i nflow. Again, take the exampl e
of 10% anestheti c del i vered wi th 50% uptake i nto the bl oodstream. The 5 parts anestheti c
absorbed by the bl oodstream are repl aced by gas i n the ci rcui t that is stil l 10% anestheti c. The 5
parts anestheti c and 90 parts other gas l eft in the l ungs mi x with 5 parts replacement gas, or 5
0.10 = 0.5 parts anestheti c. Now the al veol ar concentrati on i s (5 + 0.5)/(100%) = 5.5% (as
compared to 5.6% wi thout augmented i nflow). For 50%

anesthetic and 50% uptake, 25 parts of anestheti c removed from the al veoli are repl aced wi th 25
parts of 50% anestheti c, giving a new al veolar concentrati on of (25 + 12.5)/(100%) = 37.5% (as
compared to 50% wi thout augmented i nflow). Thus fi ve ti mes the F
I
leads to 37.5/5.5 = 6.8 ti mes
greater F
A
(compared to 6.2 times without augmented gas infl ow). Of course, thi s cycl e of
absorbed gas bei ng repl aced by fresh gas infl ow i s conti nuous and has a fi ni te rate so our exampl e
is a si mpli fi cation.
Second Gas Ef f ect
A speci al case of concentration effect appl ies to administrati on of a potent anestheti c wi th nitrous
oxi dethat i s, two gases si mul taneously. Al ong wi th the concentrati on of potent agent in the
al veol i vi a i ts uptake, there i s further concentrati on vi a the uptake of nitrous oxi de, a process
call ed the second gas effect. The second gas i s the potent agent. The pri ncipl e i s si mple (Fi gs. 15-
3 and 15-4). Consi der, for example, administeri ng 2% of a potent anestheti c in 70% ni trous oxi de
and 28% oxygen. In thi s case, ni trous oxi de, wi th i ts extremel y high vapor pressure (despi te low
solubi li ty), partiti ons into the bl ood more rapi dl y than the potent anestheti c, decreasi ng the
al veolar N
2
O concentrati on by some amount (e.g., by 50%). Ignoring uptake of the potent
anesthetic, the uptake of N
2
O i s 35 parts, leavi ng 35 parts N
2
O, 28 parts O
2
, and 2 parts potent
agent i n the al veoli . The second gas i s now present in the alveol i at a concentrati on of 2/(2 + 35
+ 28) = 3.1%. The second gas has been concentrated.
P.392
FIGURE 15-3. A graphi c and the equati ons to demonstrate the second gas effect. In this
hypotheti cal exampl e, the second gas i s set at 2% of a potent anestheti c and the model is
set for 50% uptake of the fi rst gas (nitrous oxi de) in the first inspired breath. The second
gas i s concentrated because of the uptake of N
2
O (middle panel). On repl eni shi ng the
inspi red second gas (F
I
= 2%) i n the next breath, the second gas has been concentrated to
be 2.7% because of the uptake of N
2
O i n the previous breath.
Venti l ati on Ef f ects
As i ndi cated by Fi gure 15-2 and Equati on 15-3, inhal ed anestheti cs with very low ti ssue sol ubi l ity
have an extremel y rapi d ri se i n F
A
/F
I
wi th i nducti on. Thi s suggests that there i s very l ittle room to
improve thi s rate by i ncreasing or decreasing venti l ati on. Thi s is consistent wi th the experi mental
evidence shown i n Fi gure 15-5. The greater the sol ubi l ity of an i nhal ed anestheti c, the more
rapi dl y i t i s absorbed by the bl oodstream, such that anestheti c deli very to the lungs may be rate
li mi ting. Therefore, for more sol ubl e anestheti cs, augmentati on of anesthetic del i very by
increasi ng minute venti l ati on also increases the rate of ri se i n F
A
/F
I
.
FIGURE 15-4. The concentrati on effect is demonstrated in the top hal f of the graph from
dogs recei vi ng ni trous oxi de. Admi ni strati on of 70% nitrous oxi de produces a more rapid ri se
in the F
A
/F
I
ratio of ni trous oxi de than admi ni strati on of 10% ni trous oxi de. The second gas
effect i s demonstrated i n the l ower graphs. The F
A
/F
I
ratio for 0.5% halothane ri ses more
rapi dl y when gi ven wi th 70% ni trous oxide than when gi ven wi th 10% ni trous oxi de. (Adapted
from Epstei n R, Rackow H, Sal ani tre E et al : Influence of the concentrati on effect on the
uptake of anestheti c mi xtures: The second gas effect. Anesthesi ol ogy 25:364, 1964.)
Spontaneous mi nute venti lation is not static, however, and to the extent that the inhaled
anesthetics depress spontaneous venti l ati on wi th increasi ng inspi red concentrati on,

A
wi ll decrease and so wil l the rate of ri se of F
A
/F
I
. Thi s i s demonstrated i n Fi gure 15-5. Thi s
negati ve feedback shoul d not be consi dered

a drawback of the i nhal ed anestheti cs, because the respi ratory depressi on produced at hi gh
anesthetic concentrati ons essenti al l y sl ows the ri se in F
A
/F
I
. Thi s mi ght arguabl y add a margi n of
safety i n preventi ng an overdose.
P er f usi on Ef f ect s
As with venti lation, cardiac output is not static duri ng the course of i nduction. For the i nsol uble
agents, changes i n cardi ac output do not affect the rate of rise of F
A
/F
I
to a great extent, but for
the more soluble agents the effect i s noticeabl e, as seen i n Fi gure 15-6. However, as i nspi red
concentration increases, greater cardi ovascul ar depression reduces anestheti c uptake and actual l y
increases the rate of rise of F
A
/F
I
. Thi s posi ti ve feedback can rapi dl y l ead to profound
cardi ovascul ar depressi on. Fi gure 15-6 presents experi mental data i n whi ch l ower cardi ac outputs
lead to a much more rapi d rise i n F
A
/F
I
when

A
is held constant. Thi s more rapid ri se i s greater than can be accounted for just by concentrati on
effect.
FIGURE 15-5. The F
A
/F
I
ratio rises more rapidl y if venti l ati on is i ncreased from 2 to 8 L/mi n.
Sol ubi l ity modi fi es thi s impact of venti l ati on; for exampl e, the effect i s greatest wi th the
least sol ubl e anestheti c, ni trous oxi de (top 3 l ines), and least with the more-solubl e
anesthetic, hal othane. (Adapted from Eger EI II: Ventil ati on, ci rculation and uptake. In Eger
EI II (ed): Anestheti c Uptake and Acti on, p 122. Bal ti more, Wil l iams & Wi lkins, 1974.)
P.393
Vent i l at i on P er f usi on Mi smat chi ng
Ventil ati on and perfusi on are normal ly fairl y wel l matched i n healthy pati ents such that P
A

(alveol ar partial pressure)/ P
I
and P
a
(arterial partial pressure)/ P
I
are the same curve. If
si gni fi cant intrapul monary shunt occurs, however, as in the case of i nadvertent bronchi al
intubati on, the rate of rise of al veol ar and arteri al anestheti c partial pressures can be affected.
The effects, however, depend on the sol ubi l i ty of the anestheti c, as seen i n Fi gure 15-7.
Ventil ati on of the intubated l ung i s dramaticall y i ncreased whil e perfusi on i ncreases sl ightl y. The
noni ntubated lung recei ves no ventil ati on, whi le perfusi on decreases sl ightl y. For the l ess-solubl e
anesthetics, i ncreased venti lation of the i ntubated l ung cannot appreci ably increase alveolar
parti al pressure relative to i nspi red concentrati on on that si de, but al veolar parti al pressure on
the noni ntubated si de i s essenti al l y zero. Pul monary mixed venous bl ood, therefore, comprises
nearl y equal parts blood containi ng normal amounts of anestheti c and bl ood containi ng no
anesthetic, that i s, dil uted relative to normal. Thus the rate of ri se in P
a
rel ati ve to P
I
is
si gni fi cantl y reduced. There i s l ess total anestheti c uptake, so the rate of ri se of P
A
rel ati ve to P
I

increases even though i nducti on of anesthesia is sl owed because CNS parti al pressure equil i brates
wi th P
a
. For the more sol ubl e anestheti cs, increased venti lation of the i ntubated l ung does
increase the al veolar partial pressure rel ati ve to inspi red concentrati on on that si de. Pul monary
venous bl ood from the i ntubated si de contai ns a higher concentration of anestheti c that l essens
the di l uti on by bl ood from the noni ntubated side. Thus the rate of ri se of P
a
/P
I
i s not as depressed
FIGURE 15-6. If ventilation is fixed, an increase in cardi ac output from 2 to 18 L/mi n wi ll
decrease the al veolar anestheti c concentration by augmenting uptake, thereby sl owi ng the
ri se of the F
A
/F
I
ratio. This effect i s most prominent wi th the more-solubl e anestheti cs
(hal othane) than wi th the l ess-solubl e anestheti cs (ni trous oxi de). (Adapted from Eger EI II:
Ventil ati on, ci rcul ati on and uptake. In Eger EI II (ed): Anestheti c Uptake and Acti on, p 131.
Bal timore, Wi ll i ams & Wil ki ns, 1974.)
as that for the l ess sol ubl e anestheti cs, and i nduction of anesthesi a is l ess del ayed.
El i mi nat i on
Percutaneous and Visceral Loss
Although the l oss of i nhal ed anestheti cs vi a the skin i s very smal l , i t does occur and is the
greatest for nitrous oxi de. These anesthetics al so pass across gastrointestinal viscera and the

pl eura. Duri ng open abdomi nal or thoracic surgery there i s some anesthetic l oss vi a these routes.
Rel ati ve to losses by al l other routes, l osses vi a percutaneous and vi sceral routes are
insi gni fi cant.
Diffusion between Tissues
Usi ng more el aborate mathemati cal modeli ng of inhal ed anestheti c pharmacoki netics than
presented here, several laboratori es have derived a fi ve-compartment model that best descri bes
ti ssue compartments. These compartments are the alveol i, the VRG, the muscl e, the fat, and one
addi ti onal compartment. Current opi nion is that thi s fifth compartment represents adi pose ti ssue
adjacent to l ean tissue that recei ves anestheti c via i nterti ssue diffusi on. This transfer of
anesthetic i s not i nsignificant, and may account for up to one-third of uptake duri ng long
FIGURE 15-7. When no venti lation/perfusion abnormal iti es exist, the alveol ar (P
A
) or end-
ti dal (P
ET
) and arteri al (P
a
) anesthetic parti al pressures ri se together (conti nuous l i nes)
toward the inspi red partial pressure (P
I
). When 50% of the cardiac output i s shunted through
the lungs, the rate of ri se of the end-ti dal parti al pressure (dashed l i ne) i s accelerated whil e
the rate of ri se of the arteri al parti al pressure (dot-dashed l i ne) i s slowed. The greatest
effect of shunting is found with the least sol ubl e anestheti cs. (Adapted from Eger EI II,
Severi nghaus JW: Effect of uneven pulmonary di stri buti on of bl ood and gas on induction wi th
inhalation anesthetics. Anesthesi ol ogy 25:620, 1964.)
P.394
administrati on.
Metabolism
Inhaled anesthetic bi otransformati on i s di scussed i n more depth elsewhere i n this chapter.
Metabol ism i s greatest for hal othane, up to 50% of loss. In fact, there i s evi dence that decreases
in the alveol ar concentrati ons of hal othane duri ng emergence outpace those for isofl urane,
presumabl y because of thi s si gni fi cant metaboli sm. Experimental l y, i t has been determined that
metaboli sm does not si gni fi cantl y affect recovery from i sofl urane.
Exhalation and Recovery
Recovery from anesthesi a, li ke i nducti on, depends on anestheti c sol ubi li ty, cardi ac output, and
mi nute ventil ati on. Solubi li ty i s the primary determi nant of the rate of fal l of F
A
(Fi g. 15-8). The
greater the sol ubi l ity of inhal ed anestheti c, the l arger the capaci ty for absorption in the
bl oodstream and ti ssues. The reservoi r of anesthetic i n the body at the end of admi nistrati on
depends on ti ssue sol ubi l i ty (whi ch determi nes the capaci ty) and the dose and durati on of
anesthetic (which determi ne how much of that capaci ty i s fi l l ed). Recovery from anesthesi a, or
washout, is usual l y expressed as the ratio of expi red fracti onal concentrati on of anesthetic (F
E
)
to the expi red concentration at ti me zero (F
E0
) when the anestheti c was disconti nued (or F
A
/F
A0
).
El iminati on curves of l ow and hi gh sol ubl e anestheti cs are shown i n Fi gure 15-9. The l onger the
duration of a hi ghl y soluble anesthetic, the greater the reservoir of anestheti c in the body, and
the hi gher the curve seen i n the right half of Fi gure 15-9. Thi s effect is nearly absent with l ow
solubl e agents such as nitrous oxi de, desfl urane, and sevofl urane.
3

FIGURE 15-8. El i mi nati on of anestheti c gases is defi ned as the rati o of end-ti dal anesthetic
concentration (F
A
) to the l ast F
A
during admi ni strati on and i mmedi atel y before the begi nni ng
of el i mi nation (F
AO
). During the 120-mi nute period after endi ng the anestheti c del i very, the
el i mi nation of sevofl urane and desflurane i s 2 to 2.5 ti mes faster than isoflurane or
halothane (note logari thmi c scal e for the ordinate). (Adapted from Yasuda N, Lockhart SH,
Eger EI II et al : Comparison of kineti cs of sevofl urane and isoflurane in humans. Anesth
Analg 72:316, 1991; and Yasuda N, Lockhart SH, Eger EI II et al : Ki neti cs of desfl urane,
isoflurane, and hal othane in humans. Anesthesi ology 74:489, 1991.)
There are two major pharmacoki netic di fferences between recovery and i nducti on. First, whereas
overpressurization can increase the speed of induction, there i s no under pressurizati on. Both
i nducti on and recovery rates depend on the P
A
to P
v
gradi ent, and P
A
can never fal l bel ow zero.
Second, whereas all ti ssues begin i nduction wi th zero anestheti c, each begi ns recovery with qui te
di fferent anesthetic concentrati ons. The VRG ti ssues begi n recovery wi th the same anesthetic
parti al pressure as that in alveol i, si nce P
CNS
= P
bl ood
= P
al veol i
. The parti al pressures i n muscle and
fat depend on the inspired concentrati on during anesthesi a, the durati on of admini stration, and
the anestheti c ti ssue sol ubi l iti es. As l ong as an arteri al -to-ti ssue partial pressure gradient exi sts,
these ti ssues wi l l absorb anestheti cespecial ly fat, si nce i t i s a huge potenti al reservoi r whose
anesthetic parti al pressures are typi cal ly l ow after hours of anesthesi a. After disconti nuati on of
anesthesia, muscle and fat may conti nue to absorb anestheti c, even hours l ater. The redi stributi on
conti nues until bl ood/al veol ar anestheti c partial

pressure fal l s bel ow ti ssue parti al pressure. Thi s redi stributi on causes the earl y rate of decli ne in
al veolar anestheti c concentration during recovery to exceed i ts i ncrease duri ng i nducti on.
Because VRG ti ssues are hi ghl y perfused and washout of anesthetic is mostly vi a eli mi nation from
these ti ssues earl y i n recovery, al l anestheti cs regardl ess of duration of admini stration, have
approxi mately the same rate of eli mi nation to 50% of F
E0
. Unfortunately, hal ving the CNS
concentration of anestheti c i s rarely sufficient for waking the pati ent. More commonl y, 80 to 90%
of inhaled anesthetic must be el iminated before emergence. At these amounts of washout, the
more sol uble anesthetics are eli mi nated more sl owly than l ess sol ubl e agents.
Diffusion Hypoxia
During recovery from anesthesi a, washout of hi gh concentrations of ni trous oxi de can lower
al veolar concentrations of oxygen and carbon dioxi de, a phenomenon cal l ed di ffusion hypoxi a. The
resul ti ng al veolar hypoxi a can cause hypoxemi a, and al veol ar hypocarbia can depress respi ratory
FIGURE 15-9. Both sol ubi l ity and durati on of anesthesi a affect the decrease of the al veol ar
concentration (F
A
) from i ts value i mmedi atel y preceding the cessati on of anesthetic
administrati on (F
AO
). A longer anestheti c time (from 15 mi nutes to 240 mi nutes) only sli ghtl y
sl ows the decrease with low soluble anestheti cs (left graph). An agent wi th a higher blood
and ti ssue sol ubi l ity (right graph) sl ows the el iminati on of the anestheti c and enhances the
effect of duration. (Adapted from Stoel ti ng RK, Eger EI II: The effects of venti l ati on and
anesthetic solubil i ty on recovery from anesthesia: An in vivo and anal og anal ysi s before and
after equi li brium. Anesthesi ol ogy 30:290, 1969.)
P.395
dri ve, whi ch may exacerbate hypoxemia. It i s therefore appropriate to i ni tiate recovery from
ni trous oxide anesthesia wi th 100% oxygen rather than less concentrated O
2
/air mixtures.
CLINICAL OVERVIEW OF CURRENT INHALED ANESTHETICS
Hal ot hane
Hal othane, a rel ati vel y nonfl ammable li qui d, i s the most potent of the currentl y used vol ati l e
anesthetics. It is an al kanea hal ogen-substi tuted ethane deri vative (see Fi g. 15-1)that was
pl aced into cl i ni cal use i n 1956. The hal ogenated structure provi ded nonfl ammabil i ty. It has an
intermedi ate bl ood sol ubi l ity and i s rel ati vely nonpungent; hence, i t can be inhal ed vi a the face
mask. The carbonfluori ne bond i s i mportant i n providi ng nonfl ammabi l ity of halothane at room
temperature and the tri fl uorocarbon group contributes to its mol ecular stabil i ty. Despite i ts
chemi cal stabil i ty, hal othane oxi di zes spontaneously and i s broken down by ul travi ol et li ght. It
decomposes to hydrochl ori c aci d (HCL), hydrobromic aci d (Hbr), chl ori de (CL
-
), bromi de (Br
-
), and
phosgene (COCl
2
). To prevent this decomposi ti on, halothane i s stored i n amber-col ored bottl es
and 0.01% thymol i s added as a preservative to prevent spontaneous oxi dati ve decompositi on.
The thymol preservati ve can gum up vapori zers, mandating a more di ffi cul t and more frequent
cl eaning schedul e than that for vaporizers speci fi c to other vol ati l e anestheti cs. Hal othane al so is
adsorbed by contact wi th dry soda l i me and broken down to BCDFE (2-bromo-2-chloro-1,1-
di fl uoroethene), whi ch has organ toxici ty i n ani mal model s. In humans, hal othane has been
associated wi th an i mmune-mediated hepati tis and a sensi ti zation to epi nephri ne resulti ng in
arrhythmi as. It al so has been associated wi th bradycardi a when used i n the pedi atri c popul ati on.
Enf l ur ane
Enflurane, a hal ogenated methyl ethyl ether, i s an i somer of isofl urane (see Fi g. 15-1). It i s a
nonflammable liquid at room temperature and i s pungent. Its use i n hi gh concentrations has been
associated wi th seizure-li ke acti vi ty on the EEG. Its metaboli sm has resul ted i n an i ncrease in
bl ood fluori de concentrati on and, rarel y, wi th a renal concentrati ng defi ciency. Its popul ari ty has
general ly been reserved owi ng to competi ti on from i sofl uranethe near-si multaneously i ntroduced
vol ati l e anestheti c, whi ch has few side effectsand more recently, the i ntroduction of new
anesthetics wi th l ower solubi li ties.
I sof l ur ane
Isoflurane, a halogenated methyl ethyl ether, i s a cl ear, nonfl ammabl e l iqui d at room temperature
and has a hi gh degree of pungency (see Fi g. 15-1). The second most potent of the volatil e
anesthetics i n cl ini cal use, i sofl urane has great physi cal stabi l ity and undergoes essential ly no
deteri orati on duri ng storage for up to 5 years or on exposure to sunl i ght. It has become the gol d
standard anestheti c since its introducti on i n the 1970s. There has been a bri ef period of
controversy concerni ng the use of i sofl urane i n patients wi th coronary di sease because of the
possi bi li ty for coronary steal , arisi ng from the potent effects of isofl urane on coronary
vasodil ati on. In cl i ni cal use, however, this has been, at most, a rare occurrence.
Desf l ur ane
Desfl urane i s a fl uori nated methyl ethyl ether that differs from isofl urane by just one atom: a
fl uori ne atom i s substi tuted for a chl orine atom on the -ethyl component of isofl urane (see Fi g.
15-1). The process of compl etel y fl uori nati ng the ether molecul e has several effects. It decreases
bl ood and ti ssue sol ubi l ity (the bl ood:gas sol ubi l i ty of desfl urane equal s that of

ni trous oxide), and i t results in a l oss of potency (the MAC of desflurane is fi ve ti mes higher than
isoflurane). Moreover, the complete fl uori nati on of the methyl ether mol ecul e resul ts in a hi gh
vapor pressure (owi ng to decreased i ntermol ecul ar attraction). Thus, a new vapori zer technol ogy
has been devel oped to del i ver a regulated concentrati on of desflurane as a gas. A heated,
pressuri zed vapori zer requi ri ng electrical power and more frequent servi ci ng i s required. One of
P.396
the advantages of desflurane i s the near-absent metabol ism to serum trifluoroacetate. Thi s makes
immune-mediated hepati tis extremely unl ikel y. Desflurane is the most pungent of the vol ati le
anesthetics and cannot be admi ni stered vi a the face mask as i t resul ts in coughi ng, sali vation,
breath hol di ng, and l aryngospasm. In extremel y dry CO
2
absorbers, desfl urane (and to a l esser
extent isoflurane, enfl urane, and sevofl urane) degrades to form carbon monoxi de. Desfl urane has
the lowest blood:gas sol ubi li ty of the potent vol atil e anestheti cs; moreover, i ts fat solubi li ty i s
roughl y half of that of the other vol ati le anesthetics. Thus, desflurane offers a theoreti cal
advantage in l ong surgical procedures by vi rtue of decreased ti ssue saturation. Desflurane has
been associ ated wi th tachycardi a, hypertension, and, i n sel ect cases, myocardi al i schemi a when
used in high concentrati ons or rapi dly i ncreasi ng the i nspired concentrati on (wi thout usi ng opi oid
adjuvants to prevent such a response).
Sevof l ur ane
Sevoflurane i s a sweet-smel l i ng, compl etel y fluorinated methyl isopropyl ether (see Fi g. 15-1). Its
vapor pressure is most simi lar to that of enflurane and it can be used in a conventi onal vaporizer.
The bl ood:gas sol ubi l i ty of sevofl urane i s second onl y to desflurane in terms of potent vol ati le
anesthetics. Sevofl urane i s approximatel y hal f as potent as isofl urane, and some of the
preservation of potency, despi te fl uori nation, is because of the bul ky propyl si de chai n on the
ether mol ecule. Sevofl urane has mi ni mal odor, no pungency, and i s a potent bronchodi lator. These
attri butes make sevoflurane an excell ent candi date for administrati on via the face mask on
inducti on of anesthesia i n both chil dren and adul ts. Sevofl urane is hal f as potent a coronary
vasodil ator as i sofl urane, but is 10 to 20 ti mes more vul nerable to metabol ism than i sofl urane.
Like that of enfl urane and methoxyflurane, the metabol ism of sevofl urane results i n i norganic
fl uori de; the i ncrease i n pl asma fl uoride after sevofl urane admi ni strati on has not been associ ated
with renal concentrati ng defects, as is the case with methoxyflurane. Unli ke other potent vol ati le
anesthetics, sevoflurane is not metabol i zed to tri fl uoroacetate; rather, i t i s metaboli zed to an acyl
hali de (hexafl uoroisopropanol ). Thi s does not stimul ate formati on of anti bodi es, and immune-
medi ated hepati ti s has not been reported wi th sevofl urane. Sevoflurane can form carbon monoxi de
during exposure to dry CO
2
absorbents and an exothermi c reacti on i n dry absorbent has resul ted
in canister fires. Sevoflurane breaks down in the presence of the carbon dioxi de absorber to form
a vinyl hal i de cal l ed compound A. Compound A has been shown to be a dose-dependent
nephrotoxi n i n rats, but has not been associ ated with renal i njury i n human volunteers or patients,
with or wi thout renal impai rment, even when fresh gas fl ows are 1 L/mi n or less.
Xenon
Xenon i s an i nert gas. Di fficul t to obtai n, and hence extremel y expensi ve, i t has received
consi derable i nterest i n the last few years because it has many characteri sti cs approaching those
of an ideal inhaled anestheti c.
5, 6
Its bl ood:gas parti ti on coeffici ent i s 0.14, and unli ke the other
potent volatil e anestheti cs (except methoxyflurane), xenon provi des some degree of anal gesi a.
Unfortunatel y, the MAC i n humans i s 71%, whi ch mi ght prove to be a l imitati on. It i s
nonexpl osi ve, nonpungent, and odorl ess, and thus can be inhaled with ease. In addi ti on, i t does
not produce si gni fi cant myocardi al depressi on.
5
Because of its scarci ty and high cost, new
anesthetic systems need to be devel oped to provi de for recycl i ng of xenon. If thi s proves to be too
difficult from either a techni cal or pati ent safety standpoint, i t may be necessary to use it i n a
very low, or closed, fresh gas flow system to reduce wastage.
Ni t r ous Oxi de
Ni trous oxi de is a sweet-smel l i ng, nonfl ammable gas of l ow potency (MAC = 104%) and i s
rel ati vely i nsol ubl e i n blood. It i s most commonly admini stered as an anesthetic adjuvant in
combi nation with opi oids or vol ati l e anestheti cs duri ng the conduct of general anesthesi a.
Although not fl ammabl e, ni trous oxi de wi ll support combustion. Unli ke the potent vol atil e
anesthetics i n cl i ni cal use, ni trous oxide does not produce significant skel etal muscl e rel axati on,
but i t does have documented anal gesi c effects. Despi te a l ong track record of use, controversy has
surrounded nitrous oxi de i n four areas: i ts rol e in postoperati ve nausea and vomi ti ng, its potenti al
toxi c effects on cel l functi on vi a i nacti vati on of vitami n B
12
, i ts adverse effects rel ated to
absorpti on and expansi on i nto air-fi l l ed structures and bubbl es, and l ast, its effect on embryoni c
development. The one concern that seems most val i d and most cl inicall y rel evant i s the abi l ity of
ni trous oxide to expand ai r-fil l ed spaces because of i ts greater sol ubi l i ty i n bl ood compared to
ni trogen. Several cl osed gas spaces such as the bowel and mi ddl e ear exi st i n the body and other
spaces may occur as a resul t of disease or surgery such as a pneumothorax. The ni trogen cannot
be removed readi l y vi a the bl oodstream. Unfortunatel y, ni trous oxide del i vered to a pati ent
diffuses from the blood into these cl osed gas spaces qui te easil y such that the spaces must
i ncrease pressure and potenti all y expand. Movement of ni trous oxide into these spaces conti nues
unti l the partial pressure equals that of the bl ood and al veol i . Compl i ant spaces wil l conti nue to
expand unti l suffici ent pressure i s generated to oppose further N
2
O fl ow into the space. The higher
the inspired concentrati on of ni trous oxi de, the hi gher the parti al pressure requi red for
equil i bration.
Seventy-five percent N
2
O can expand a pneumothorax to double or tri ple its size in 10 and 30
mi nutes, respecti vel y. Air-fil l ed cuffs of pul monary artery catheters and endotracheal tubes al so
expand wi th the use of N
2
O, possi bl y causi ng ti ssue damage vi a i ncreased pressure i n the
pul monary artery or trachea, respecti vely.
6, 7
In a rabbi t model , the vol ume of an ai r embol us
resul ti ng in cardi ovascul ar compromi se i s l ess duri ng coadmini stration of ni trous oxi de.
8

Accumul ati on of nitrous oxi de i n the mi ddle ear can dimi ni sh heari ng postoperati vel y
9
and i s
rel ati vely contrai ndicated for tympanoplasty because the increased pressure can disl odge a
tympani c graft.
NEUROPHARMACOLOGY OF INHALED ANESTHETICS
The i nhal ed anestheti cs establ i sh the anestheti c state by effects on spontaneous neuronal acti vi ty
and metabol ism. The exact anesthetic mechani sms of i nhal ed agents remain poorl y understood
and the associ ated nervous system effects may i n part be medi ated by these undetermi ned
mechani sms. Therefore as a whol e, the current understandi ng of inhal ed anestheti c
neuropharmacol ogy tends to be more descripti ve than mechani sti c in nature.
The mechanisms of anesthesia are el usi ve partl y because there i s no uniform definiti on of when
the brai n i s anestheti zed;

however, a useful defi niti on may be a brai n that i s i ncapabl e of sel f-awareness or subsequent
recal l . Thi s defi ni tion i s hel pful conceptual l y, but from a practi cal standpoint i t i s di ffi cul t to know
when the brai n is no l onger sel f-aware or wi l l have no recal l, and to know the dose of i nhal ed
anesthetic at that poi nt. The abi l ity to determi ne, establ i sh, and mai ntai n thi s level of anesthesia
is part of the art of anesthesia. It depends on the i ntegrati on of knowl edge of i nhal ed anestheti c
pharmacokineti cs and pharmacodynamics, di rect observati on of the pati ent, and interpretati on of
data from a compl ex array of monitors. Wi th the recent advent of the processed
el ectroencephal ogram (EEG) moni tor, the fi rst, albei t crude, index of anestheti c depth via
conti nuous real -ti me anal ysis of the pati ent' s EEG mi ght provi de rel evant i nformati on. The util i ty
of this devi ce remai ns controversi al, and i t is l i kel y that rel evant i nformati on might need tai l oring
to each anestheti c regi men.
P.397
Mi ni mum Al veol ar Concent r at i on
The pharmacodynami c effects of i nhal ed anestheti cs must be based on a dose, and thi s dose
is the mi ni mum al veolar concentrati on or MAC. MAC i s the al veol ar concentrati on of an
anesthetic at one atmosphere that prevents movement i n response to a surgi cal sti mulus i n 50%
of patients. It i s anal ogous to the ED
50
expressed for i ntravenous drugs. A variety of surgi cal
stimul i have been used to establ i sh the MAC for each i nhal ed anestheti c, but the cl assi c, defi ni ng,
noxious stimul us i s i ncisi on of the abdomen. Likewise, skeletal muscle movement i s the defi ni ng
patient response, but other responses have been used to establ i sh MAC as wel l . Experi mentall y
determined MAC values for humans for the inhaled anesthetics are shown i n Tabl e 15-1.
The 95% confi dence ranges for MAC are approximately 25% of the li sted MAC val ues.
Manufacturer's recommendati ons and cl inical experience establi sh 1.2 to 1.3 times MAC as a dose
that consi stentl y prevents pati ent movement during surgical stimul i . Loss of consci ousness
typi cal l y precedes the absence of stimul us-induced movement by a wide margin. While 1.2 to 1.3
MAC values do not absol utel y ensure the defi ni ng cri teri a for brain anesthesi a (the absence of
sel f-awareness and recal l ), vast cl inical experi ence suggests i t i s extremel y unl i kely for a patient
to be aware of, or to recal l the surgi cal i ncisi on at these anestheti c concentrati ons unless other
condi ti ons exi st such that MAC i s increased i n that patient (Tabl e 15-4).
Concentrati ons of i nhal ed anestheti cs that provi de l oss of sel f-awareness and recal l are about 0.4
to 0.5 MAC. Several l ines of reasoni ng lead to this conclusi on. Fi rst, most pati ents recei vi ng onl y
50% ni trous oxide (approxi mately 0.4 to 0.5 MAC) as i n a typi cal denti st' s offi ce wi ll have no
recal l of thei r procedure duri ng N
2
O admi ni strati on. Second, various studi es have shown that a
shift i n EEG dominance to the anteri or l eads, that i s, the shi ft from self-aware to nonsel f-aware,
accompani es l oss of consci ousness, and i n pri mates, the EEG shi ft and loss of consciousness occur
at 0.5 MAC.
10
Thi rd, in dogs, loss of consciousness accompani es a sudden nonli near fall i n cerebral
metaboli c rate (CMR) at approxi matel y 0.5 MAC (Fi g. 15-10).
TABLE 15-4 Factors That Increase MAC
Increased central neurotransmi tter level s (monoamine oxi dase inhi bi tors, acute
dextroamphetami ne admini stration, cocai ne, ephedri ne, l evodopa)
Hyperthermi a
Chronic ethanol abuse (determined i n humans)
Hypernatremi a
MAC val ues can be establi shed for any measurable response. MAC-awake, or the alveol ar
concentration of anestheti c at which a pati ent opens hi s or her eyes to command, varies from 0.15
to 0.5 MAC.
11
Interesti ngl y, transi tion from awake to unconscious and back typi cal l y shows some
hysteresis, i n that i t qui te consi stentl y takes 0.4 to 0.5 MAC to l ose consci ousness, but l ess than
that (as low as 0.15 MAC) to regain consci ousness. Thi s may be because of the speed of al veolar
washin versus washout.
12
MAC-BAR, or the alveol ar concentrati on of anestheti c that blunts
adrenergi c responses to noxi ous sti muli , has l i kewi se been establ ished and is approxi mately 50%
higher than standard MAC.
13
MAC al so has been establ i shed for di screet l evel s of EEG acti vi ty,
such as onset of burst suppression or i soelectri ci ty.
Standard MAC val ues are roughl y addi ti ve. Admi ni stering 0.5 MAC of a potent agent and 0.5 MAC
of ni trous oxide i s equi val ent to 1 MAC of potent agent in terms of preventi ng patient movement,
al though this does not hold over the enti re range of N
2
O doses. MAC effects for other response
parameters are not necessari ly additi ve. Because MAC-movement probabl y di ffers from MAC for
vari ous secondary si de effects (such hypothetical si tuati ons as MAC-dysrhythmi a, MAC-
hypotensi on, or MAC-tachycardi a, etc.), combi nations of a potent agent and ni trous oxi de may
decrease or i ncrease these secondary effects relati ve to potent agent al one. For exampl e,
combi ni ng 0.6 MAC of ni trous oxi de with 0.6 MAC of i sofl urane produces less hypotensi on than 1.2
MAC of i sofl urane alone because i sofl urane i s a more potent vasodi l ator and myocardial depressant
at equi val ent MAC than N
2
O.
FIGURE 15-10. The effects of hal othane on CMRO
2
as a percentage of control (awake).
CMRO
2
i s pl otted versus end-ti dal i soflurane concentration. Regressi on l i nes for changes i n
CMRO
2
are drawn for each EEG determi ned area. The pattern depi cted here is characteri sti c
of al l of the anestheti cs exami ned (enfl urane, hal othane, and i sofl urane). (Adapted from
Stull ken EH Jr, Mi l de JH, Mi chenfel der JD et al : The non-li near responses of cerebral
metaboli sm to low concentrations of hal othane, enfl urane, i sofl urane and thi opental .
TABLE 15-5 Factors That Decrease MAC
Increasi ng age
Metabol ic acidosis
Hypoxi a (PaO
2
, 38 mm Hg)
Various factors increase (Tabl e 15-4) or decrease (Tabl e 15-5) MAC. Unfortunatel y, no si ngl e
mechani sm expl ai ns these al terati ons in MAC, supporti ng the vi ew that anesthesi a is the net resul t
of numerous and wi del y varyi ng physi ol ogic al terati ons. In general , those factors that i ncrease
CNS metabol ic acti vi ty and neurotransmi ssi on, i ncrease CNS neurotransmi tter l evels, and
upregulation of CNS responses to chroni cal l y depressed neurotransmi tter l evels (as i n chronic
al cohol ism) al so seem to increase MAC. Conversely, those factors that

decrease CNS metabol i c activi ty and neurotransmi ssi on, decrease CNS neurotransmi tter level s,
and downregul ati on of CNS responses to chronicall y elevated neurotransmi tter level s seem to
decrease MAC. Many notabl e factors do not alter MAC, i ncl udi ng duration of inhal ed anestheti c
administrati on, gender, type of surgi cal stimul ati on, thyroid functi on, hypo- or hypercarbia,
metaboli c alkal osi s, hyperkalemia, and magnesium level s. However, there may be a geneti c
component i nfluenci ng MAC. Redheaded femal es have a 19% increase i n MAC compared to dark-
hai red femal es.
14
These data suggest i nvol vement of mutations of the MCIR al l ele. Variants of the
MCIR al l ele al so have been i mpl i cated in alteri ng anal gesic responses to a opi oi d.
15
MAC al so can
vary i n rel ati onshi p to genotype and chromosomal substi tutions as shown in rats.
16

The Effect of Age on MAC
The MAC for each of the potent anestheti c gases shows a cl ear, age-rel ated change (Fi g. 15-11).
MAC decreases wi th age and there are simil ari ties between agents i n the decl ine i n MAC and age.
Excl udi ng data i n pati ents less than 1 year of age (where MAC can be lower
17
), there i s a li near
model that descri bes the decrease i n MAC wi th i ncreasi ng age.
18
The sl ope of thi s model i s: MAC =
a(10
bx
), where x is the di fference i n age i n years from 40, b is .00269, and a is the MAC at
age 40. Thi s equati on defi nes a change i n MAC of approxi matel y 6% per decade, a 22% decrease
Induced hypotensi on (MAP <50 mmHg)
Decreased central neurotransmi tter level s (al pha-methyl dopa, reserpi ne, chroni c
dextroamphetami ne administrati on, l evodopa)
Al pha-2 agoni sts
Hypothermia
Hyponatremi a
Li thi um
Hypoosmol al i ty
Pregnancy
Acute ethanol admi ni strati on
a

Ketamine
Pancuroni um
a

Physostigmi ne (10 ti mes cl ini cal dose)
Neosti gmi ne (10 times cl i ni cal dose)
Li docai ne
Opi oi ds
Opi oi d agoni stantagonist analgesi cs
Barbiturates
a

Chl orpromazi ne
a

Diazepam
a

Hydroxyzine
a

-9-Tetrahydrocannabi nol
Verapami l
Anemi a (<4.3 mL O
2
/dL bl ood)
a
Determi ned i n humans.
P.398
in MAC from age 40 to age 80, and a 27% decrease in MAC from age 1 to 40 years. MAC is
typi cal l y expressed for an i ntermedi ate age (40 years), and these are:
Hal othane 0.75%
Isoflurane 1.17%
Enflurane 1.63%
Sevoflurane 1.80%
Desfl urane 6.60%
Ni trous Oxi de 104.00%
Ot her Al t er at i ons i n Neur ophysi ol ogy
The four, current, wi dely used, potent agents, hal othane, isofl urane, desflurane, and sevoflurane,
al l have reasonably si mil ar effects on a wi de range of parameters incl udi ng cerebral metabol ic
rate, the EEG, cerebral blood fl ow (CBF), and fl owmetaboli sm coupl ing. There are notable
di fferences i n effects on intracerebral pressure, cerebrospi nal fl ui d producti on and resorption, CO
2

vasoreactivity, CBF autoregul ati on, and cerebral protection. Ni trous oxi de departs from the potent
agents i n several i mportant respects, and i s therefore di scussed separately.
Cerebral Metabolic Rate and Electroencephalogram
Al l of the potent agents depress cerebral metabol i c rate (CMR) to varyi ng degrees i n a nonli near
fashi on. In i sofl urane-anesthetized dogs, there i s a sudden decrease i n CMRO
2
paral l el i ng a
change in the EEG from an awake to anestheti zed pattern at about 0.4 to 0.6 MAC as seen i n
Fi gure 15-10.
19
For most of the potent agents, CMR i s decreased onl y to the extent that
spontaneous corti cal neuronal activity (as refl ected i n the EEG) i s decreased. Once spontaneous
FIGURE 15-11. Effect of age on MAC. Regressi on l i nes are fi tted to publ i shed val ues from
separate studi es. Data are from patients ages 1 to 80 years. (Adapted from Mapl eson WW:
Effect of age on MAC i n humans: A meta-anal ysi s. Br J Anaesth 76:179, 1996.)
corti cal neuronal activity i s absent (an isoel ectric EEG), no further decreases in CMR are
generated. Halothane i s the excepti on. Hal othane causes a 20 to 30% decrease i n CMR at normal
cl i ni cal concentrati ons, and at 4.5% produces an isoelectri c EEG. Further i ncreases i n inspi red
concentration cause further decreases in CMRO
2
. Thi s further depressi on of CMRO
2
is because of
toxi c effects on oxi dati ve phosphorylation. Toxic effects begin at concentrati ons as l ow as 2.3%,
at which poi nt brai n l actate concentrati ons increase, but thi s dose i s typi cal l y wel l above those
used cl i ni cal l y for hal othane.
Isoflurane causes a larger MAC-dependent depressi on of CMR than hal othane, and does not
depress CMRO
2
once an i soelectri c EEG is produced.
20
Because of this greater depressi on i n
neuronal acti vi ty, i sofl urane abol i shes EEG activi ty at doses used cli nicall y and can usual l y be
tol erated from a hemodynami c standpoi nt.
38
Desflurane and sevoflurane both cause decreases i n
CMR si mil ar to isofl urane.
21, 22
Interesti ngl y,

whi l e both desfl urane and sevofl urane depress the EEG and abol i sh activity at cl inicall y tolerated
doses of approximatel y 2 MAC,
21, 22
in dogs desflurane-induced i soelectri c EEG reverts to
conti nuous acti vi ty wi th ti me despi te an unchangi ng MAC, a property unique to desfl urane.
21

Sevoflurane at i soelectri c EEG concentrations i n cats is not associ ated with a reversion to
conti nuous EEG activi ty, al though species di fferences coul d account for the di fferi ng resul ts.
23
The
reversi on from an isoel ectri c to a conti nuous EEG does not occur in desfl urane anestheti zed
swi ne
24
and there are no case reports of this phenomenon in humans.

Potential for cerebral toxi ci ty has been studi ed for sevoflurane as compared to hal othane. At
normal CO
2
and bl ood pressure no evi dence of sevoflurane toxi ci ty exi sts.
25
With extreme
hyperventi lation to decrease cerebral bl ood fl ow by hal f, brai n l actate l evels increase, but
si gni fi cantl y less than wi th hal othane. There are confl i cti ng data as to whether sevoflurane has a
proconvul sant effect.
22, 23, 26
Hi gh, l ong-lasti ng concentrations of sevofl urane (1.5 to 2.0 MAC), a
sudden increase i n cerebral sevoflurane concentrati ons, and hypocapni a can tri gger EEG
abnormali ties that often are associ ated with increases i n heart rate in both adults and
chil dren.
27, 28
Thi s has rai sed the questi on as to the appropri ateness of sevofl urane i n pati ents with
epi l epsy.
29

Cerebral Blood Flow, FlowMetabolism Coupling, and
Autoregulation
Al l of the potent agents i ncrease CBF i n a dose-dependent manner. Hal othane i s a very
potent cerebral vasodi lator
30
and causes the greatest increase i n CBF per MAC-mul tipl e.
Because of thi s, hal othane is rarel y used i n neurosurgery today, even though i t was the domi nant
anesthetic for these cases unti l the earl y 1970s. Despi te causi ng the greatest i ncrease i n CBF, the
vasodil ati ng effects of hal othane are blunted by hyperventi l ati ng subjects to a PaCO
2
of 25 mm Hg
pri or to or simul taneous to the admi ni strati on of hal othane.
31

Isoflurane, sevofl urane, and desfl urane cause far l ess cerebral vasodi lation per MAC-mul tipl e than
halothane (Fi g. 15-12).
30, 32, 33
In human studi es, isofl urane produces insignificant or no changes in
CBF.
34
Desflurane and sevoflurane both i nfluence CBF in a fashion si mi l ar to isofl urane.
21, 22
Al l of
these i nhal ed anestheti c agents affect CBF in a time-dependent as well as dose-dependent
manner. In animal s, an i ni ti al dose-dependent i ncrease in CBF wi th hal othane and i sofl urane
administrati on recovers to preinducti on l evel s approximatel y 2 to 5 hours after i nducti on. The
mechani sm of thi s recovery is uncl ear.
P.399
The i ncrease in CBF wi th i ncreasing dose caused by the potent agents occurs despite decreases i n
CMR. Thi s phenomenon has been cal led uncoupl ing, but from a mechani sti c standpoint, true
uncoupl ing of fl ow from metabol ism may not occur. That is, as CMR is depressed by the vol ati l e
anesthetics there sti ll i s a coupl ed decli ne in CBF opposed by a coi nci dent direct vasodil atory
effect on the cerebral bl ood vessel s. The net effect on the cerebral vessel s depends on the sum of
i ndi rect vasoconstri cti ng and direct vasodi lating i nfl uences.
Thi s vi ew i s supported by several facts. First, at l ow doses, both hal othane (<0.375%) and
isoflurane (0.5%) can actual ly decrease CBF.
35, 36
Thi s li kel y refl ects i ntact coupl i ng of CBF to CMR
with the depression in neuronal activity and metaboli sm causi ng a coupl ed decl i ne i n perfusi on. At
hi gher doses, i ncreases i n CBF occur presumabl y because di rect vasodi l ati on at these doses
outwei ghs i ndi rect vasoconstriction. Second, if CMR is maximally or near maximally depressed
with a barbiturate, halothane and i soflurane produce si mil ar i ncreases in CBF.
37
Thi s is consistent
wi th the greater depressi on of CMR seen with i sofl urane. From a starti ng poi nt of normal CMR,
isoflurane causes a greater dose-dependent decrease i n CMR resul ti ng i n greater i ndi rect
vasoconstri cti on and l ess vasodil ati on. When CMR is maximal l y depressed prior to i sofl urane or
halothane admi ni strati on, no further indi rect vasoconstri cti on i s possibl e, and the two agents
di l ate cerebral vessel s to a si mi l ar extent. Thi rd, CBF to CMRO
2
ratios are the same for many
vol ati l e anestheti cs at equi valent MAC, and increase wi th increasi ng dose i n a si mi lar fashi on.
38

Fi nal ly, regi onal CBFCMR rel ati onshi ps are arguabl y a better i ndi cator of coupl i ng than the gl obal
CBF to CMR ratio, and both i soflurane and halothane show strong coupli ng between decreases i n
CMR and CBF in indivi dual brai n regi ons.
39

Autoregul ati on i s the intri nsi c myogeni c regulati on of vascul ar tone. In normal brain, the
mechani sms of autoregul ation of CBF over a range of mean arterial pressures from 50 to 150 mm
Hg are i ncompl etel y understood. Because the volatil e anestheti cs are di rect vasodil ators, al l are
consi dered to dimi ni sh autoregul ati on i n a dose-dependent fashi on such that at hi gh anestheti c
doses CBF i s essenti al l y pressure-passi ve. Sevoflurane preserves autoregul ati on up to
approxi mately 1 MAC.
22
At 1.5 MAC, the dynamic rate of autoregul ati on (change i n mi ddl e cerebral
FIGURE 15-12. Cerebral bl ood fl ow (and vel ocity) measured i n the presence of normocapni a
and in the absence of surgi cal stimul ati on i n vol unteers receiving hal othane or i sofl urane. At
li ght l evel s of anesthesi a, halothane (but not i sofl urane) increased cerebral blood fl ow. At 1.6
MAC i sofl urane also i ncreased cerebral blood flow. (Adapted from Eger, E. I. II. Isoflurane
(Forane): A compendium and reference. Madison, Ohi o Medi cal Products.) Cerebral blood flow
vel oci ty measured before and duri ng sevofl urane and desfl urane anesthesi a up to 1.5 MAC
showed no change in CBFV. (Adapted from Bedforth NM, Hardman JG, Nathanson MH:
Cerebral hemodynami c response to the i ntroducti on of desflurane: A compari son wi th
sevofl urane. Anesth Analg 91:152, 2000.)
artery bl ood fl ow to a rapi d change i n bl ood pressure [BP]) i s better preserved with sevofl urane
than isofl urane (Fi g. 15-13). Thi s may be a result of l ess of a direct vasodil ator effect of
sevofl urane, preservi ng the abi li ty of the vessel to respond to changes i n BP at 1.5 MAC. Based on
a si mi l ar model but a separate study of dynami c autoregulation of cerebral bl ood fl ow, 0.5 MAC
desfl urane reduced autoregul ati on and isofl urane did not. At 1.5 MAC, both anestheti cs
substanti al l y reduced autoregul ati on (see Fi g. 15-13).
Intracerebral Pressure
Probabl y the area of greatest cl i ni cal i nterest to the anesthesi ol ogi st is the effect of vol ati l e
anesthesia on intracerebral pressure (ICP). In general , ICP wi l l increase or decrease i n proporti on
to changes i n CBF. Hal othane i ncreases ICP to the greatest extent, refl ecting i ts effects on CBF
that are the largest of the potent agents.
52
In fact, brain protrusion duri ng crani otomy is greater
with hal othane than isofl urane, consi stent with the greater i ncrease i n ICP by halothane.
40
At
concentrations above 0.5 MAC, hal othane has the propensi ty to increase

CBF and ICP. Thi s effect, i n associ ati on wi th a bl ood pressure decrease, may cause profound
decreases in cerebral perfusion pressure. Prei nduction hyperventi lation and hyperventi l ati on wi th
inducti on bl unt the i ncreases i n ICP seen wi th hal othane admi ni stration.
52
Barbi turate
coadmini stration li kewi se bl unts or prevents hal othane-induced i ncreases i n ICP.
In contrast to hal othane, i sofl urane i ncreases ICP mi ni mal ly in ani mals both wi th and wi thout
brain pathol ogy, i ncl udi ng those wi th an al ready elevated ICP.
51
In human studi es there usuall y
are mi l d i ncreases i n ICP wi th i sofl urane admi ni strati on that, as wi th hal othane, are blocked or
bl unted by hyperventi l ati on or barbiturate coadmi ni strati on.
41
There are some contradi ctory data,
however. In one human study, hypocapni a did not prevent elevations i n ICP wi th i sofl urane
administrati on i n pati ents wi th space-occupyi ng brain l esi ons.
42
Nonethel ess, the i ncrease in ICP i s
far l ess for i sofl urane than for hal othane. Furthermore, any i soflurane-induced i ncreases i n ICP
tend to be of short duration, in one study onl y 30 minutes,
43
as opposed to hal othane i n whi ch ICP
increases may l ast for hours.
FIGURE 15-13. Dynamic rate of autoregul ation (dRoR) during awake (or fentanyl and N
2
O
baseli ne), 0.5, and 1.5 mi nimum al veolar anestheti c concentration (MAC) anesthesi a. Val ues
are mean SD (SE for i so/des). * p<0.05 versus basel ine, ** p<0.001 versus basel ine and
sevofl urane. (Data from Summors AC, Gupta AK, Matta BF: Dynami c cerebral autoregulation
duri ng sevofl urane anesthesia: A compari son with isofl urane. Anesth Anal g 88:341, 1999;
and Strebel S, Lam A, Matta B et al : Dynamic and stati c cerebral autoregul ation during
isoflurane, desfl urane, and propofol anesthesia. Anesthesi ol ogy 83:66, 1995.)
P.400
Like isofl urane, both sevofl urane and desfl urane above 1 MAC produce mil d i ncreases i n ICP,
paral l el i ng their mi l d i ncreases i n CBF.
21, 22, 44, 45
One potenti al advantage of sevofl urane i s that i ts
lower pungency and ai rway irritati on may lessen the ri sk of coughi ng and bucki ng and the
associated ri se in ICP as compared to desfl urane or i sofl urane. In fact, i ntroducti on of desflurane
after propofol i nducti on of anesthesi a has led to signi ficant increases i n HR, MAP, and mi ddl e
cerebral artery bl ood fl ow veloci ty that were not noted i n pati ents given sevofl urane.
54
Thi s may
rel ate to the ai rway i rritant effects of desfl urane rather than a specific al terati on i n
neurophysiol ogy. However, several studi es i n both chi l dren and adults suggest that i ncreases i n
ICP from desfl urane are sl i ghtly greater than from either i sofl urane or sevofl urane.
46, 47
The
bottom li ne is that al l four potent agents may be used at appropri ate doses, especi al l y wi th
adjuncti ve and compensatory therapi es, i n just about any neurosurgi cal procedure. However,
patients with traumati c head i njuries, elevated ICP, or space-occupyi ng brain l esi ons are probabl y
better served wi th isofl urane, sevoflurane, and possibl y desfl urane than halothane.
Cerebrospinal Fluid Production and Resorption
Studies i ndi cate that 1 MAC hal othane decreases cerebrospinal fluid (CSF) producti on but
increases resi stance to resorpti on, the net effect bei ng an increase i n CSF vol ume.
63
Isofl urane
does not appear to alter CSF producti on,
43
but may increase, decrease, or l eave unchanged the
resi stance to resorpti on dependi ng on dose. Sevofl urane at 1 MAC depresses CSF producti on up to
40%.
48
Desflurane at 1 MAC leaves CSF producti on unchanged or i ncreased.
47, 49
In general ,
anesthetic effects on ICP via changes in CSF dynami cs are cl i ni cal l y far l ess i mportant than
anesthetic effects on CBF.
Cerebral Blood Flow Response to Hyper- and Hypocarbia
Significant hypercapnia i s associ ated wi th dramati c i ncreases i n CBF whether volatil e anestheti cs
are admini stered or not. As discussed earli er, hypocapnia can bl unt or abol i sh vol ati le anesthetic-
i nduced i ncreases i n CBF dependi ng on when the hypocapni a i s produced. Thi s vasoreacti vi ty to
CO
2
may be somewhat al tered by the vol ati l e anestheti cs as compared to normal. Nei ther
isoflurane nor hal othane abol ish hypocapni c vasoconstri cti on, and at least two studies suggest
that hal othane actuall y enhances CO
2
reacti vi ty.
32, 50
CO
2
vasoreacti vi ty under desfl urane
anesthesia i s normal up to 1.5 MAC,
51
and CO
2
vasoreacti vi ty for sevofl urane i s preserved at 1
MAC.
52

Cerebral Protection
Because al l of the potent agents si gni fi cantl y depress CMR, one mi ght reason that they al l coul d
offer some degree of neuroprotecti on. Unfortunately, thi s is not the case. In hal othane
anesthetized dogs, focal ischemia caused by mi ddl e cerebral artery occlusion led to larger i nfarct
si ze and worse neurol ogi cal outcome than for awake animal s.
53
Fortunatel y the wel l -known
neuroprotecti ve effects of pentobarbi tal are preserved with hal othane si nce pentobarbital
coadmini stration mi ni mi zed the pathol ogi cal and functional damage.
54

In comparison, i soflurane may provi de neuroprotecti ve effects in both mi ce and dogs duri ng
hypoxemi a or i schemi a.
55, 56
In one study, cerebral hypoperfusi on secondary to hypotension from
isoflurane was associ ated wi th better tissue oxygen content than duri ng hypotensi on by other
means, consi stent with the profound decrease i n CMRO
2
seen wi th isofl urane.
57
The most
compel li ng evi dence for an advantage of i soflurane over hal othane for neuroprotecti on was shown
in two studi es of human carotid endarterectomy surgery. In these pati ents, not only was the
inci dence of i schemi c EEG changes l ess using i sofl urane than halothane,
58
but i schemi c EEG
changes occurred at a l ower CBF wi th i sofl urane than with hal othane.
59

Both sevofl urane and desfl urane have been shown to i mprove neurologi cal outcome i n compari son
to N
2
O-fentanyl after i ncompl ete cerebral ischemia i n a rat model .
60, 61
In pi gl ets undergoi ng l ow-
flow cardi opul monary bypass, desfl urane i mproved neurologi c outcome compared to a
fentanyl /droperi dol -based anestheti c.
62
In humans, desfl urane has been shown to increase brai n
ti ssue PO
2
during admi ni strati on, and to mai ntai n PO
2
to a greater extent than thi opental during
temporary cerebral artery occl usi on duri ng cerebrovascul ar surgery.
63
Human neuroprotecti on
outcome studies for sevofl urane and desfl urane have not been publ i shed. Interpretati on of the
publ i shed data suggests that surgi cal cases in whi ch temporary cerebral arteri al occlusi on i s
pl anned or probabl e woul d benefi t more from i sofl urane, sevofl urane, or desflurane than hal othane
anesthesia, but further studi es are necessary.

Nitrous Oxide
The effects of ni trous oxide on cerebral physi ology are not cl ear. Both the MAC for N
2
O and its
effects on CMR vary wi del y dependi ng on speci es. The di fference i n CMR effects may i n part be
accounted for by di fferences i n MAC, but MAC-equival ent effects on CMR al so di ffer. In several
studies in dogs, goats, and swine N
2
O causes an i ncrease in CMRO
2
and CBF, whi l e i n rodents no
such i ncreases or only sli ght increases occur. In human studi es, N
2
O admi ni strati on preserved CBF
but decreased CMRO
2
.
38

Another probl em is the fact that N
2
O i s a coanestheti c used to supplement potent agents, not a
compl ete anesthetic i n itself, and CMR effects may di ffer dependi ng on presence or absence of
potent agent as wel l as the particular agent and dose. N
2
O causes a greater increase i n CBF and
CMR in dogs at 0.2% halothane than at 0.8% hal othane. In contrast, addi ti on of N
2
O to 1 or 2.2
MAC i sofl urane does not al ter CMRO
2
, but does i ncrease CBF at 1 MAC and not 2.2 MAC.
Barbi turates, narcoti cs, or a combi nation of the two appear to decrease or el i mi nate the i ncreases
i n CMR and CBF produced by N
2
O. The effect of pentobarbi tal/N
2
O i s dose dependent, wi th
preserved increases i n CMR by N
2
O at l ow-dose pentobarbi tal , and no changes i n CMR at hi gh-dose
pentobarbi tal .
64
N
2
O and benzodi azepi ne coadmi ni strati on i s parti cul arly confusi ng. Mi dazol am/N
2
O
i n dogs i ncreased CBF but di d not al ter CMRO
2
65
whi l e the opposi te was true in rats,
66
and both
CBF and CMRO
2
decl i ned i n rats gi ven di azepam/N
2
O. N
2
O admi ni strati on increases ICP, but as i s
the case for CMR and CBF, changes in ICP are decreased or el iminated by a variety of co-
anestheti cs and more i mportantl y by hypocapni a.
N
2
O appears to have an anti neuroprotecti ve effect, as addi tion of N
2
O to isofl urane duri ng
temporary i schemi a is associ ated wi th greater ti ssue damage and worsened neurol ogi c outcome.
66

In a study i n mi ce, survi val time after a hypoxi c event was decreased by addi ti on of N
2
O.
68
Given
the confl i cti ng data on the effects of N
2
O on CMR, CBF, ICP, and the apparent anti neuroprotective
effect of thi s agent, avoi dance or disconti nuati on of i ts use shoul d be consi dered i n surgi cal cases
with a hi gh l i kel ihood of el evated ICP or significant cerebral ischemia.
THE CIRCULATORY SYSTEM
Hemodynami cs
The cardi ac, vascul ar and autonomi c effects of the vol ati l e anestheti cs have been carefull y defined
by a number of studies carried out i n human vol unteers not undergoi ng surgery.
69, 70, 71, 72, 73, 74, 75
In
general , the i nformati on from these vol unteer studi es has translated wel l to the pati ent popul ation
commonly exposed to these anesthetics duri ng el ecti ve and emergent surgeries. There are cl earl y
factors such as interacti ons with anestheti c adjuvants and altered responses because of underlying
di sease that modify the ci rcul atory effects of the volatil e anestheti cs.
A common effect of the potent volati l e anestheti cs has been a dose-rel ated decrease i n arteri al
bl ood pressure, with essenti al l y no differences between the vol ati l e anestheti cs at steady-state,
equi -anesthetic concentrati ons (Fi g. 15-14). However, the mechanism by which they decrease
arterial bl ood pressure i s somewhat more speci fi c for each anestheti c. Halothane is most noted for
its decrease i n cardi ac output and thi s contributes i mportantly to i ts blood pressure l oweri ng
effect (Fi g. 15-15).
76
The mechanism by whi ch halothane decreases cardi ac output i s pri maril y a
resul t of a profound depressi on of myocardi al contractil i ty and has been associated wi th an
increase in right atri al pressure (see Fi g. 15-15).
77
Thi s contrasts to the newer vol ati l e
anesthetics, desfl urane, sevofl urane, and i sofl urane, whi ch are known to mai ntain cardiac
P.401
output.
73, 78
Thei r pri mary mechani sm to decrease bl ood pressure wi th i ncreasing dose i s rel ated to
thei r potent effects on regional and systemic vascul ar resistance (see Fi g. 15-15). Enflurane fal l s
somewhere between halothane and the newer volatil e anestheti cs in terms of its effects on cardi ac
output and peri pheral resi stance.
FIGURE 15-14. Heart rate and bl ood pressure changes (from awake basel i ne) i n vol unteers
recei vi ng general anesthesi a wi th a potent anestheti c. Hal othane and sevofl urane produced
li ttl e change i n heart rate at l ess than 1.5 MAC. All anesthetics caused si mil ar decreases i n
bl ood pressure. (Adapted from Mal an TP Jr, Di Nardo JA, Isner RJ et al : Cardiovascular effects
of sevofl urane compared wi th those of i sofl urane i n vol unteers. Anesthesi ology 83:918, 1995;
Wei skopf RB, Cahal an MK, Eger EI II et al : Cardiovascular actions of desfl urane i n
normocarbi c vol unteers. Anesth Anal g 73:143, 1991; and Cal verley RK, Smi th NT, Prys-
Roberts C et al : Cardi ovascular effects of enfl urane anesthesia duri ng control led ventil ati on
in man. Anesth Anal g 57:619, 1978.)
In terms of the effects of the vol ati l e anestheti cs on heart rate, data from animal studi es
indicate that desflurane consi stentl y increases heart rate,
79, 80
whereas sevofl urane provi des a
rel ati vely stabl e heart rate.
81
In vol unteers, sevofl urane and hal othane up to about 1 MAC resul t
in mi ni mal , i f any, changes i n steady-state heart rate (see Fi g. 15-14). Thi s contrasts to both
enfl urane and i sofl urane, whi ch have been associ ated with an i ncrease in heart rate of 10 to 20%
at 1 MAC. At anestheti c level s greater than 1 MAC, desfl urane has been associ ated with an
FIGURE 15-15. Cardi ac i ndex, systemi c vascular resi stance, and central venous pressure (or
ri ght atri al pressure) changes (from awake basel ine) in vol unteers recei vi ng general
anesthesia with a potent anestheti c. Increases i n central venous pressure from hal othane and
desfl urane mi ght be because of di fferent mechani sms. With halothane, the increase might be
because of myocardi al depressi on, whereas with desfl urane, the increase i s more li kel y
because of venoconstri cti on. (Adapted from Mal an TP Jr, Di Nardo JA, Isner RJ, et al :
Cardiovascul ar effects of sevofl urane compared wi th those of i sofl urane i n volunteers.
Anesthesi ol ogy 83:918, 1995; Weiskopf RB, Cahalan MK, Eger EI II, et al: Cardiovascular
acti ons of desfl urane in nonmocarbi c vol unteers. Anesth Anal g 73:143, 1991; and Cal verley
RK, Smith NT, Prys-Roberts C, et al : Cardi ovascul ar effects of enflurane anesthesia duri ng
control led venti lation in man. Anesth Anal g 57:619, 1978.).
increase i n heart rate to equal that of isofl urane.
82
Thi s is generall y refl ected as a 10 to 15
beats/mi n increase i n heart rate. Both desfl urane and, to a lesser extent, i sofl urane have been
associated wi th transi ent and si gni fi cant i ncreases in heart rate duri ng rapi d i ncreases i n the
inspi red concentration of either anestheti c.
82
Al though the mechani sm(s) underl yi ng these
transi ent heart rate surges are not known, it i s conjectured that the rel ati ve pungency of these
anesthetics acti vates airway receptors leadi ng to a refl ex tachycardi a.
83
Thi s tachycardi a can be
lessened with fentanyl, alfentani l or cl onidi ne pretreatment.
84, 85, 86

Myocar di al Cont r act i l i t y
Myocardi al contracti li ty i ndi ces have been directl y eval uated i n ani mals and i ndirectl y eval uated in
humans during the admi nistrati on of each of the vol atil e anestheti cs.
87
The ol der anestheti cs,
halothane and enfl urane, have been studied i n humans usi ng a rel ati vel y i mpreci se techni que
call ed bal li stocardiography, which permits an indi rect measure of contracti li ty (IJ ampli tude). At 1
MAC, enflurane caused a 40% decrease i n IJ ampl i tude, whereas hal othane caused a 30% decrease
in IJ ampli tude.
69, 70
At 1.5 MAC, greater depressi on of myocardi al contractil i ty was noted for both
vol ati l e anestheti cs. These changes were noted in conjuncti on wi th approxi mately 20% decreases
in cardiac output at 1 MAC hal othane and enfl urane. Animal and human studi es indicate that the
myocardi al depressi on from hal othane i s greater than i sofl urane and enfl urane. In contrast, human
studi es wi th the newer vol ati l e anestheti cs, i soflurane, sevofl urane, and desflurane, have not
demonstrated significant changes i n echocardi ographi c-determi ned i ndi ces of myocardial functi on,
incl udi ng the more noteworthy measurement of the vel ocity of ci rcumferential fi ber shorteni ng
(Fi g. 15-16). More precise i ndi ces of myocardial contractil i ty have been obtai ned for sevofl urane,
isoflurane, and desflurane in chroni cal l y i nstrumented dogs after autonomic i nnervation of the
heart was pharmacol ogi cal l y bl ocked. These studi es of the direct myocardial effects of the volatil e
anesthetics demonstrate that i sofl urane, desfl urane, and sevofl urane cause dose-dependent
depressi on of myocardi al functi on wi th no di fferences between the three anestheti cs (Fi g. 15-17).
Thus, the direct effect of vol ati le anestheti cs i s a dose-dependent myocardi al depressi on;
however, halothane and enfl urane have greater effects on myocardial contractil i ty than do
isoflurane, sevofl urane, and desfl urane.
P.402
FIGURE 15-16. Noninvasi ve assessment of myocardial contractil i ty wi th echocardiography
duri ng anesthesi a in volunteers. Sevofl urane, desfl urane, and i soflurane di d not cause
changes suggesti ve of myocardi al depression. (Adapted from Mal an TP Jr, Di Nardo JA, Isner
RJ, et al: Cardiovascular effects of sevofl urane compared wi th those of isoflurane in
vol unteers. Anesthesiol ogy 83:918, 1995; Wei skopf RB, Cahal an MK, Eger EI II, et al :
Cardi ovascul ar acti ons of desflurane in normocarbi c volunteers. Anesth Analg 73:143, 1991;
and Calverl ey RK, Smi th NT, Prys-Roberts C, et al : Cardi ovascular effects of enfl urane
Ot her Ci r cul at or y Ef f ect s
The majori ty of the vol ati l e anestheti cs have been studi ed during both control l ed and spontaneous
ventil ati on.
71, 73, 88
The process of spontaneous ventil ati on reduces the hi gh i ntrathoraci c pressures
from posi ti ve pressure venti l ati on. The negati ve i ntrathoracic pressure duri ng the inspiratory
phase of spontaneous venti lati on augments venous return and cardi ac fi ll i ng and improves cardi ac
output and, hence, bl ood pressure. A second resul t of spontaneous venti l ati on i s hi gher PaCO
2
,
anesthesia duri ng control led ventil ati on i n man. Anesth Anal g 57:619, 1978.)
FIGURE 15-17. Myocardi al contractil i ty indi ces from chronicall y instrumented dogs. For
these measurements, pharmacol ogic bl ockade of the autonomi c nervous system was
establ i shed to el i mi nate neural or ci rculating humoral i nfl uences on the inotropi c state of the
heart. The conscious control data were assi gned 100%, and subsequent reducti ons i n the
inotropi c state are depi cted for both 1 and 1.5 minimum alveol ar anestheti c concentrati ons of
sevofl urane, desflurane, and isofl urane. There were no di fferences between these three
vol ati l e anestheti cs. M
w
, slope of the regi onal prel oad recrui tabl e stroke work rel ati onshi p;
dP/dt
50
, change i n pressure per uni t of ti me. (Adapted from Pagel PS, Kampi ne JP, Schmel ing
WT et al : Influence of vol ati le anesthetics on myocardi al contractil i ty in vi vo: Desfl urane
versus i sofl urane. Anesthesi ol ogy 74:900, 1991; and Harkin CP, Pagel PS, Kersten JR et al :
Direct negati ve i notropi c and l usi tropi c effects of sevofl urane. Anesthesi ol ogy 81:156, 1994.)
and thi s change causes cerebral and systemic vascul ar relaxati on and further contri butes to an
improved cardiac output vi a afterload reduction. Thus, spontaneous venti l ation decreases systemi c
vascul ar resi stance and increases heart rate, cardi ac output, and stroke vol ume as contrasted to
positi ve pressure venti l ati on. It has been suggested that spontaneous venti l ation mi ght i mprove
the safety of i nhaled anestheti c administration, because the concentrati on of a vol ati le anesthetic
that produces cardi ovascul ar col l apse exceeds the concentration resul ting i n apnea.
A curi ous observati on with the potent vol ati le anesthetics has been an alteration in the
cardi ovascul ar effects duri ng prol onged anestheti c exposures, noted as a smal l increase i n heart
rate and cardiac index, a gradual decrease i n systemi c vascul ar resistance, and no change i n
myocardial indi ces.
72, 73
Acti vati on

of beta-sympatheti c receptors has been suggested as a mechani sm contri buting to the increased
heart rate and cardi ac output from prol onged anesthesi a with halothane; however, thi s possibi l i ty
has been questi oned based on recent studi es wi th prol onged exposure to desflurane anesthesi a.
72

Ni trous oxi de is commonl y combi ned wi th potent vol ati le anesthetics to mai ntain general
anesthesia. Ni trous oxide has uni que cardiovascul ar actions.
75, 89
It i ncreases sympatheti c nervous
system acti vi ty and vascular resi stance when gi ven in a 40% concentrati on.
89
When ni trous oxide
is combined wi th vol ati le anestheti cs and compared to equi potent concentrati ons of the vol ati le
anesthetic wi thout ni trous oxide, there stil l i s evidence of sympatheti c nervous system activati on,
with an i ncreased systemi c vascular resi stance and an i mproved arteri al pressure wi th l i ttl e effect
on cardiac output.
73
Part of these effects might not be because of the ni trous oxi de per se, but
may simpl y be attributed to a decrease i n the concentrati on of the co-administered potent vol ati l e
anesthetic to achieve a MAC equi valent when usi ng nitrous oxi de.
Oxygen consumpti on i s decreased approxi matel y 10 to 15% duri ng general anesthesi a. The
di stri bution of cardiac output al so is al tered by anesthesi a. Bl ood fl ow to liver, ki dneys, and gut i s
decreased, particularl y at deep level s of anesthesi a. In contrast, blood fl ow to the brai n, muscl e,
and skin i s increased or not changed duri ng general anesthesi a.
79, 90
In humans, i ncreases i n
muscl e bl ood fl ow are noted wi th i sofl urane, desfl urane, and sevoflurane wi th very smal l
di fferences between anestheti cs at equi potent concentrati ons.
91

In contrast to hal othane, the ether-based anestheti cs (i sofl urane, enfl urane, sevofl urane, and
desfl urane) have not predi sposed pati ents to ventricul ar arrhythmi as, nor sensi ti zed the heart to
the arrhythmogenic effects of epinephrine (Fi g. 15-18). The use of IV l i docaine can lessen the
epi nephri ne effect duri ng hal othane anesthesia. Some of the differences between vol ati l e
anesthetics i n thei r abi l ity to promote arrhythmi as can be attri buted to their di rect effects on
cardi ac pacemaker cel l s and conducti on pathways.
92
SA node di scharge rate is slowed by the
vol ati l e anestheti cs and conducti on i n the Hi s-Purkinje system and conducti on pathways i n the
ventri cl e are al so prol onged by the vol ati le anestheti cs.
92
A greater sl owi ng by hal othane over
isoflurane in the Hi s-Purkinje system mi ght promote dysrhythmi as via a reentry phenomena.
P.403
Cor onar y St eal
Because the potent volatil e anestheti cs rel ax vascular smooth muscl e and l ead to vasodi lation,
there has been a concern rel ated to abnormal distributi on of bl ood fl ow i n coronary bl ood vessel s
of patients with ischemi c heart di sease. Thi s effect has been cal l ed coronary steal and became a
concern wi th the i ntroducti on of i sofl urane to cl ini cal practi ce. Isofl urane (and most other potent
vol ati l e anestheti cs) i ncreases coronary blood fl ow many ti mes beyond that of the myocardi al
oxygen demand, thereby creati ng potential for steal . Steal is the di version of blood from a
myocardi al bed wi th l i mi ted or inadequate perfusi on to a bed wi th more adequate perfusi on,
especial ly one that has a remai ni ng el ement of autoregul ation. In i nstrumented ani mal models, the
pronounced coronary vasodi lation produced by i sofl urane was shown to cause steal
93
and earl y

patient studi es provi ded addi ti onal support.
94
However, more recent work in a chroni cal l y
instrumented, cani ne model of mul tivessel coronary artery obstructi on has shown that nei ther
isoflurane, sevofl urane, nor desfl urane at concentrati ons up to 1.5 MAC resulted i n abnormal
coll ateral coronary blood fl ow redi stri buti on (steal ), whereas adenosi ne, a potent coronary
vasodil ator, cl earl y resul ted i n abnormal fl ow di stri buti on.
95, 96, 97
Interesti ngl y, sevofl urane
favorabl y i ncreased (rather than decreased) col lateral coronary bl ood fl ow i n thi s i nstrumented
animal model when aortic pressure was held constant (si mi lar to what mi ght be seen wi th systemi c
bl ood pressure support).
95

Myocar di al I schemi a and Car di ac Out come
Not surpri si ngl y, the cli ni cal relevance of coronary steal wi th isofl urane has been debated and i s
general ly thought to be mi ni mal .
98
Outcome studi es have fai l ed to associ ate the use of i sofl urane
in pati ents undergoing coronary artery bypass operati ons with an increased i nci dence of
myocardial i nfarction or peri operati ve death.
98, 99
Most studies woul d suggest that determinants of
myocardi al oxygen suppl y and demand, rather than the anestheti c, are of far greater i mportance
to pati ent outcomes.
Several studi es have eval uated the two new anesthetics, sevoflurane and desfl urane, to
comparator anestheti cs, i n terms of myocardi al ischemi a and outcome i n pati ents with coronary
artery di sease either undergoi ng noncardiac or coronary artery bypass graft (CABG) surgery.
100, 101

In both popul ati ons, sevofl urane appears to be essenti all y equival ent to isofl urane in terms of the
i nci dence of myocardi al ischemi a and adverse cardi ac outcomes. Desfl urane appears to resul t i n
si mi l ar outcome effects as isoflurane in cardi ac pati ents havi ng coronary artery bypass grafti ng,
102

with one excepti on. In a study where desfl urane was given wi thout opioi ds to pati ents wi th
coronary artery disease requi ri ng CABG surgery, si gni fi cant i schemi a mandati ng the use of beta-
bl ockers was noted.
103
Desflurane has not been evaluated i n terms of i schemi a and outcome i n a
patient population with coronary di sease undergoing noncardi ac surgery.
FIGURE 15-18. The dose of epinephrine associ ated with cardi ac arrhythmi as in ani mal and
human model s was least with halothane. The ether anesthetics, i sofl urane, desfl urane, and
sevofl urane, requi red 3- to 6-fol d greater doses of epinephrine to cause arrhythmi as.
(Adapted from Navarro R, Wei skopf RB, Moore MA, et al : Humans anestheti zed wi th
sevofl urane or i soflurane have simil ar arrhythmi c response to epi nephri ne. Anesthesi ol ogy
80:545, 1994; Wei skopf RB, Eger EI II, Hol mes MA, et al : Epi nephrine-induced premature
ventri cul ar contractions and changes i n arteri al bl ood pressure and heart rate during I-653,
isoflurane, and hal othane anesthesia i n swine. Anesthesiol ogy 70:293, 1989; Hayashi Y,
Sumi kawa K, Tashi ro C, et al : Arrhythmogenic threshol d of epinephrine duri ng sevofl urane,
enfl urane, and i soflurane anesthesi a in dogs. Anesthesi ol ogy 69:145, 1988; and Moore MA,
Wei skopf RB, Eger EI II, et al: Arrhythmogeni c doses of epi nephri ne are si mi l ar during
desfl urane or isoflurane anesthesi a i n humans. Anesthesi ol ogy 79:943, 1993.)
P.404
Car di opr ot ect i on f r om Vol at i l e Anest het i cs
There i s a new body of l iterature descri bi ng the potenti al for organ protecti ve effects (parti cul arly
cardi oprotecti ve effects) of the potent inhal ed agents.
104, 105
Organ protecti on woul d be defi ned as
reduci ng ti ssue damage after hypoxic i schemi a or toxi c i nsul t. A precondi ti oni ng sti mulus of bri ef
coronary occl usion and i schemia i ni tiates a si gnali ng cascade of i ntracel l ul ar events that reduces
i schemi a and reperfusi on myocardi al injury. There is a memory effect from an ischemic sti mul us
that offers 2 to 3 hours of protection. The vol atile anesthetics mi mic i schemi c precondi ti oni ng and
trigger a si mi l ar cascade of intracel lul ar events resulti ng i n myocardial protecti on that l asts
beyond the el iminati on of the anesthetic. Numerous factors may be i nvol ved i n precondi ti oni ng,
i ncl udi ng the sodi um:hydrogen exchanger, the adenosi ne receptor (particul arl y a1 and a2
subtypes), i nhi bi tory g protei ns, protei n ki nase c, tyrosi ne ki nase, and potassi um (K
ATP
) channel
openi ng. Pharmacol ogi c blockade of these factors, for example, with adenosine blockers, del ta-1
opi oi ds, pertussis toxi n, or gli bencl ami de, reduces or eli mi nates the cardioprotective effect of
ischemi c precondi ti oni ng and of the volatil e anestheti cs.
106, 107
Al ternati vel y, admi nistrati on of
certai n drugs can mi mi c i schemic or volati l e anestheti c precondi ti oni ng. These i ncl ude adenosi ne,
opi oi d agoni sts, and K
ATP
channel openers. In contrast to the i nhal ati on of vol ati le anesthetics,
these cardi oprotecti ve drugs must be given i nto a coronary artery because systemi c administration
has serious si de effects.
Lipophi l ic vol ati le anesthetics di ffuse through myocardial cell membranes and alter mi tochondrial
el ectron transport l eadi ng to reacti ve oxygen speci es formati on.
107
Thi s may be the tri gger for
precondi ti oni ng vi a protei n ki nase C acti vati on of K
ATP
channel opening.
108
Approxi matel y 30 to
40% of the cardioprotection from the volatil e anestheti cs appears to be rel ated to a reduced
loadi ng of cal ci um i nto the myocardi al cel ls duri ng ischemi a.
105
Precondi ti oned hearts may tolerate
ischemi a for 10 mi nutes l onger than noncondi ti oned hearts.
109
Whi le these evol vi ng data general ly
deri ve from ani mal model s, there now i s i ncreasi ng evi dence in cardi ac pati ent popul ati ons that
anesthetic cardi oprotecti on l essens myocardi al damage (based on troponin level s) during on and
off pump cardi ac surgery.
110
Thi s effect seems to be common to al l current-day potent vol ati le
anesthetics and may favorably i nfl uence ICU l ength of stay after coronary surgery.
111

Sul fonyl urea oral hypergl ycemi c drugs close K
ATP
channel s abol ishing anestheti c precondi ti oni ng.
They shoul d be di sconti nued 24 to 48 hours prior to el ecti ve surgery in high-ri sk pati ents.
106
But
hyperglycemia also prevents preconditi oning, so i nsuli n therapy shoul d be started when hol di ng
oral agents.
112

Aut onomi c Ner vous Syst em
Studies that have focused on the efferent acti vi ty of the parasympatheti c and sympathetic nervous
systems i ndi cate that the volati l e anestheti cs depress thei r acti vi ty i n a dose-dependent
fashion.
113, 114
However, because the autonomi c nervous system (ANS) i s importantl y modul ated by
baroreceptor refl ex mechani sms, the effects of the anestheti c on the efferent system cannot be
reported wi thout taki ng into account thei r effects on different components of the barorefl ex arc.
Thus, al though both l i mbs of the autonomi c nervous system have been shown to be attenuated by
the anestheti cs, the afferent activity from the arteri al baroreceptors has been found to be
increased wi th some of the anestheti cs, i ncl udi ng halothane and isoflurane.
113, 115, 116
Thi s
increased di scharge of the baroreceptors actual l y contri butes to the depressi on of the entire
barorefl ex arc by toni cal l y l oweri ng the overall l evel of the outfl ow of the sympathetic nervous
system. From the perspecti ve of cl i ni cal relevance, studi es have exami ned the behavi or of arteri al
barorefl ex system during a hypotensive or hypertensi ve sti mul us by eval uating changes i n heart
rate and sympatheti c nerve acti vi ty. The arterial barorefl ex is the most rapi d system responding
to bl ood pressure perturbati ons. Earl y investi gati ons focused pri mari l y on the regulati on of heart
rate (and thi s reflects pri mari l y a vagal l y medi ated end point). Hal othane, enfl urane, and
isoflurane
117, 118
al l depress, i n a dose-dependent fashi on, the arteri al barorefl ex control of heart
rate, al though there was a suggesti on that isofl urane had l ess of a promi nent effect than
halothane or enfl urane.
117
Similar effects on the refl ex control of heart rate have recentl y been
P.405
demonstrated wi th sevofl urane and desfl urane (Fi g. 15-19).
119, 120, 121

There i s greater di fficul ty i n eval uati ng the sympatheti c component of the barorefl ex arc in
humans, but a techni que call ed sympathetic mi croneurography has been uti l ized to di rectl y record
vasoconstri ctor impul ses directed to blood vessel s in humans.
74, 82
There is a dose-dependent
depressi on of the refl ex control of sympatheti c outflow that appears to be relati vel y equi val ent for
isoflurane, sevofl urane, and desfl urane (Fi g. 15-20). Importantl y, at low level s of anesthesi a, for
example, 0.5 MAC, there i s li ttl e i f any depressi on of refl ex functi on and thi s mi ght have i mportant
impli cati ons in the compromi sed pati ent popul ati on. Opi oi d and benzodi azepi ne adjuvants have
only mi ni mal effects on refl ex functi on and combi ni ng these wi th l ow l evel s of potent anestheti cs
mi ght preserve refl ex functi on.
122, 123
Another important observation has been the more rapi d
return of baroreflex functi on with the less-solubl e anestheti c sevofl urane versus isoflurane.
124
Thi s
mi ght add to hemodynami c stabi l i ty in the postoperati ve period when ti ssue concentrati ons of the
vol ati l e anestheti cs are decl ini ng.
FIGURE 15-19. Summary data of the barorefl ex regul ati on of heart rate (R-R interval) i n
response to a decreasi ng pressure stimul us (sodi um ni troprussi de) or i n response to an
increasi ng pressure stimul us (phenyl ephri ne). These data were acqui red i n healthy vol unteers
who were randomi zed to recei ve i sofl urane, desfl urane, or sevoflurane. With increasi ng
mi ni mum al veol ar anesthetic concentrati on (MAC), each of the volatil e anestheti cs led to a
progressi ve reduction in the cardiac barosl ope (an i ndex of barorefl ex sensi ti vi ty deri ved by
rel ati ng changes i n mean pressure to changes in R-R interval). There were no statistical
di fferences between anestheti cs. (Adapted from Ebert TJ, Harkin CP, Muzi M: Cardi ovascul ar
responses to sevofl urane: A review. Anesth Anal g 81:S11, 1995.)
Desfl urane has a uni que and promi nent effect on sympatheti c outflow in humans, whi ch i s not
apparent i n ani mal model s. Wi th i ncreasi ng steady-state concentrati ons of desfl urane, there i s a
progressi ve i ncrease i n resti ng sympatheti c nervous system activity and pl asma norepi nephri ne
level s.
74, 82, 125
Despi te thi s increase i n toni c sympatheti c outfl ow, blood pressure decreases
si mi l arly to sevofl urane and i soflurane. Thi s raises the question as to whether desflurane has the
abi li ty to uncoupl e neuroeffector responses. In additi on, desflurane can cause marked acti vati on
of the sympatheti c nervous system when the i nspired concentrati on i s increased, especial ly to
concentrations above 5 to 6% (Fi g. 15-21).
74, 82, 125
There is a transi ent surge in sympathetic
outfl ow l eadi ng to both hypertensi on and tachycardi a. In addi ti on, the endocri ne axi s is acti vated
as evi denced by 15- to 20-fol d i ncreases in pl asma anti diuretic hormone and epinephrine (Fi g. 15-
22). The hemodynami c response persists for 4 to 5 mi nutes and the endocrine response persi sts
for 15 to 25 mi nutes. Adequate concentrati ons of opi oi ds or cl onidi ne given prior to i ncreasing the
concentration of desfl urane have been shown to attenuate these responses.
84, 85, 86
The source of
the neuroendocrine acti vati on has been acti vel y sought, and i t would appear that there are
receptors i n both the upper and the l ower ai rways, and/or perhaps i n a hi ghl y perfused ti ssue near
the ai rways, that i ni tiates the sympatheti c acti vati on.
83
The possi bi li ty that desflurane acti vates
ai rway

irri tant receptors i s qui te strong, since desflurane i s the most pungent of the anestheti cs avai l abl e
for cl i ni cal use.
126

FIGURE 15-20. The sympatheti c barorefl ex function of healthy vol unteers randomi zed to
recei ve isofl urane, desflurane, or sevoflurane. The sl ope (sensiti vi ty) i s the rel ati onshi p
between decreasi ng di astol i c pressure and i ncreasi ng efferent sympatheti c nerve acti vi ty. The
refl ex regul ati on of sympathetic outfl ow was fai rly wel l preserved at 0.5 and 1.0 mi ni mum
al veolar anestheti c concentrati on (MAC) of anestheti c. At 1.5 MAC, there was a 50% decrease
in the slope wi th al l anesthetics. (Adapted from Ebert TJ, Harki n CP, Muzi M: Cardi ovascul ar
responses to sevofl urane: A review. Anesth Anal g 81:S11, 1995.)
P.406
FIGURE 15-21. Consecuti ve measurements of sympatheti c nerve acti vi ty (SNA)(mean SE)
from human volunteers duri ng i nducti on of anesthesia wi th propofol and the subsequent mask
administrati on of sevofl urane or desfl urane for a 10-mi nute period. The i nspi red
concentration of these anesthetics was increased at 1-mi nute interval s begi nni ng preci sel y 2
mi nutes after propofol administrati on (0.41 MAC of sevoflurane and desflurane). In both
groups, propofol reduced SNA and MAP. Desfl urane resul ted i n si gni fi cant increases i n
sympatheti c nerve acti vi ty that persi sted throughout the 10-mi nute mask administrati on
peri od. (Adapted from Ebert TJ, Muzi M, Lopatka CW: Neuroci rcul atory responses to
sevofl urane i n humans. A compari son to desfl urane. Anesthesi ology 83:88, 1995.)
FIGURE 15-22. Stress hormone responses to a rapid increase i n anestheti c concentration,
from 4 to 12% inspired. Volunteers gi ven desfl urane showed a l arger increase i n plasma
epi nephri ne and norepi nephri ne concentrations than when gi ven isoflurane. Data are mean
SE. A, awake value; B, val ue after 32 mi nutes of 0.55 MAC; ti me represents mi nutes after
the fi rst breath of i ncreased anestheti c concentrati on. (Adapted from Wei skopf RB, Moore MA,
Eger EI II et al : Rapi d increase i n desflurane concentration i s associ ated wi th greater
transi ent cardi ovascul ar sti mul ati on than with rapi d i ncrease i n i sofl urane concentrati on i n
humans. Anesthesiol ogy 80:1035, 1994.)
THE PULMONARY SYSTEM
The vol ati le anesthetics have mul tipl e and i mportant effects on many aspects of pulmonary
physi ol ogy, i ncl udi ng respi ratory rate and ti dal volume, responses to CO
2
and hypoxi a, effects on
bronchi ol ar smooth muscl e tone, and mucocil i ary functi on. Less pronounced, but sti ll i mportant
effects of the vol ati le anesthetics have been observed on pulmonary vascul ar resi stance and
pul monary blood fl ow.
Gener al Vent i l at or y Ef f ect s
All vol ati le anesthetics decrease ti dal vol ume but have lesser effects on decreasing minute
ventil ati on because of an offsetti ng

response to i ncrease respiratory rate (Fi g. 15-23). These effects are dose dependent, wi th hi gher
concentrations of vol ati le anesthetics, resulti ng i n greater decreases i n ti dal vol ume and greater
increases i n respi ratory rate. Their net effect of a gradual decrease i n mi nute ventil ati on has been
associated wi th i ncreasing resting PaCO
2
. The relative i ncreases i n PaCO
2
as an index of
respiratory depressi on with vol ati l e anestheti cs eval uated at l ess than 1.24 MAC are as fol l ows:
enfl urane > desfl urane = isofl urane > sevofl urane = hal othane. The respi ratory depression can be
parti all y antagonized duri ng surgi cal stimul ati on where respi ratory rate has been shown to
increase, resul ting i n a decrease in the PaCO
2
(Fi g. 15-24). In addi ti on, resti ng PaCO
2
duri ng
desfl urane or sevofl urane anesthesia i s si gnifi cantly decreased (returned toward normal) with the
addi ti on of ni trous oxide. Thi s compari son (with and wi thout nitrous oxi de) requires a lessening of
the potent vol ati le anesthetic to maintai n an equi -MAC concentrati on when adding nitrous oxi de to
the inspired gas and this probabl y contributes to the return of PaCO
2
toward normal . The degree
of respi ratory depression from inhaled anestheti cs may be l essened duri ng prol onged
administrati on of the anestheti c.
127

P.407
Vent i l at or y Mechani cs
Functi onal residual capaci ty i s decreased duri ng general anesthesia and thi s has been expl ai ned by
a number of mechani sms, including a decrease i n the i ntercostal muscl e tone, alteration in
di aphragm posi tion, changes in thoraci c bl ood vol ume, and the onset of phasi c expi ratory acti vi ty
of respi ratory muscl es.
128, 129, 130
About 40% of the muscular work of breathi ng i s vi a intercostal
muscles and about 60% is from the diaphragm. The diaphragmati c muscl e functi on i s rel ati vel y
spared when contrasted to the parasternal intercostal muscl es.
128
However, inspiratory ri b cage
expansi on i s reasonabl y wel l mai ntained during anesthesi a because of preserved acti vi ty of the
scal ene muscl es.
128
Expi rati on i s general l y consi dered a passi ve function medi ated by the elasti c
recoi l of the l ung. The process of applying a resi stance or l oad to expi rati on typi cal l y results i n a
sl owing of respi ration but under anesthesia addi ti onal noted responses included a substantial
FIGURE 15-23. Comparison of mean changes in resting PaCO
2
, ti dal volume, respi ratory
rate, and mi nute ventil ati on i n pati ents anesthetized wi th ei ther halothane, isofl urane,
enfl urane, sevoflurane, desfl urane, or ni trous oxi de. Anestheti c-induced tachypnea
compensates i n part for the ventil atory depressi on caused by al l vol ati l e anestheti cs
(decrease in mi nute venti lation and tidal volume and concomi tant i ncrease i n PaCO
2
).
Desfl urane resul ts i n the greatest increase i n PaCO
2
wi th correspondi ng reducti ons i n ti dal
vol ume and minute venti lation. Isofl urane, li ke al l other i nhal ed agents, increases respi ratory
rate, but does not result i n dose-dependent tachypnea. (Adapted from Lockhart SH, Rampi l
IJ, Yasuda N, et al : Depression of venti lation by desfl urane in humans. Anesthesi ology
74:484, 1991; Doi M, Ikeda K: Respi ratory effects of sevoflurane. Anesth Anal g 66:241,
1987; Fourcade HE, Stevens WC, Larson CP Jr, et al: The venti latory effects of Forane, a new
inhaled anesthetic. Anesthesi ol ogy 35:26, 1971; and Cal verl ey RK, Smi th NT, Jones CW, et
al : Ventil atory and cardi ovascul ar effects of enfl urane anesthesi a during spontaneous
ventil ati on i n man. Anesth Anal g 57:610, 1978.)
FIGURE 15-24. The effect of surgi cal stimul ati on on the ventil atory depression of inhal ed
anesthesia wi th i sofl urane i n the presence and absence of ni trous oxi de. Surgical sti mulation
increased alveol ar ventil ati on and decreased PaCO
2
at al l depths of anesthesia exami ned.
(Adapted from Eger EI II, Dol an WM, Stevens WC et al : Surgi cal stimul ati on antagoni zes the
respiratory depressi on produced by forane. Anesthesi ology 36:544, 1972.)
asynchrony of the thoracic movements wi th respi rati on.
131
Thi s suggests that in pati ents wi th
pul monary disease associated wi th i ncreased expiratory resi stance, the act of spontaneous
ventil ati on duri ng general anesthesi a mi ght be associ ated wi th i ncreased ri sk.
Response t o Car bon Di oxi de and Hypoxemi a
In awake subjects a high sensitivity to CO
2
has been noted by i ncreases i n mi nute ventil ati on of
approxi mately 3 L/mi n per 1 mm Hg increase in PaCO
2
. It i s medi ated by central chemoreceptors
and has been used as an i ndex of venti l atory dri ve. Al l of the i nhal ed anestheti cs produce a dose-
dependent depressi on of the venti l atory response to hypercarbi a (Fi g. 15-25). Earl y studi es
suggested that the addi tion of ni trous oxi de to hal othane depressed venti l ati on l ess than an equi -
MAC dose of hal othane al one;
132
however, thi s does not appear to be the case for desfl urane (see
Fi g. 15-25). Duri ng anesthesi a wi th spontaneous ventil ati on, an apneic threshol d can be
determi ned that is generall y 4 to 5 mm Hg below the prevai li ng resting PaCO
2
, and thi s threshol d
is not rel ated to the sl ope of the CO
2
response curves or to the l evel of the resti ng PaCO
2
. The
cl i ni cal rel evance of thi s threshol d may be important when assisting venti lation in an anestheti zed
patient who i s breathi ng spontaneousl y. Thi s only serves to l ower the PaCO
2
to approach that of
the apneic threshol d, therefore mandati ng more control of venti lation.
Inhaled anesthetics, i ncl udi ng nitrous oxi de, al so produce dose-dependent attenuation of the
ventil atory response to hypoxi a.
133, 134
Thi s action appears to be dependent on the peri pheral
chemoreceptors. In fact, even subanestheti c concentrations of vol ati le anesthetics (0.1 MAC) el ici t
anywhere from a 15 to 75% depressi on of the ventil atory dri ve to hypoxia (Fi g. 15-26).
135
The
mechani sm of thi s depressi on sti l l remai ns poorl y understood. Studi es have suggested that
hypoxi a may decrease the probabi l i ty that potassi um channels are open, thus causi ng membrane
depol arizati on, i nfl ux of cal ci um ions, and rel ease of neurotransmi tters.
136
One theory is that the
potassium channel s are respondi ng to reacti ve oxygen speci es, such as those formed as a result of
halothane admi ni strati on. In one study, the admi ni strati on of antioxi dants pri or to the
administrati on of halothane prevented the depressi on of the hypoxi c
FIGURE 15-25. Al l i nhaled anestheti cs produce si mi l ar dose-dependent decreases i n the
ventil atory response to carbon di oxide. (Adapted from Eger EI II: Desfl urane. Anesth Rev
20:87, 1993.)

response.
137
The extreme sensiti vi ty of the vol ati le anestheti cs i n terms of i nhibi ting hypoxic
responsi veness has i mportant cl i ni cal impl icati ons. Resi dual effects of vol ati l e anestheti cs may
impai r the venti latory drive of pati ents in the recovery room. In thi s regard, the short-acti ng
anesthetics (sevofl urane and desfl urane) may prove advantageous because of thei r more rapi d
washout and their minimal effect on hypoxi c sensi tivity at subanestheti c concentrati ons (see Fi g.
15-26). The effects of the volatil e anestheti cs on hypoxi c dri ve may pl ay an even more i mportant
role i n pati ents who rely on hypoxic dri ve to set their level of ventil ati on, such as those wi th
chroni c respi ratory fai lure.
Br onchi ol ar Smoot h Muscl e Tone
Bronchoconstriction under anesthesi a occurs because of di rect sti mulation of the laryngeal and
tracheal areas and the admi ni strati on of adjuvant drugs that cause histamine rel ease, and from
noxious stimul i especi al l y in l i ghtly anestheti zed pati ents.
138
These responses are enhanced i n
patients with known reacti ve ai rway disease, (i ncl udi ng those requi ri ng bronchodil ator therapy or
those wi th chroni c smoki ng hi stori es). Airway smooth muscl e, which extends as far di stall y as the
termi nal bronchi oles, i s under the infl uence of both parasympathetic and sympatheti c nerves. The
parasympatheti c nerves mediate basel ine ai rway tone and refl ex bronchoconstri cti on, vi a an M3
muscari ni c receptor on the airway smooth muscl e that i ncreases intracel l ul ar cycli c GMP.
Adrenergic receptors also are l ocated on bronchial smooth muscle with the beta-2 receptor
subtype pl ayi ng an i mportant rol e in promoting bronchiol ar muscl e relaxati on through an i ncrease
in intracel l ul ar cycli c-AMP. The vol ati l e anestheti cs relax ai rway smooth muscl e by directl y
depressi ng smooth muscl e contracti li ty and i ndirectl y by inhi bi ti ng the refl ex neural pathways.
139

They al so may have protective effects by acting on the bronchi al epi thel ium via a nonadrenergic,
noncholi nergi c mechani sm, possi bly i nvol vi ng the ni tric oxi de pathway.
140
A recent study in
patients compari ng i soflurane, hal othane, and sevofl urane to a control group recei vi ng thi opental
indicated that sevofl urane may have a more rapid onset of bronchodi l ati on than i sofl urane or
halothane.
141
Studi es from our l aboratory suggest that desflurane administrati on shortl y after
thiopental i nducti on and tracheal i ntubation resul ts i n a transi ent i ncrease i n respi ratory system
resistance (bronchoconstri cti on), and we have attri buted thi s to a di rect effect from the pungency
P.408
FIGURE 15-26. Influence of 0.1 MAC of five volatile anesthetic agents on the ventil atory
response to a step decrease i n end-ti dal oxygen concentrati on. Val ues are mean SD.
Subanestheti c concentrati ons of the volatil e anestheti cs, except desflurane and sevofl urane,
profoundl y depress the response to hypoxi a. (Adapted from Sarton E, Dahan A, Teppema L et
al : Acute pai n and central nervous system arousal do not restore i mpai red hypoxi c
ventil atory responses during sevoflurane sedati on. Anesthesi ology 85:295, 1996.)
and ai rway i rri tabil i ty of desfl urane (Fi g. 15-27). Thi s effect i s worsened i n pati ents wi th an acti ve
smoki ng hi story. Volati l e anestheti cs have been used effecti vel y to treat status asthmaticus when
other conventional treatments have fai led.
142
Al though hal othane has been successfull y used i n
these si tuati ons, sevofl urane may be a better choi ce because of i ts qui ck onset, lack of pungency,
lack of cardi ovascul ar depression, and l ower risk of cardi ac arrhythmias compared to hal othane.
Mucoci l i ar y Funct i on
Adequate mucoci li ary functi on may be i mportant i n preventi ng postoperati ve atel ectasi s and
hypoxemi a. There are a number of factors i nvol ved in di mi ni shed mucoci li ary functi on, parti cul arly
in the mechanicall y ventil ated pati ent. Anesthesia pl ays an as yet poorl y defi ned rol e. Hal othane,
enfl urane, and nitrous oxi de wi th hal othane have been shown to decrease, i n a dose-dependent
fashi on, mucoci l iary movement. It al so i s known that smokers have impai red mucocil i ary function
compared to nonsmokers, and the combi nati on of a volatil e anestheti c i n a smoker who i s
mechani cal ly venti l ated sets up a scenario for inadequate clearing of secreti ons, mucous pl ugging,
atelectasis, and hypoxemi a.
P ul monar y Vascul ar Resi st ance
Although vascular smooth muscle i s clearl y affected by the volatil e anestheti cs, the pul monary
vasodil ator action of the cl i ni cal l y relevant concentrati ons of inhaled anesthetics, i ncl udi ng
halothane, i sofl urane, enfl urane, sevofl urane, and desfl urane, i s mi ni mal . In addi ti on, any
decrease i n cardiac output that might occur from a volatil e anestheti c tends to offset the direct
vasodil ator action of the anestheti c, resul ting i n l i ttl e or no change in pul monary artery pressures
and pul monary bl ood

fl ow. Even ni trous oxi de, whi ch has l i ttl e effect on cardiac output and pul monary bl ood flow, has
at best a smal l effect to increase pul monary vascul ar resistance. However, the effect of ni trous
oxi de may be magni fi ed i n patients with resti ng pul monary hypertensi on.
143
Perhaps more
important i n terms of vol ati le anestheti cs and pul monary blood fl ow i s thei r potenti al to attenuate
hypoxi c pul monary vasoconstriction (HPV). During peri ods of hypoxemi a, HPV reduces bl ood fl ow
to underventi l ated areas of the l ung, thereby di verti ng bl ood fl ow to areas of the l ung wi th greater
FIGURE 15-27. Changes i n respi ratory system resi stance (Rrs) expressed as a percentage of
the thiopental baseli ne recorded after tracheal intubati on but pri or to administrati on of
sevofl urane or desfl urane to the inspired gas mi xture. Airway resi stance responses to
sevofl urane were si gnifi cantly di fferent from desfl urane (*p<0.05). (Adapted from Goff MJ,
Arai n SR, Fi cke DJ et al : Absence of bronchodi lation duri ng desflurane anesthesia: A
compari son to sevofl urane and thi opental . Anesthesiol ogy 93:404, 2000.)
P.409
ventil ati on. The net effect i s to i mprove the V/Q matching, resulti ng i n a reduced amount of
venous admi xture and i mproved arteri al oxygenati on. Al though al l of the i nhal ed anestheti cs in
hi gh concentrati ons have been shown to attenuate HPV i n animal model s, the situation is l ess
cl ear i n patient studi es. Thi s may refl ect the mul tifactorial effects of the vol atil e anestheti cs on
factors involved in pulmonary bl ood flow, incl uding their cardi ovascul ar, autonomi c and humoral
acti ons. Furthermore, nonpharmacol ogi c vari ables i mpai r HPV, i ncludi ng surgi cal trauma,
temperature, pH, PaCO
2
, size of the hypoxic segment, and intensity of the hypoxi c sti mulus. In
patients undergoi ng one lung ventil ati on duri ng thoraci c surgery, PaO
2
and i ntrapul monary shunt
fracti on (Qs/Qt) have been mi ni mal ly affected when changing from two-lung to one-lung
ventil ati on (OLV) during either hal othane, i soflurane, enfl urane, desfl urane anesthesi a (Fi g. 15-
28).
144
Isofl urane appears to be l ess i nhi bi tory on HPV than hal othane and, al though thi s effect i s
subtl e,
144
it might be attri buted to the greater mai ntenance of cardiac output known to occur wi th
isoflurane. Both sevoflurane and desflurane preserve cardi ac output and should al so hel p lessen
shunt fracti on duri ng OLV. Propofol appears to be no more benefi cial on shunt fraction during OLV
compared to sevoflurane.
145
Fi nal l y, the addi tion of 4 cm posi tive end-expi ratory pressure (PEEP)
to the dependent l ung may not i mpai r cardi ac output but reduces shunt fraction during OLV.
146

HEPATIC EFFECTS
Although postoperati ve l i ver dysfuncti on has been associated wi th many of the vol ati le anesthetics
in current use, the most concern has been focused on hal othane. There appears to be two di sti nct
mechani sms by whi ch hal othane can cause hepati tis. One is more common but rel ati vely mi l d,
does not require a previous exposure, and has a l ow morbi di ty. The second i s associated wi th
repeat exposure and probabl y represents an immune reaction to oxi dati vel y deri ved metabol i tes of
FIGURE 15-28. Shunt fraction (top panel) and the alveol ararterial oxygen gradient
(bottom panel) i mmedi atel y before, duri ng, and after one-lung ventil ati on (OLV) i n pati ents
anesthetized wi th desfl urane or i sofl urane. Data are means. (Adapted from Pagel PS, Fu JL,
Damask MC et al : Desfl urane and i soflurane produce simil ar al terati ons i n systemi c and
pul monary hemodynami cs and arterial oxygenati on i n pati ents undergoi ng one-lung
ventil ati on duri ng thoracotomy. Anesth Analg 87:800, 1998.)
halothane and has been associ ated wi th severe l i ver damage and ful minant hepati c fail ure.
The l i ver has two bl ood suppl i es. One i s the wel l -oxygenated bl ood from the hepatic artery and the
second i s the poorl y oxygenated bl ood suppl y from the portal vei n. Hepatocyte hypoxi a is a
si gni fi cant contri butor to postoperati ve hepati c i njury. A pl easant attribute of the ether-based
anesthetics (isofl urane, sevofl urane, and desfl urane) i s their abil i ty to maintai n or i ncrease
hepati c artery bl ood fl ow whi l e decreasi ng (or not changi ng) portal vei n bl ood fl ow.
79, 147
Thi s
contrasts to halothane where decreases in portal vei n bl ood fl ow are not compensated by
increases i n hepatic artery bl ood fl ow (Fi g. 15-29). Rather, hal othane causes sel ecti ve hepatic
artery vasoconstri cti on. It i s esti mated i n animal model s that there i s a 65% reduction in oxygen
avai labi li ty duri ng halothane anesthesi a, whil e duri ng isoflurane the reducti on i n avail abil i ty i s
only 35%.
148

Situations that decrease hepatic bl ood flow or increase hepati c oxygen demand make pati ents
vul nerabl e to the unwanted effects of halothane on hepati c bl ood fl ow. For exampl e, surgery i n the
area of the li ver (or el sewhere in the abdomi nal cavi ty) that might compromi se hepati c blood fl ow
puts patients at risk for hepati c cel l injury. In additi on, enzyme i nducti on, whi ch i ncreases oxygen
demand, enhances the vul nerabil i ty of pati ents to the effects of hal othane. Furthermore, patients
who are criti cal ly dependent on oxygen suppl y for

survi val of remaining l iver ti ssue, such as the cirrhoti c pati ent, are at a hi gher ri sk for further
hepati c injury than nonci rrhoti c i ndi vi duals.
149
Whether this injury can si mpl y be expl ai ned by a
di rect effect of hal othane during hypoxic condi tions or be attri buted to reductive metabol ism of
halothane that is enhanced under hypoxic conditi ons is not enti rel y cl ear.
150

Changes i n l i ver functi on tests have been used as an i ndex of hepati c i njury during anesthesi a.
FIGURE 15-29. Changes (%, mean SE) i n hepati c bl ood flow duri ng admi ni stration of
isoflurane or hal othane. Decreases in portal vei n bl ood fl ow produced by 2 MAC isofl urane are
offset by increases i n hepatic artery bl ood fl ow (autoregul ati on). Hal othane resul ted i n
decreases in both portal vei n and hepati c artery bl ood fl ow, thereby si gnifi cantly
compromisi ng total hepati c artery bl ood fl ow. (Adapted from Gel man, S, Fowl er, KC, Smi th,
LR: Liver ci rcul ati on and functi on duri ng i soflurane and halothane anesthesia. Anesthesi ology
61:726, 1984.)
P.410
Transient increases i n pl asma al ani ne aminotransferase (ALT) acti vi ty foll owed the admi ni strati on
of enfl urane, but not desfl urane, i soflurane, or sevoflurane i n human vol unteers.
147, 151, 152

Al though changes i n the ALT or aspartate aminotransferase (AST) i s an accepted index of l i ver cel l
damage, these measures may not accuratel y reflect the extent of hepati c i njury and are not
uni quel y speci fic to the l iver. Most cases of hal othane hepati ti s demonstrate l esions i n the
centril obul ar area of the l i ver and not coi nci dental l y, thi s area i s most suscepti ble to hypoxia.
Therefore, a more sensi ti ve measure of i njury may be gl utathi one-S-transferase (GST) since it is
di stri buted pri mari l y i n the centri l obular hepatocytes. In pati ent studies comparing hal othane
anesthesia to isofl urane and enflurane,
153
si gnifi cant increases i n GST occurred after hal othane
(i ncreases of 24 to 50%) and enflurane (20%), but not after isofl urane. There were two peaks i n
the GST responses; the first was 3 to 6 hours after hal othane and the other was approxi matel y 24
hours after halothane. It has been suggested that the earl y peak refl ects di rect damage or
i mpai red l i ver bl ood fl ow and the second peak may be caused by metabol i tes or an i mmune
response. The i mmune mechani sm of hepatiti s is considered l ater i n thi s chapter in the secti on
l abel ed Anestheti c Metabol i sm.
NEUROMUSCULAR SYSTEM AND MALIGNANT HYPERTHERMIA
Compared to the al kane halothane, the ether-deri ved, fl uorinated, volatil e anestheti cs produce
about 2-fol d greater skel etal muscl e relaxati on. Ni trous oxi de does not relax skel etal muscl es and
i n doses greater than 1 MAC may, i n fact, resul t i n skeletal muscle ri gidi ty. Interestingly, the
inhaled anestheti cs, i n addi tion to the di rect effects of rel axing skeletal muscle, al so potenti ate
the action of neuromuscul ar bl ocking drugs.
154, 155
Al though the mechani sm of thi s potenti ati on i s
not enti rel y cl ear, i t appears to be l argel y because of a postsynaptic effect at the ni coti ni c
acetylchol ine receptor located at the neuromuscul ar junction.
156
Speci fi cal l y, at the receptor l evel,
the volatil e anestheti cs act synergi sti cal l y wi th the neuromuscul ar bl ocki ng drugs to enhance their
acti on.
157
The degree of enhancement is rel ated to their aqueous concentrati on so that at equi -
MAC concentrati ons, the less potent anesthetics (e.g., desflurane and sevofl urane versus
isoflurane) shoul d have a greater i nhi bitory effect on neuromuscul ar transmissi on. Support for thi s
concept comes from a cli ni cal study demonstrati ng 20% l ower requi rement for vecuroni um to
maintai n a stabl e twitch depressi on duri ng 1.25% desfl urane compared to 1.25% i sofl urane.
158
In
contrast, equi potent concentrati ons of desflurane, isofl urane, and sevofl urane acted si mil arl y to
enhance the effect of ci satracuri um on neuromuscul ar function.
154
Thi s may rel ate to major
structural differences between neuromuscular blocki ng drugs.
All of the potent volatil e anestheti cs serve as tri ggers for mali gnant hyperthermia i n geneti cal l y
suscepti bl e pati ents.
159, 160, 161
In contrast, nitrous oxi de i s only a weak tri gger for mal i gnant
hyperthermia.
161
Studi es eval uating the caffei ne-induced contractures i ndicate the augmentati on
of the contractures by ni trous oxi de is 1.3, whereas that for i sofl urane i s 3-fol d, enfl urane 4-fol d,
and hal othane 11-fol d.
161
Thus, halothane may be the most potent tri gger of the volatil e
anesthetics for mali gnant hyperthermi a. Although desflurane is a weak trigger for mali gnant
hyperthermia, it has been associ ated wi th an unusual delayed onset of symptoms if succi nylchol ine
was not used for neuromuscular blockade.
159, 162

GENETIC/CELLULAR EFFECTS
In tests empl oyed to i dentify chemicals that cause a mutagenic or carci nogeni c response, al l of
the volatil e anestheti cs, incl uding ni trous oxi de, have proven to be negati ve. The Ames test
identi fi es chemi cal s that act as mutagens and carci nogens and has been shown to be negati ve for
enfl urane, isofl urane, desflurane, sevofl urane, and ni trous oxide.
149
Al though hal othane resul ts in
a negati ve Ames test, metabol i tes may be posi ti ve.
Virtual l y every vol ati l e anestheti c agent has been shown to be teratogeni c in ani mal studi es, but
none has been shown to be teratogeni c in humans. Animal studi es have i ndi cated that ni trous
oxi de exposure in the earl y peri ods of gestati on may resul t i n adverse effects, incl uding an
increased incidence of fetal resorption.
163
The same vul nerabil i ty does not exi st during the
administrati on of the potent vol ati le anestheti cs.
164

P.411
However, learning function may be i mpai red in newborn animal s exposed i n utero to inhaled
anesthetics.
165

There has been an ongoing concern about the i nci dence of spontaneous aborti ons in operati ng
room personnel chroni cal ly exposed to trace concentrati ons of inhaled anesthetics, especi all y
ni trous oxide.
163
Ani mal studies usi ng intermi ttent exposure to trace concentrati ons of nitrous
oxi de, hal othane, enflurane, and isofl urane have not reveal ed harmful reproductive effects.
166

Methi oni ne synthetase and thymi dyl ate synthetase are vi tami n B12dependent enzymes that have
been shown to decrease i n activity during ni trous oxi de exposure. The mechani sm appears to be
an i rreversi ble oxi dati on of the cobal t atom of vitami n B12 by nitrous oxi de. The hal f-ti me for
inactivation of methi oni ne synthetase is 46 minutes when 70% ni trous oxi de i s admi nistered to
patients (Fi g. 15-30). Methi oni ne synthetase and thymidylate synthetase are i nvol ved i n the
formation of myelin and the formation of DNA, respecti vel y. Thus, the concern that these changes
mi ght have an effect on a rapi dl y devel opi ng embryo/fetus seems appropri ate. Inhibi tion of these
enzymes coul d al so manifest as depressi on of bone marrow functi on and neurol ogi c disturbances.
In fact, megal oblasti c changes in bone marrow are consi stentl y observed i n pati ents exposed to
ni trous oxide for 24 hours,
239
and four days of exposure to ni trous oxide has resul ted in
agranul ocytosi s. Furthermore, animals exposed to 15% nitrous oxi de for up to 15 days devel oped
a neuropathy presented as ataxia and spi nal cord and peri pheral nerve degenerati on. A sensory
motor pol yneuropathy that is often combi ned with si gns of posteri or l ateral spinal cord
degenerati on resembli ng pernici ous anemi a has been descri bed in humans who chronicall y inhale
ni trous oxide for recreational use.
167
These effects have been attributed to reduced acti vi ty of the
vitami n B12dependent enzymes.
Despi te the unproven infl uence of trace concentrati ons of the volatil e anestheti cs on congeni tal
development and spontaneous aborti ons, these concerns have resul ted i n the use of scavengi ng
systems to remove anesthetic gases from the operati ng room and the establ i shment of
Occupati onal Saftey and Heal th Admi ni strati on standards for waste gas exposure. The Nati onal
FIGURE 15-30. Time course of inactivati on of hepatic methioni ne synthase (synthetase)
acti vi ty duri ng admini stration of 50% ni trous oxide to rats or 70% nitrous oxi de to humans.
The hal f-li fe was substanti al l y l ess in rats. (Adapted from Royston BD, Nunn JF, Weinbren HK
et al : Rate of inactivati on of human and rodent hepati c methi onine synthase by nitrous oxide.
Insti tute for Occupati onal Safety and Heal th recommended exposure level s for ni trous oxi de is 25
parts per mi l li on (ppm) as a ti me-weighted average over the ti me of exposure. The exposure l i mi t
for hal ogenated anestheti cs (without nitrous oxi de exposure) i s 2 ppm.
OBSTETRIC EFFECTS
Simil ar to the effects of volatil e anestheti cs on vascul ar smooth muscl e, a dose-dependent
decrease i n uterine smooth muscl e contracti l ity and blood fl ow occurs, and the response appears
to be simi lar among the vol ati le anestheti cs.
168, 169
Consequentl y, a common technique used to
provi de general anesthesi a for urgent Caesarean secti ons i s to admi ni ster low concentrati ons of
the volatil e anestheti c, such as 0.5 MAC, combi ned wi th ni trous oxi de. Thi s decreases the
li kel ihood of uterine atony and bl ood l oss, especi al l y at a ti me after del i very when uterine
contracti on i s essenti al .
170
Uteri ne relaxation can become troubl i ng at concentrati ons of vol ati l e
anesthesia greater than 1 MAC, and hi gher concentrati ons mi ght delay the onset ti me of newborn
respirati on.
170
In some situations, uteri ne relaxati on may be desi rabl e, such as to remove a
retai ned pl acenta. In this case, a bri ef, high concentrati on of a volatil e anestheti c may be
advantageous. In terms of neonatal effects of general anesthesi a, APGAR scores and aci d-base
bal ance are not affected by anestheti c technique, such as spinal versus general .
171
More sensi ti ve
measures of neurol ogi c and behavi oral function, such as the Scanl on Earl y Neonatal
Neurobehavi oral Scale (ENNS) and the neurologi cal and adapti ve capaciti es score (NACS) indicate
some transient depressi on of scores fol l owing general anesthesi a that did not persi st at 24 hours
postdel i very measurements.
171, 172
Fetal loss seems to increase fol l owi ng surgery i n the fi rst or
second tri mester, but the majority of these findi ngs have been i n pati ents foll owi ng acute
abdomen or trauma in emergency setti ngs. General l y, el ecti ve surgeri es are del ayed unti l at l east
6 weeks postpartum, or until the l ate second or earl y third tri mester. Perhaps the most i mportant
factor i n promoti ng good fetal outcome is mai ntai ni ng good uteri ne bl ood fl ow duri ng anesthesi a
and surgery.
ANESTHETIC DEGRADATION BY CARBON DIOXIDE ABSORBERS
The majori ty of adul t general anesthesi a i s given through cl osed or semicl osed breathi ng ci rcuits.
Thi s mandates the use of a carbon dioxi de absorbent i n the circui t. One of the probl ems wi th the
CO
2
absorbents in use today is thei r chemi cal makeup, whi ch consi sts of monoval ent hydroxi de
bases (KOH and NaOH). These strong bases resul t i n breakdown or degradati on of al l modern-day,
potent anestheti cs.
173
Degradati on of the anesthetics i s sl i ghtly greater wi th potassium hydroxi de.
Bari um hydroxi de li me, whi ch contai ns potassium but not sodi um hydroxi de, causes more
anesthetic degradation than soda l ime (whi ch contai ns l ess potassium hydroxi de and more sodi um
hydroxide).
174
In the case of hal othane and sevofl urane, the reacti on wi th carbon di oxi de
absorbents resul ts in degradati on of these anestheti cs to hal oal kenes.
5
Hal othane degrades to
form trace amounts of BCDFE (2-bromo-2-chloro-1,1-di fl uoroethene) and sevofl urane degrades to
form trace amounts of compound A (2,2-di fl uoro-1-[trifluoromethyl ] vi nyl ether). These
haloal kenes have been shown to be nephrotoxi c in rats,
175
al though cli ni cal l y si gni fi cant renal
effects of hal oalkene formati on i n surgi cal pati ents have not been reported. In dehydrated carbon
di oxi de absorbents, degradati on of desfl urane, enflurane, isofl urane, and sevofl urane resul ts i n
carbon monoxi de formation
176, 177
,
248

Speci al mention of several novel carbon dioxi de absorbents that have reduced or el i mi nated
sodi um and potassi um hydroxi de content i s warranted pri or to delving i nto the discussion of
compound A, carbon monoxide, and fi res. The new absorbents, call ed Amsorb Plus and
DrgerSorb Free, contain primari ly cal ci um hydroxi de. These new absorbents are chemi cal ly
unreactive wi th sevofl urane, enfl urane, i sofl urane, and desfl urane, and thus, they essential ly
el i mi nate the degradati on of these anestheti cs to carbon monoxi de and compound A (Fi g. 15-
31).
178, 179, 180

Compound A
Sevoflurane undergoes base-catal yzed degradati on i n carbon di oxide absorbents to form a vinyl
ether cal l ed compound A. The producti on of compound A i s enhanced i n low-flow or closed-
ci rcuit breathi ng systems and by warm or very dry CO
2
absorbents. Barium hydroxide l i me
produces more compound A than soda li me and thi s can be attri buted to sl ightl y hi gher absorbent
temperature duri ng CO
2
extracti on.
174

Studies i n rats where compound A has been administered i n the inspired gas have i dentifi ed a
threshold for renal tubul ar necrosi s between 290 and 340 parts per mil l ion (ppm) hour (e.g., 50
ppm 6 hr = 300 ppm
.
hr) (Fi g. 15-32).
181, 182
The nephrotoxici ty i s characteri zed by cel l necrosi s
of the corti cal medul lary tubul es located i n the proxi mal tubul es.
175
The associ ated bi ochemical
markers include elevations of serum BUN and creati ni ne, glucosuri a, and protei nuri a.
175, 181
In
addi ti on, several enzymes from the tubul e cell s have been used as markers of cel l i njury including
increases i n uri nary excreti on of n-acetyl-beta-D-gl ucosaminidase (NAG) and al pha-gl utathi one-S-
transferase (GST).
175, 181

FIGURE 15-31. Compound A l evel s produced from three carbon dioxi de absorbents duri ng 1
MAC sevoflurane anesthesi a del i vered to vol unteers at 1 l pm fresh gas fl ow (mean SE). Gas
sampl es were taken from the i nspired l imb of the anesthesia ci rcui t. *different from
Baralyme or soda lime (p<0.05). (Adapted from Mchaourab A, Arai n SR, Ebert TJ: Lack of
degradation of sevofl urane by a new carbon dioxi de absorbent in humans. Anesthesi ol ogy
94:1007, 2001.)
P.412
There are wel l -defined speci es differences i n the threshol d for compound Ai nduced
nephrotoxi ci ty. The threshol d i s approxi mately 300 ppmhr in 250-gm rats,
181
,
262
greater than 612
ppmhr i n pi gs,
183
and between 600 and 800 ppmhr in monkeys.
184
In pati ents and volunteers
recei vi ng sevofl urane i n cl osed-ci rcuit or l ow-flow del i very systems, inspired compound A
concentrations averaged 8 to 24 and 20 to 32 ppm wi th soda l i me and bari um hydroxi de l ime,
respectively.
185, 186, 187
Total exposures as high as 320 to 400 ppmhr have had no cl ear effect on
cl i ni cal markers of renal functi on.
188, 189
In randomized and prospecti ve vol unteer and pati ent
studi es, no adverse renal effects from l ow-fl ow (0.5 to 1.0 L/mi n) or cl osed-ci rcuit sevoflurane
anesthesi a were detected usi ng both standard cli nical markers of renal function (serum creati ni ne
and BUN concentrati ons) and experimental markers of renal functi on and structural integrity
(proteinuri a, gl ucosuria, and enzymuri a).
185, 186, 189, 190, 191, 192
In fact, several new studi es eval uated
the renal effects of long durati on, low-flow sevoflurane i n patients with preexi sti ng renal di sease
(pl asma creati ni ne >1.5 mg/dL).
193, 194
The fresh gas fl ow was 1 LPM, bari um hydroxi de absorbent
was employed, and mi ni mal anestheti c adjuvants were gi ven to maximi ze the dose of sevofl urane
and production of compound A. There were no adverse effects from sevofl urane determi ned with
both standard cli nical markers and biochemi cal markers of renal function. Recent evi dence from
patients undergoi ng elective surgery i ndi cates that transi ent proteinuri a, gl ucosuria, and
enzymuri a al so occur after desflurane, isofl urane, and propofol anesthesia, without changes in
serum BUN and creati ni ne.
186, 187
Despi te sol id evi dence for the renal safety of low-flow
sevofl urane from randomi zed prospecti ve studi es, the renal safety of sevofl urane has been
questi oned and debated.
195, 196

Asi de from the high probabil i ty that the absence of renal injury in pati ents is because of low
compound A l evel s duri ng the cli nical use of sevofl urane i n a low-flow system, another probable
explanation must be consi dered. Compound A is not i tsel f toxic to organs. Rather i t is the
bi odegradati on of compound A to cystei ne conjugates and the further action of a renal enzyme
call ed beta-lyase on the conjugates that can resul t i n formati on of a potential ly toxi c thi ol (Fi g.
15-33).
182, 197
There is cl ear evi dence for species di fferences in the bi otransformati on of compound
A to cystei ne-s conjugates.
198
Recent evi dence suggests that the cystei ne conjugates can be
handl ed in one (or both) of two ways.
199
They can be acetylated to mercapturi c aci d through a
detoxi cati on pathway, whi ch resul ts i n no organ toxi city, or acted on by an enzyme in the kidneys

call ed renal beta-lyase, to form reacti ve intermedi ates (toxi fi cation pathway). These reacti ve
intermedi ates are responsibl e for the renal cel l necrosi s seen i n rats. The beta-lyase-dependent
metaboli sm pathway i n humans i s far l ess extensi ve than the beta-lyase pathway in rats (8 to 30
ti mes l ess acti ve).
198
Thus, compared wi th rats, humans recei ve markedl y l ower doses of
compound A and metabol ize a lower fracti on of compound A vi a the renal beta-lyase pathway. This
may account for the safety of sevoflurane i n both human vol unteers and pati ents when compared
to rat model s. Fi nal ly, pharmacovi gi lance suggests sevofl urane i s not nephrotoxi c. The anestheti c
has been i n cl ini cal use for nearl y a decade, and many countri es outsi de the Uni ted States have no
fl ow restri cti ons on sevofl urane, yet not a si ngl e case report of renal harm from sevoflurane has
been presented i n the li terature.
FIGURE 15-32. Renal bi opsy resul ts from rats inhali ng different concentrations of compound
A for 3 hours. The deri ved threshol d to cause renal necrosis i s around 100 ppm (300
ppmhr). The typi cal human exposure duri ng the admi ni stration of sevofl urane i n a
semi cl osed circui t i s between 10 and 35 ppm of compound A, whi ch fal ls wel l bel ow the
threshold to cause renal i njury i n rats. (Adapted from Kharasch ED, Hoffman GM, Thorni ng D
et al : Role of the renal cysteine conjugate -lyase pathway i n i nhaled compound A
nephrotoxi ci ty i n rats. Anesthesi ol ogy 88:1624, 1998.)
P.413
Car bon Monoxi de and Heat
CO
2
absorbents degrade sevofl urane, desflurane, enfl urane, and i soflurane to carbon
monoxide when the normal water content of the absorbent (13 to 15%) i s markedl y
decreased below 5%.
176, 177, 200
The degradation i s the resul t of an exothermi c reacti on of the
anesthetics wi th the absorbent. The anestheti c mol ecular structure and the presence of a strong
base i n the carbon dioxi de absorbent are involved i n the formati on of CO. Desflurane, enfl urane,
and isofl urane contain a di fl uoromethoxy moiety that i s essenti al for the formation of CO. When
studi es are conducted wi th CO
2
absorbents mai ntai ned at or just above room temperature,
desfl urane and enfl urane gi ven at just under 1 MAC produced up to 8,000 and 4,000 ppm of CO,
respecti vel y, versus 79 ppm with nearl y 2 MAC sevoflurane.
176
In dehydrated barium hydroxide,
CO production from desflurane was nearly 3-fold higher than wi th soda l i me but was trivi al wi th
sevoflurane. In normal clinical use, CO
2
cani ster temperatures are 25 to 45C, but can be hi gher
when empl oying a very l ow fresh gas flow. In a l aboratory setti ng, when CO
2
cani ster temperature
is not control l ed and sevoflurane is admi ni stered to desi ccated bari um hydroxi de, the exothermi c
reacti on can increase canister temperatures. If CO
2
cani ster temperature exceeds 80C, signi fi cant
CO producti on i s noted wi th sevofl urane.
177
Instances of CO poisoning have been reported in
si tuati ons where the CO
2
absorbent has been presumabl y dri ed (desi ccated) because an anestheti c
machi ne has been l eft on wi th a hi gh fresh gas fl ow passi ng through the CO
2
absorbent over an
extended peri od of ti me.
201, 202, 203, 204
In an experi mental setti ng, overnight dryi ng of bari um
hydroxide for 14 hours at 10L/min fresh gas fl ow did not resul t in significant CO producti on from
desfl urane, whereas 24 to 66 hours of fresh gas fl ow drying produced si gni fi cant CO production.
205

Al though desfl urane produces the most CO with anhydrous CO
2
absorbers, the reacti on wi th
sevofl urane produces the most heat. The strong exothermi c reacti on has caused si gni fi cant heat
producti on, fires, and pati ent i njuri es.
206, 207
Although sevoflurane is not flammable at less than
11%, formal dehyde, methanol , and formate have been i dentifi ed and these al one or in
combi nation with oxygen mi ght be fl ammabl e at high cani ster temperatures. In experi mental
setti ngs, l ong exposure of 1 MAC sevofl urane to desi ccated absorbents resul ted i n cani ster
temperatures i n excess of 300C and can be associ ated wi th smol deri ng, mel ti ng of plasti c
FIGURE 15-33. Known pathways for metabol ism and eli minati on of compound A in humans.
A potenti al toxin resul ts only from the acti on of renal beta-lyase on cystei ne-S-conjugates.
The activity of this enzyme in humans is 8- to 30-fol d l ess than i n rats. Considerabl e
handl ing of the cystei ne-S-conjugates i n humans is vi a N-acetylation to mercapturic acid.
(Adapted from Kharasch ED, Jubert C: Compound A uptake and metabol i sm to mercapturi c
acids and 3,3,3-trifluoro-2-fluoromethoxypropanoic acid during l ow-flow sevofl urane
anesthesia. Anesthesi ol ogy 91:1267, 1999.)
components, expl osi ons, and fi res.
177

There are newer CO
2
absorbents that do not degrade anestheti cs (to ei ther compound A or carbon
monoxi de) and they shoul d reduce exothermi c reacti ons. From a pati ent safety perspecti ve,
widespread adopti on of a nondestructive CO
2
absorbent shoul d be axi omati c.
173
Al though the cost
of these new CO
2
absorbents (Amsorb Pl us and DrgerSorb Free) i s hi gher and the absorptive
capaci ty may be lower than ei ther barium hydroxide l i me or soda li me, their benefi t may be
substantial . The use of a nondestructive absorbent el i mi nates all of the potenti al compl icati ons
rel ated to anesthetic breakdown and therefore mi ni mi zes the possi bi li ty of addi ti onal costs as a
resul t of those compl i cations, i ncl udi ng addi tional l ab tests, hospi tal days and medi cal /l egal
expenses. Adoption of these new absorbents into routi ne cl i ni cal practice i s consi stent with the
patient safety goal s of our anesthesi a societi es.
ANESTHETIC METABOLISM
Fl uor i de- I nduced Nephr ot oxi ci t y
Metabol ism (bi otransformation) of hal ogenated anestheti cs to free inorgani c fl uori de, resul ti ng i n
nephrotoxi ci ty, i s now an accepted fact for the anestheti c methoxyfl urane. The metabol ism of
methoxyfl urane and, to a l esser extent, enfl urane has resul ted i n a well -descri bed i njury to renal
coll ecti ng tubul es.
208, 209
The nephrotoxici ty associ ated wi th these anestheti cs presents as a hi gh
output renal i nsuffici ency that i s unresponsi ve to vasopressi n and is characteri zed by dil ute
pol yuri a, dehydrati on, serum hypernatremi a, hyperosmol ali ty, el evated BUN, and creati ni ne. An
association between i ncreased plasma fluoride concentrati ons and metabol i sm of these anestheti cs
led to a fluori de hypothesis.
208
Nephrotoxi city is caused by metabol i sm of the vol ati l e
anesthetics to fluori de, and the i norganic fl uoride i s the ulti mate substance produci ng the renal
injury. Thi s hypothesis has been reexami ned recently i n part because sevofl urane undergoes 5%
metaboli sm that resul ts in transi ent i ncreases i n serum fl uori de concentrati ons but has not been
associated wi th a renal concentrati ng defect.
209
The tradi ti onal hypothesis stated that both the
duration of the hi gh systemi c fl uori de concentrati ons (area under the fl uoride ti me curve) and the
peak fluori de concentrati on (peaks above 50 M appear to represent the toxi c threshol d) were
rel ated to nephrotoxici ty (Fi g. 15-34).
208
The safety of sevoflurane and the rel ati ve safety of
enfl urane wi th regard to fluori de concentrati ons may be because of a rapi d decl i ne i n pl asma
fluori de concentrati ons as a resul t of l ess avai labil i ty of the anestheti c for metabol i sm from a
faster washout compared to methoxyflurane.
210

A recent report further cl ari fi es this i ssue and has l ed to a modificati on of the tradi tional fl uori de
hypothesi s for renal toxici ty.
211
That is, the si te of metabol ism is an important factor i n toxi city
(i .e., i ntrarenal metaboli sm contri butes to nephrotoxici ty). The metabol i sm of methoxyfl urane to
fluoride in the kidney is significantly greater than that of sevoflurane and enflurane. Thi s may be
rel ated to the multi ple cytochrome P450 enzymes i n the ki dney responsibl e for metabol ism of
methoxyfl urane (P450-2A6, P450-3A, P450-2E1).
211
In contrast, sevofl urane and enflurane are
pri mari l y metabol i zed by the cytochrome P450-2E1. Thus, i ntrarenal fl uoride generated from
methoxyfl urane metabol i sm and/or the mul ti pl e P450 isoenzymes involved i n methoxyfl urane
metaboli sm may account for the nephrotoxi city from thi s anesthetic. Therefore, the potenti al for
toxi ci ty from rel ati vel y hi gh pl asma l evels of fluori de foll owing l ong exposure to sevoflurane and
enfl urane i s offset by the mi ni mal amount of renal defl uori nati on and thi s may expl ai n the rel ati ve
absence of renal concentrating defects wi th these anestheti cs.
209, 211
,
273

Factors such as total dose of anestheti c, enzyme i nducti on, and obesi ty have been proven to
enhance bi otransformati on. The activity of hepati c cytochrome P450 enzymes is i ncreased by a
vari ety of drugs, includi ng phenobarbi tal , phenytoi n, and i soniazi d.
212
Obesi ty causes i ncreased
metaboli sm (defl uori nation) i n halothane, enflurane, and i sofl urane. However, the effects of
obesity on the defl uori nation of sevofl urane are less cl ear.
213

FIGURE 15-34. Pl asma i norgani c fl uori de concentrati ons (mean SE) before and after 2 to
4 hours of methoxyflurane, enfl urane, sevoflurane, isofl urane, and desfl urane anesthesi a.
(Adapted from Kharasch ED, Armstrong AS, Gunn K, et al: Cl ini cal sevofl urane metabol i sm
and di sposi ti on. II. The rol e of cytochrome P450 2E1 i n fluori de and hexafl uoroi sopropanol
formation. Anesthesi ology 82:1379, 1995; Mazze RI: Metaboli sm of the inhaled anaesthetics:
Impli cati ons of enzyme i nducti on. Br J Anaesth 56:27S, 1984; and Sutton TS, Kobl i n DD,
Gruenke LD, et al : Fl uori de metabol i tes after prol onged exposure of vol unteers and pati ents
to desflurane. Anesth Anal g 73:180, 1991.)
P.414
Hepat i c I nj ur y f r om Met abol i sm: Hal ot hane Hepat i t i s
Although postoperati ve l i ver dysfuncti on has been associ ated wi th most of the vol ati le
anesthetics i n current use, the most focused attenti on has been directed to halothane. This i s
i n part because of the rel ati vel y recent demonstrati on of bi ndi ng of an oxi dati vel y deri ved
metaboli te of hal othane to l iver cytochromes, which coul d then act as haptens and i nduce an
immune reacti on. Thi s hypersensi tivity reaction has been associ ated with severe li ver damage and
ful mi nant hepati c fai l ure. There are many causes of postoperati ve jaundice and abnormal li ver
functi on tests, including vi ral hepati tis, coexisting l iver di sease (such as Gil bert' s disease), bl ood
transfusions, septicemi a, drug reactions, i ntra- and postoperati ve hypoxia and hypotension, and
di rect tissue trauma as a resul t of the surgi cal procedure.
150
The di agnosi s of hal othane hepati tis
i s general l y made based on i ncompl ete excl usi on, defined as the appearance of l i ver damage
within 28 days of hal othane exposure i n a person in whom other known causes of li ver di sease
have been excl uded.
Hal othane was introduced into cl ini cal practi ce in 1956, and case reports of unexplai ned jaundi ce
fol l owing anesthesi a wi th hal othane began to appear in 1958. By 1963, at l east 350 putati ve cases
of halothane hepatiti s had been reported. In 1967, i t was i denti fi ed that approxi matel y 18% of
hal othane was metabol i zed i n man.
214
The metabol ites were oxi dati vel y derived. It is now known
that oxi dati ve metabol ism of hal othane, catal yzed by hepatic cytochrome P450 2E1, produces a
reacti ve intermedi ate, trifl uoroacetyl (TFA) that can coval entl y modi fy li ver mi crosomal protei ns.
Thi s compl ex can produce an i mmune response i n some i ndi vi dual s that i s characteri zed by
i mmunogl obul i n G anti bodi es. However, hal othane-associated hepati tis can present as one of two
cl i ni cal syndromes and i t is l i kely that only one syndrome can be expl ained by an i mmune
mechanism.
150, 215
Each syndrome may develop after an uneventful anesthesia and surgery wi th no
apparent ti me-to-dose rel ati onshi p. The most common syndrome, whi ch occurs i n cl ose to 20% of
the adult patients recei vi ng halothane, i s a mi ld, sel f-li mi ted postoperati ve i ll ness that has been
attri buted to reductive metabol ism of halothane and this route of metabol ism is enhanced under
low oxygen or hypoxi c condi tions. Reductive metabol ism of isofl urane, desflurane, sevofl urane,
and enfl urane does not occur. Thi s may rel ate to the fact that halothane uni quel y reduces hepati c
bl ood flow (both portal vein and hepati c artery bl ood fl ow).
216, 217
The typi cal presentati on of
hepati ti s from reducti ve metabol i sm i s a rapi d (1 to 3 days) but mi l d, unprogressi ng pattern of
li ver i njury characteri zed by nausea, l ethargy, fever, moderatel y i ncreased concentrati ons of li ver
transami nases, and, rarely, transi ent jaundi ce. It does not requi re a repeat exposure, as does the
immune mechanism of hepatitis; it can occur on the fi rst exposure to hal othane.
Several more recent observati ons suggest that reductive metabol ism is not an important
mechani sm i n the evol uti on of the i mmune-mediated hal othane hepati tis.
150
The possi bi li ty exi sted
that bi ndi ng of a metabol i te of halothane to li ver cytochromes coul d act as haptens and i nduce a
hypersensi tivity response.
218
Supporti ng thi s possi bil i ty were the cli ni cal manifestati ons of
hepati ti s, including eosi nophi l ia, fever, rash, arthral gi a, and pri or exposure to hal othane. The
possi bi li ty of a geneti c susceptibi l ity factor i s suggested by case reports of hal othane hepati ti s i n
cl osel y related pati ents.
215
The most compel l ing evi dence for an immune-mediated mechanism is
the presence of circul ati ng i mmunogl obul i n G (IgG) anti bodi es i n up to 70% of pati ents wi th
di agnosi s of hal othane hepati tis.
150, 218
Thi s anti body i s not di rected agai nst the reductive
metaboli te of hal othane, but agai nst an oxi dative compound, TFA hal i de, which is i ncorporated
onto the surface of the hepatocyte (Fi g. 15-35).
219
TFA protei ns have been i denti fi ed from the
li ver of rats after halothane exposure with enzyme-li nked immunosorbent assays and
immunobl otti ng techni ques. These al tered proteins can be seen by the i mmune

system as nonsel f (neoanti gen), generati ng producti on of anti bodi es. These can now be i denti fi ed
from serum sampl es of humans by i denti fyi ng anti -TFA al bumin acti vi ty on an ELISA screeni ng
eval uation.
220

P.415
Thi s metaboli c pathway i nvol vi ng the cytochrome P450 2E1 system during hal othane exposure i s
identi cal to the metaboli c pathway noted wi th enfl urane, i sofl urane, and desflurane. However, the
expressi on of the neoanti gens shoul d be rel ated to the amount of metabol i sm of each agent. Thi s
woul d suggest that hal othane i s > enflurane > isoflurane > desfl urane in terms of anti geni c
load.
221
Indeed, case reports have appeared i n the li terature l i nking each of these anestheti cs wi th
immune-mediated hepati tis.
220, 222, 223
,
311
If the incidence of fulminant hepati c fail ure after
halothane i s 1 i n 35,000,
224
hepati c fail ure caused by i soflurane may occur i n only 1 i n 3,500,000
isoflurane anesthetics, and a l ower inci dence woul d be expected wi th desfl urane. There are no
reports of ful mi nant hepati c necrosi s associ ated wi th sevofl urane i n humans. Sevoflurane is not
metaboli zed to a TFA hal ide; rather i t i s metabol i zed to hexafl uoroisopropanol , whi ch does not
serve as a neoantigen (Fi g. 15-36).
147
Desflurane is the l east metabol i zed of the volatil e
anesthetics, resulti ng i n very small amounts of adduct, and onl y one case report of hepatotoxi ci ty
from desfl urane has been descri bed.
220
Sensi ti zati on of this pati ent by two exposures to hal othane
(18 years and 12 years previousl y) preci pitated massive hepatotoxi city. Anti -TFA anti bodi es were
identi fi ed i n the serum.
FIGURE 15-35. Halothane i s metabol ized to a tri fl uoroacetyl ated (TFA) adduct that bi nds to
li ver protei ns. In suscepti ble patients, thi s adduct (altered protei n) i s seen as nonsel f
(neoantigen), generating an i mmune response (producti on of anti bodi es). Subsequent
exposure to halothane may resul t in hepatotoxi city. A simil ar process may occur in
geneti cal l y suscepti bl e indi vi duals after anesthetic exposure to other fluori nated vol ati l e
anesthetics (enfl urane, i sofl urane, desfl urane) that also generate a TFA adduct. (Adapted
from Njoku D, Laster MJ, Gong DH et al : Biotransformati on of hal othane, enfl urane,
isoflurane, and desflurane to tri fl uoroacetyl ated l i ver protei ns: Associ ati on between protei n
acyl ati on and hepati c i njury. Anesth Anal g 84:173, 1997.)
Herei n l i es another probl em. Immunol ogic memory resul ti ng i n hepati tis has been reported 28
years after an i ni tial hal othane exposure.
225
In additi on, cross-sensi ti vi ty has been reported in
whi ch exposure to one anesthetic can sensi ti ze patients to a second but different anesthetic.
220, 226

Recentl y these autoantibodi es have been identi fi ed i n 10% of health care workers (PACU nurses,
nurse anestheti sts, and anesthesi ol ogi sts) chronicall y exposed to low l evel s of anestheti cs.
221, 227

Although thi s fi ndi ng i s i ntri guing i f not alarmi ng, the impli cati on that anestheti cs with the hi ghest
rates of metabol i sm (halothane, enfl urane, and perhaps even i sofl urane) shoul d be removed from
the OR setti ng requi res further vali dati on. It i s worth recal li ng that despite case reports of hepati c
damage associ ated wi th hal othane, which appeared i n the l iterature wi thi n 2 years of its
introducti on, i t has taken some 35 years of research and debate to reach the current consensus on
the mechani sm of hal othane-associated hepati tis and ful minant hepati c fail ure. It i s the opi ni on of
these authors that hal othane shoul d not be used i n adult surgical cases and shoul d be strongly
di scouraged i n the pedi atri c popul ation. Al though the inci dence of hepati ti s appears to be much
l ower i n the pedi atri c popul ati on, our concern i s related to i mmunol ogi c memory resul ting i n
hepati ti s l ater in l ife during a repeat exposure to anesthesi a; addi tional concerns rel ate to heal th
care workers who are chroni cal ly exposed to trace amounts of halothane. The new vol ati l e
anesthetics have an extremel y low potenti al for hepatotoxi city and the possi bil i ty of avoi di ng even
one case of fulminant hepatic fail ure from a vol ati le anesthetic is sufficiently compel l ing to
di scourage use of the ol der, more metabol ized anestheti cs i ncl udi ng halothane and enflurane.
CLINICAL UTILITY OF VOLATILE ANESTHETICS
For I nduct i on of Anest hesi a
Although current-day practi ces for establi shi ng the anestheti c state consist of i ni tial
administrati on of an IV sedativehypnoti c, there i s an increasi ng interest i n the use of vol ati le
anesthetics vi a the face mask. Thi s is commonpl ace in pediatri c anesthesi a but rel ati vel y rare i n
adult anesthesi a. Hi stori cal ly, i n the days of ether and cycl opropane, the standard induction
technique was a mask induction. The renewed i nterest i n thi s techni que i s attri buted primari ly to
the newer potent and poorl y sol uble anestheti c, sevofl urane, whi ch i s nonpungent and, therefore,
can easil y be inhal ed.
228
An important attribute of the gaseous i nducti on techni que i s the abil i ty to
take the patient deep in a rapi d fashion, thereby avoi di ng some of the unwanted si de effects of
FIGURE 15-36. Pathway for oxi dati ve metabol ism of sevofl urane (UDPGA, uri di ne
di phosphate glucuroni c aci d). Tri fl uoroacetylated (TFA) adducts are not formed from the
metabol i sm of sevofl urane. (Adapted from Frink EJ Jr, Ghantous H, Malan TP et al : Pl asma
inorganic fluori de wi th sevoflurane anesthesi a: Correl ati on wi th i ndi ces of hepati c and renal
functi on. Anesth Anal g 74:231, 1992.)
stage 2 of anesthesi a (exci tation, sal ivati on, coughi ng, movement), noted hi stori cal l y with the use
of the hi ghl y sol ubl e anestheti c, ether. Inducti on of anesthesia with halothane i n the pediatri c
popul ati on i s qui te common. The resurgence of i nterest in mask induction in the adul t population
centers on the potenti al safety and uti l ity of thi s technique when usi ng sevofl urane.
229, 230, 231, 232

The safety issues consi st pri mari l y of the fact that spontaneous venti lation is preserved wi th a gas
i nducti on, and pati ents essential ly regulate their own depth of anesthesi a, as excessive
sevofl urane woul d, i n fact, suppress venti lation. Safety woul d be compromi sed i f stage 2
exci tati on was problemati c; however, cli ni cal studi es indicate that thi s is not the case. It i s l ikel y
that the l ow blood:gas sol ubi li ty of sevofl urane makes for a rapid inducti on. Typical ti mes to loss
of consciousness average approxi matel y 1 mi nute when deli vering 8% sevofl urane via the face
mask. Sevofl urane al so has been used i n the approach to the di ffi cul t adult airway because of the
preservation of spontaneous venti lation and absence of sali vation with thi s technique.
233
The
tradi tional awake l ook in the suspected diffi cult ai rway (where IV drugs are ti trated to a l evel
that al l ows di rect l aryngoscopy i n the awake pati ent) has been modi fi ed to consist of spontaneous
ventil ati on of hi gh concentrati ons of sevoflurane unti l laryngoscopic eval uation is tolerated.
Laryngeal mask pl acement can be successful ly achieved 2 mi nutes after admi ni steri ng 7%
sevofl urane vi a the face mask.
230
The addi ti on of nitrous oxi de to the inspired gas mi xture does
not add si gni fi cantl y to the i nducti on sequence. The gas i nducti on techni que i s promoted by
pretreatment wi th benzodi azepi nes but compl i cated by apnea wi th opi oid pretreatment.
231
Of
course the uti li ty of thi s techni que i s that cl i ni ci ans simpl y need to pay attenti on to the airway
duri ng the i nducti on sequence, rather than reaching for drugs and injecti ng them through an IV
port. Importantl y, pati ent acceptance of thi s techni que has been rel ati vely hi gh, exceedi ng 90% of
the cases.
232
There have been a number of techniques descri bed to use sevofl urane for inducti on

of anesthesi a via face mask. These i ncl ude pri mi ng the circui t (emptyi ng the rebreathi ng bag,
openi ng the pop-off val ve, dial ing the vapori zer to 8% whi l e usi ng a fresh gas fl ow of 8 L/mi n,
and maintai ni ng this for 60 seconds pri or to appl yi ng the face mask to the pati ent); a si ngl e-
breath i nduction from end-expiratory volume to maxi mum i nspi red vol ume; and simpl y deep
breathing. Al l seem to have the successful end resul t of l oss of consciousness, generall y withi n 1
minute.
For Mai nt enance of Anest hesi a
The vol ati le anesthetics are clearly the most popul ar drug used to maintai n anesthesia. They are
easil y administered via i nhal ati on, they are readil y ti trated, they have a hi gh safety rati o i n terms
of preventi ng recal l , and the depth of anesthesi a can be qui ckly adjusted i n a predi ctable way
whi l e moni toring tissue l evel s vi a end-ti dal concentrati ons. They are effecti ve regardl ess of age or
body habi tus. They have some properties that prove benefi cial in the operating room, i ncl udi ng
rel axation of skeletal muscle, in most cases preservati on of cardi ac output and cerebral bl ood
fl ow, and rel ati vel y predi ctabl e recovery profi l es. Some of the drawbacks to the use of the current
vol ati l e anestheti cs are the absence of anal gesi c effects, thei r associ ati on wi th postoperati ve
nausea and vomi ti ng, and thei r potential for carbon monoxi de poi soni ng and hepati ti s.
PHARMACOECONOMICS AND VALUE-BASED DECISIONS
In the current envi ronment of cost containment, cl i ni cians are constantl y bei ng pressured to use
less-expensive anestheti c agents, i ncl udi ng anti emeti cs, neuromuscul ar bl ocki ng drugs, and
vol ati l e anestheti cs. If succumbi ng to these pressures, the cl i ni ci an must focus on provi di ng val ue-
based anesthesi a. That is, to obtain the best resul ts at the most practi cal cost. Factors i nvol ved in
the value-based deci sion include the effi cacy of the drug, the side effects, i ts di rect costs, and i ts
indirect effects. In terms of effi cacy, al l of the vol atil e anestheti cs are reasonabl y si mi l ar, that i s,
they can be used to establ i sh state of anesthesi a for surgi cal i nterventi ons and can be easi ly
reversed. In terms of si de effects, the things to consider are seri ous si de effects or toxici ti es
versus manageabl e si de effects, and to what extent these manageabl e side effects i ncrease the
cost. Regardi ng serious si de effects, al though hal othane i s the l east expensi ve of the vol ati l e
anesthetics, i t has defi ni te l i fe-threatening potenti al i n terms of sensi ti zati on of the heart to
arrhythmi as and the devel opment of an i mmune response that can cause fulmi nant hepati c
P.416
necrosi s. One can make a strong argument that hal othane does not bel ong in the operating room.
A common si de effect of the volatil e anestheti cs is nausea and vomi ting. The need for rescue
medicati ons to treat nausea and vomi ti ng after volatil e anesthesi a needs to be wei ghed i nto any
legi ti mate cost anal ysi s. Di rect costs are not si mpl y the cost/mL of l i qui d or cost/bottl e of
anesthetic. Rather, they refl ect the combi nati on of the potency of the drug to establi sh a MAC
level , the fresh gas fl ow, and the cost of the anestheti c. At 2 L/mi n fresh gas fl ow, del iveri ng 1
MAC, both desflurane and sevoflurane cost about $13.00 to $15.00/hr. Thi s contrasts to
generi cal l y priced i sofl urane, whi ch costs $1.00 to $2.00/MAC
-
hr when del ivered at 2 L/mi n.
234

Simply reducing the fresh gas fl ow of sevofl urane and desfl urane can halve the cost/MAC
-
hr of
these more expensi ve anestheti cs without compromi sing thei r speed and effecti veness. The
indirect costs are probabl y the most di ffi cul t to pi npoi nt, but may be the most important to
eval uating the cost of usi ng the new volati l e anestheti cs. Exampl es of indi rect costs i ncl ude costs
associated wi th OR ti me, ti me in the PACU versus bypassi ng the PACU to a step-down uni t, and
labor costs and outcome related costs, such as l i ti gati on to defend a bad outcome from an
anesthetic drug.
One of the arguments for using the newer, more expensi ve vol ati l e anestheti cs, sevofl urane and
desfl urane, has been their relati ve speed i n terms of emergence from anesthesi a. It seems that
this speed matches the ambul atory anesthesi a envi ronment i n whi ch we practi ce and the move
'em i n, move ' em out approach to surgi cal pati ents. Thi s argument has been tempered somewhat
by the basi c knowl edge that one of the ski ll s of the cl inici an i s the titration of the volatil e
anesthetics. Even the more sol uble drugs can be ti trated based on cl i ni cal experience or wi th the
ai d of processed EEG moni tors (such as the bispectral i ndex system), permi tti ng fast wake-ups
regardl ess of the choi ce of anestheti c agent. However, there i s strong evi dence to support the use
of the less-solubl e (but most expensi ve) drugs i n the longest surgi cal cases (Fi g. 15-37).
3
In these
cases the hi gh direct cost of the anesthetic i s bal anced by the much i mproved recovery profi le,
i ncl udi ng a more rapi d ti me to emergence and a more rapi d di scharge from the recovery room.
Curiousl y, the discharge advantage wi th the l ow sol ubl e anestheti cs has been diffi cult to show
after shorter surgi cal procedures.
ACKNOWLEDGMENTS
FIGURE 15-37. The recovery ti mes to ori entation after anesthesi a of varying durati ons. With
the less-solubl e anestheti c sevofl urane, the ti me to ori entation was independent of the
anesthetic duration. In contrast, l ong anestheti c durati ons wi th isofl urane were associ ated
with delayed ti mes to ori entati on. (Adapted from Ebert TJ, Robi nson BJ, Uhri ch TD et al :
Recovery from sevofl urane anesthesia: A compari son to i sofl urane and propofol anesthesi a.
The author wi shes to acknowledge the contri buti on of Dr. Phil i p Schmi d, Department of
Anesthesi ol ogy, Uni versi ty of Iowa, for his work on the section entitl ed Pharmacokineti c Princi pl es
in the previous edi tion of this chapter.
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191. Bi to H, Ikeda K: Renal and hepati c functi on i n surgi cal patients after l ow-flow
sevofl urane or i soflurane anesthesia. Anesth Anal g 82:173, 1996
192. Groudi ne SB, Fragen RJ, Kharasch ED, Ei senman TS, Fri nk EJ, McConnel l S: Compari son
of renal functi on fol l owi ng anesthesi a wi th low-flow sevofl urane and i soflurane. J Cli n Anesth
11:201, 1999
193. Litz RJ, Hbl er M, Lorenz W, Mei er VK, Al brecht DM: Renal responses to desfl urane and
isoflurane in pati ents wi th renal insuffici ency. Anesthesi ol ogy 97:1133, 2002
194. Conzen PF, Kharasch ED, Czerner SFA et al : Low-flow sevoflurane compared with
low-flow isoflurane anesthesia in patients with stable renal insufficiency.
195. Mazze RI, Jami son RL: Low-flow (1 l /mi n) sevofl urane: Is i t safe? Anesthesiol ogy
86:1225, 1997
196. Bedford RF, Ives HE: The renal safety of sevofl urane. Edi torial . Anesth Anal g 90:505,
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197. Sprackli n D, Kharasch ED: Evi dence for the metaboli sm of fl uoromethyl -1,1-di fl uoro-1-
(trifluoromethyl )vinyl ether (Compound A), a sevofl urane degradati on product, by cystei ne
conjugate -lyase. Chem Res Toxicol 9:696, 1996
198. Iyer RA, Anders MW: Cysteine conjugate -lyase-dependent bi otransformati on of the
cysteine S-conjugates of the sevofl urane degradation product compound A i n human,
nonhuman, nonhuman pri mate, and rat ki dney cytosol and mi tochondria. Anesthesi ol ogy
85:1454, 1996
199. Kharasch ED, Jubert C: Compound A uptake and metabol ism to mercapturic acids and
3,3,3-trifluoro-2-fluoromethoxypropanoic aci d duri ng l ow-fl ow sevofl urane anesthesi a.
200. Fang ZX, Eger EI II: Source of toxi c CO expl ai ned: -CHF
2
anestheti c + dry absorbent.
UCSF research shows CO comes from CO
2
absorbent. APSF Newsl etter 9:25, 1994
201. Woehlck HJ, Dunning MI, Gandhi S, Chang D, Milosavljevic D: Indirect detection
of intraoperative carbon monoxide exposure by mass spectrometry during isoflurane
anesthesia. Anesthesiology 83:213, 1995
202. Lentz RE: CO poi soni ng during anesthesi a poses puzzl e. APSF Newsl etter 9:13, 1994
203. Woehl ck HJ: Severe intraoperati ve CO poisoni ng. Anesthesi ology 90:353, 1999
204. Berry PD, Sessl er DI, Larson MD: Severe carbon monoxi de poi soni ng duri ng desfl urane
205. Woehl ck HJ, Dunni ng MI, Raza T, Rui z F, Boll a B, Zi nk W: Physi cal factors affecti ng the
producti on of carbon monoxide from anesthetic breakdown. Anesthesi ology 94:453, 2001
206. Fatheree RS, Lei ghton BL: Acute respiratory di stress syndrome after an exothermi c
Baralyme-sevofl urane reacti on. Anesthesi ol ogy 101:531, 2004
207. Castro BA, Freedman LA, Crai g WL, Lynch CI: Expl osi on wi thin an anesthesia machi ne:
Baralyme, hi gh fresh gas fl ows and sevoflurane concentrati on. Anesthesiol ogy 101:537,
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208. Cousi ns MJ, Mazze RI: Methoxyflurane nephrotoxici ty: A study of dose-response i n man.
JAMA 225:1611, 1973
209. Fri nk EJ Jr, Mal an TP Jr, Isner RJ, Brown EA, Morgan SE, Brown BR Jr: Renal
concentrating functi on with prolonged sevofl urane or enfl urane anesthesi a i n vol unteers.
210. Mazze RI: The safety of sevofl urane i n humans. Anesthesi ology 77:1062, 1992
211. Kharasch ED, Hankins DC, Thummel KE: Human kidney methoxyflurane and
sevoflurane metabolism. Intrarenal fluoride production as a possible mechanism of
methoxyflurane nephrotoxicity. Anesthesiology 82:689, 1995
212. Kharasch ED: Bi otransformati on of sevofl urane. Anesth Anal g 81:S27, 1995
213. Fri nk EJ Jr, Mal an TP Jr, Brown EA, Morgan S, Brown BR Jr: Pl asma i norgani c fl uori de
level s wi th sevofl urane anesthesi a in morbi dl y obese and nonobese pati ents. Anesth Anal g
76:1333, 1993
214. Rehder K, Forbes J, Al ter H, Hessl er O, Sti er A: Halothane bi otransformati on i n man: A
quantitati ve study. Anesthesi ology 28:711, 1967
215. Brown BR Jr, Gandol fi AJ: Adverse effects of vol ati le anaesthetics. Br J Anaesth 59:14,
1987
216. Fri nk EJ Jr, Morgan SE, Coetzee A, Conzen PF, Brown BR Jr: The effects of sevoflurane,
halothane, enflurane, and i sofl urane on hepati c blood fl ow and oxygenati on in chroni cal ly
instrumented greyhound dogs. Anesthesi ology 76:85, 1992
217. Gatecel C, Losser M-R, Payen D: The postoperative effects of hal othane versus isofl urane
on hepati c artery and portal vei n blood fl ow in humans. Anesth Anal g 96:740, 2003
218. Kenna G, Satoh H, Chri st DD, Pohl LR: Metabol i c basi s for drug hypersensi tivity;
anti bodi es i n sera from pati ents wi th hal othane hepati sis recogni se l iver neo-anti gens that
contai n the tri -fluoroacetyl group deri ved from hal othane. J Pharmacol Exp Ther 245:1103,
1988
219. Kenna JG, Marti n JL, Satoh H, Pohl LR: Factors affecti ng the expression of
trifluoroacetylated li ver mi crosomal protein neoanti gens i n rats treated wi th hal othane. Drug
Metab Di spos 18:188, 1990
220. Marti n JL, Plevak DJ, Flannery KD et al : Hepatotoxici ty after desfl urane anesthesi a.
221. Njoku D, Laster MJ, Gong DH, Eger EII, Reed GF, Marti n JL: Biotransformati on of
halothane, enflurane, isofl urane, and desfl urane to tri fl uoroacetylated l iver proteins:
Associ ati on between protei n acyl ation and hepati c i njury. Anesth Anal g 84:173, 1997
222. Lewis JH, Zi mmerman HJ, Ishak KG, Mul li ck FG: Enfl urane hepatotoxi city. A
cl i ni copathol ogi c study of 24 cases. Ann Intern Med 98:984, 1983
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224. Ray DC, Drummond GB: Hal othane hepati tis. Br J Anaesth 67:84, 1991
225. Marti n JL, Dubbi nk DA, Pl evak DJ et al : Hal othane hepati tis 28 years after pri mary
exposure. Anesth Analg 74:605, 1992
226. Sigurdsen J, Hrei darsson AB, Thiodl eifsson B: Enfl urane hepati tis. A report of a case wi th
a previ ous hi story of hal othane hepati tis. Acta Anaesthesi ol Scand 29:495, 1985
227. Njoku DB, Greenberg RS, Bourdi M et al : Autoantibodies associated with volatile
anesthetic hepatitis found in the sera of a large cohort of pediatric anesthesiologists.
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229. Tanaka S, Tsuchi da H, Nakabayashi K, Seki S, Nami ki A: The effects of sevoflurane,
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79:392, 1997
234. Dion P: The cost of anestheti c vapors. Can J Anaesth 39:633, 1992
Neuromuscul ar Bl ocki ng Agents
Chapter 16
Neuromuscular Blocking Agents
Donati Franois
Bevan David R.
KEY POINTS
Neuromuscul ar bl ocking agents are used to i mprove condi tions for tracheal
intubati on, to provide immobil i ty duri ng surgery, and to facil i tate mechani cal
ventil ati on.
The mai n si te of action of neuromuscul ar bl ocki ng agents (muscl e rel axants) i s
on the ni coti ni c chol i nergic receptor at the endplate of muscl e. They al so have
effects at presynaptic receptors l ocated on the nerve termi nal.
Succi nylchol i ne i s a blocking agent that produces depol ari zati on at the endpl ate
and binds to extrajunctional receptors. In spi te of many side effects, such as
hyperkal emi a, i ts rapi d offset makes i t the drug of choi ce for rapi d sequence
inducti on.
All other drugs avai labl e are nondepol arizing. They compete wi th acetyl chol ine
for the same bi ndi ng si tes.
Fade-in response to high frequency sti mulation (e.g. train-of-four, 2 Hz for 2
sec) is a characteristic of nondepolari zi ng bl ockade. Trai n-of-four fade is
di fficul t to evaluate manuall y or vi suall y duri ng recovery when rati o i s >0.4.
The upper airway i s particularl y sensi ti ve to the effects of nondepol ari zi ng
bl ockade. Complete recovery does not occur unti l trai n-of-four rati o at the
adductor pol l i ci s >0.9.
Resi dual paral ysi s is more frequent wi th long-duration than i ntermediate-
duration agents.
Reversal wi th anti choli nesterases shoul d be attempted when a certai n degree of
spontaneous recovery is manifest. Ideal l y, al l four twi tches i n response to train-
of-four sti mul ati on shoul d be vi si bl e before reversal i s gi ven.
It appears paradoxi cal that drugs havi ng peripheral effects on neuromuscul ar transmission mi ght
have a rol e in anesthesi a. If the patient is anestheti zed, why provi de agents to prevent
movement? Yet, the introducti on of muscl e rel axants, more appropri atel y call ed neuromuscular
bl ocking agents, into cl i ni cal practice more than 60 years ago i s an important mi lestone in the
hi story of anesthesi a.
1
However, in 1954, i n a paper on anestheti c mortal ity, Beecher and Todd
cl ai med that mortal ity increased by si xfold when muscl e rel axants were used.
2
Thi s si tuati on was
probabl y because of the subopti mal use of mechani cal venti lation and reversal drugs, but other
controversi es arose i n recent years, for a variety of reasons.
For example, the i ncidence of awareness i s greater when neuromuscul ar bl ocking agents are
used,
3
and some authors recommend restri cti ng the use of these drugs whenever possi bl e, as
patient movement mi ght be an i ndi cator of

consciousness. However, anestheti cs act at the spinal cord l evel to produce immobi li ty, and
movement i n response to a noxi ous sti mulus indicates i nadequate anal gesi a, not i nsuffici ent
unconsci ousness.
4
Therefore, awareness does not occur because too much of a neuromuscul ar
bl ocking agent has been gi ven, but because too l i ttl e anestheti c i s admi ni stered. Thi s seems to be
supported by an i nci dent report review where an i nadequate dose of anestheti c drugs was
suspected in 68 of 81 cases of awareness.
3

Complete paralysi s i s not requi red al l the ti me for al l surgi cal procedures. For exampl e,
anesthesiol ogi sts might tend to i nject more mi vacuri um than real l y needed by surgeons.
However, neuromuscul ar bl ocki ng agents were found to make a difference in l ower abdominal
surgery, where, in spi te of generous doses of isofl urane, surgical condi ti ons were better in
patients recei vi ng vecuroni um (Fi g. 16-1).
5
In addi ti on to provi di ng i mmobi l i ty and better surgi cal
condi ti ons, neuromuscular bl ocki ng agents i mprove intubati ng condi tions. The doses of narcotics
requi red for acceptabl e i ntubating conditi ons in the absence of muscle paral ysi s produce
si gni fi cant hypotensi on (Fi g. 16-2).
6
Provi ding opti mal intubati ng condi tions i s not a trivial
objecti ve. It has been demonstrated that poor intubati ng condi ti ons are associated wi th an
increased i nci dence of voice hoarseness and vocal cord damage (Fi g. 16-3).
7
Furthermore, giving
neuromuscul ar bl ocki ng agents improved the quali ty of i ntubating conditi ons.
P.422
FIGURE 16-1. Surgeon's assessment of muscl e rel axati on duri ng l ower abdomi nal surgery.
Rating goes from 1 (excel lent) to 4 (poor). The incidence of poor rati ng was greater in
patients not gi ven vecuronium (29%) compared wi th those who recei ved the drug (2%).
Redrawn from Ki ng et al.
5

FIGURE 16-2. Neuromuscular blocki ng agents provide better i ntubating conditi ons than hi gh
doses of narcoti cs, wi thout hypotension. In the study menti oned earli er, pati ents were
randomi zed to remifentani l , 2 g/kg (Remi 2), or 4 g/kg (Remi 4), or succi nyl chol ine 1
mg/kg (Sux 1). Mean arterial pressure decreased by a mean val ue of 21, 28, and 8%,
respectively. Intubati ng condi tions were rated as i mpossi bl e or accordi ng to the degree of
coughing produced (persi stent, moderate, or none). Data from McNei l et al .
6

As i t i s important to provi de adequate anesthesia whi le a patient is total ly or parti al l y paral yzed,
it i s al so essential to make sure that the effects of neuromuscul ar bl ocki ng drugs have worn off or
are reversed before the pati ent regai ns consci ousness. Wi th the i ntroducti on of shorter acting
neuromuscul ar bl ocki ng agents, i t was thought that reversal of bl ockade coul d be omi tted.
However, residual paral ysis i s sti l l a probl em, even 25 years after i f was fi rst descri bed (Tabl e 16-
1).
8
In additi on, the threshol d for complete neuromuscul ar recovery i s now consi dered to be a
trai n-of-four (TOF) rati o of 0.9, i nstead of the tradi tional 0.7 (Fi g. 16-4).
9
Thus, an understanding
of the pharmacology of neuromuscul ar bl ocking agents and reversal drugs i s essential .
FIGURE 16-3. Neuromuscular blocki ng agents i mprove i ntubati ng condi tions and reduce
vocal cord sequel ae. The graph depi cts the inci dence of excel lent and acceptabl e (defined as
good or excel lent) i ntubating conditi ons after atracurium or sal i ne. The percentage of
patients who reported hoarseness and those with vocal cord lesi ons documented by
stroboscopy i s al so shown. Data from Mencke et al .
7

TABLE 16-1 Reports of Residual Paralysis 19792004
STUDY LONG-
ACTING
DRUGS USED
INTERMEDIATE-ACTING DRUGS
USED
REVERSAL TOF
THRESHOLD
R
PA
P
Viby-
Mogensen
et al
1979
8
d-
tubocurari ne
Pancuroni um
Gal lami ne
Yes 0.7
Bevan et
al
1988
169
Pancuroni um Atracuri um
Vecuroni um
Yes
Yes
Yes
0.7
0.7
0.7

PHYSIOLOGY AND PHARMACOLOGY
St r uct ur e
The cel l bodi es of motor neurons supplying skel etal muscl e li e i n the spinal cord. They recei ve and
integrate i nformati on from the central nervous system. Thi s informati on i s carried vi a an
el ongated structure, the axon, to di stant parts of the body. Each nerve cel l suppli es many muscl e
cel ls (or fi bers) a short distance after branchi ng into nerve termi nal s. The terminal porti on of the
axon is a speci ali zed structure, the synapse, desi gned for the producti on and rel ease of
acetylchol ine. The synapse i s separated from the endpl ate of the muscl e fi ber by a narrow gap,
call ed the synapti c cl eft, whi ch is approxi mately 50 nm i n width (0.05 m) (Fi g. 16-5).
10
The
nerve termi nal i s surrounded by a Schwann cel l , and the synapti c cl eft has a basement membrane
and contains fi laments that anchor the nerve termi nal to the muscl e.
AMG, acceleromyography; TOF, train-of-four ratio.
FIGURE 16-4. Upper esophageal resti ng tone in vol unteers gi ven vecuronium. Train-of-four
rati o was measured at the adductor pol l ici s. Statisticall y si gni fi cant decreases compared wi th
control were found at all l evel s of paralysi s unti l TOF >0.9. Redrawn from Eri ksson et al .
146

P.423
The endpl ate i s a speci al i zed porti on of the membrane of the muscl e fi ber where ni cotinic
acetylchol ine receptors are concentrated. Duri ng development, multi ple connections are made

between nerve terminal s and a singl e muscl e fi ber. However, as maturati on conti nues, most of
these connections atrophy and di sappear, usual l y l eavi ng onl y one connection per muscle fiber.
Thi s endplate conti nues to di fferenti ate from the rest of the muscle fiber. The nerve terminal
enl arges, and folds appear. The acetyl chol i ne receptors cl uster at the endplate, especi al l y at the
crests of the fol ds and their densi ty decreases to al most zero in extrajuncti onal areas.
11, 12

Mammali an endpl ates usual l y have an oval shape wi th the short axi s perpendicul ar to the fi ber.
The wi dth of the endpl ate i s someti mes as l arge as the di ameter of the fi ber, but i s usual l y
smal l er. However, its l ength i s onl y a smal l fracti on of that of the fi ber.
Ner ve St i mul at i on
Under resting conditi ons, the el ectri cal potenti al of the i nside of a nerve cel l i s negati ve with
respect to the outsi de (typi cal l y 90 mV). If thi s potenti al i s made l ess negative (depolarizati on),
sodium channel s open and all ow sodi um ions to enter the cel l . Thi s i nfl ux of posi tive i ons makes
the potenti al inside the membrane posi tive wi th respect to the outsi de. This potential change in
turn causes depol ari zation of the next segment of membrane, causing more sodi um channel s to
open, and an el ectrical impul se, or acti on potenti al , propagates. The durati on of the acti on
potential i s bri ef (<1 msec), because of rapi d i nacti vati on of sodium channels and activation of
potassium channel s. An acti on potential al so triggers the openi ng of calci um channel s, all owing
calci um i ons to penetrate the cell . This entry of calci um faci l itates release of the neurotransmi tter
at the nerve termi nal.
The sodi um channels i n the axon may be activated i n response to electri cal depol ari zati on
provi ded by a nerve stimul ator. A peri pheral nerve i s made up of a large number of axons, each of
whi ch axon responds i n an al l -or-none fashi on to the sti mulus appl i ed. Thus, in the absence of
neuromuscul ar bl ocki ng agents, the rel ati onship between the ampl itude of the muscl e contraction
and current appli ed i s si gmoi d.
13
At low currents, the depol ari zati on i s insuffici ent in all axons. As
current i ncreases, more and more axons are depol ari zed to threshol d and the strength of the
FIGURE 16-5. Schemati c representati on of the neuromuscul ar junction (not drawn to scale).
P.424
muscle contracti on i ncreases. When the sti mulating current reaches a certain l evel, al l axons are
depol ari zed to threshol d and propagate an acti on potenti al . Increasing current beyond thi s poi nt
does not increase the ampli tude of muscle contracti on: the sti mulation is supramaxi mal (Fi g. 16-
6). Most commercial ly avai l abl e sti mulators del i ver impul ses l asti ng 0.1 to 0.2 msec.
Rel ease of Acet yl chol i ne
Acetyl chol i ne i s synthesi zed from chol ine and acetate and packaged into 45-nm vesi cl es. Each
vesi cle contai ns 5,000 to 10,000 acetylchol ine molecul es. Some of these vesi cl es cl uster near the
cel l membrane opposi te the crests of the junctional fol ds of the endpl ate, i n areas cal l ed acti ve
zones (see Fi g. 16-5).
12

Although there have been doubts regarding the vesi cul ar hypothesi s, it i s now widel y accepted
that acetyl choli ne i s released in packets, or quanta, and that a quantum represents the contents
of one vesicl e.
14
In the absence of nerve sti mul ati on, quanta are rel eased spontaneousl y, at
random, and this i s seen as smal l depol ari zations of the endpl ate (mi niature endpl ate potenti al ;
MEPP). When an acti on potenti al invades the nerve terminal , ~200 to 400 quanta are released
si multaneously, unloadi ng ~1 to 4 mi l li on acetyl choli ne molecul es i nto the synapti c cleft.
10, 14

Cal cium, whi ch enters the nerve terminal through channel s that open in response to
depol arizati on, i s required for vesi cle fusi on and release. Calci um channel s are l ocated near
docki ng protei ns, and this speci al geometri c

arrangement provi des hi gh i ntracel lular concentrati ons of cal ci um to al low binding of speci ali zed
protei ns on the vesicl e membrane with docki ng protei ns.
12
Bi ndi ng produces fusi on of the
membranes and release of acetylchol ine ensues. When the cal ci um concentrati on i s decreased, or
if the acti on of cal cium i s antagoni zed by magnesi um, the rel ease process i s i nhi bi ted and
transmi ssi on fail ure may occur. Other protei ns regulate storage and mobi l izati on of acetyl chol i ne
vesi cles. It appears that a small proporti on of vesi cl es is immedi atel y releasabl e, whil e a much
l arger reserve pool can be mobi l i zed more sl owl y. Each impul se rel eases 0.2 to 0.5% of the
75,000 to 100,000 vesi cles i n the nerve terminal .
14
With repetiti ve sti mulation, the amount of
acetylchol ine rel eased decreases rapi dl y because onl y a smal l fraction of the vesicl es is i n a
positi on to be rel eased i mmedi atel y. To sustain release during hi gh-frequency sti mul ati on, vesi cl es
FIGURE 16-6. Exampl e of i ncreasi ng sti mulating current i n one pati ent. Current pulses, 0.2-
msec duration, were del i vered to the ulnar nerve at the wri st every 10 seconds. The force of
contracti on of the adductor poll i ci s was measured and appears as spi kes. No twitch was seen
if the current was <28 mA. At current strengths of 40 mA, the current became
supramaxi mal, i ncreasi ng the current produced l i ttl e change i n force.
P.425
must be mobi l i zed from the reserve pool , and thi s process requi res calci um.
14

P ost synapt i c Event s
The 1 to 10 mi ll i on receptors located at the endpl ate are made up of fi ve gl ycoprotei n subuni ts
arranged i n the form of a rosette and l yi ng across the whol e cell membrane (Fi g. 16-7). Two of
these noncontiguous subuni ts, desi gnated , are identi cal . The other three units are cal led ,
and or There are two acetylchol ine bi ndi ng si tes, each l ocated on the outside part of the
subuni t. When two acetyl chol i ne mol ecul es bi nd si mul taneousl y to each bi nding site, an openi ng is
created i n the center of the rosette, all owing sodi um i ons to enter the cell .
10, 15
Thi s depol ari zes
the endpl ate, that is, i ts inside becomes less negati ve. There is a hi gh densi ty of sodi um channels
in the fol ds of synapti c clefts and i n the peri juncti onal area.
15
These channel s open when the
membrane i s depol ari zed beyond a cri tical poi nt, al lowi ng more sodi um to enter the cel l , and
produci ng further depol ari zati on. Thi s depol ari zati on generates an action potenti al , whi ch
propagates by activati on of sodi um channel s along the whol e length of the muscl e fiber. The
muscle acti on potential has a durati on 5 to 15 mi l l i seconds and can be recorded as a
el ectromyogram (EMG). It precedes the onset of contracti on, or twi tch, whi ch l asts 100 to 200
mi ll i seconds. With hi gh-frequency (>10 Hz) sti mul ati on, the muscl e fi ber does not have time to
rel ax before the next i mpul se, so contracti ons fuse and add up, and a tetanus is obtai ned.
There are two types of nicoti ni c acetyl chol i ne receptors. Early i n development, receptors are
evenl y di stri buted al ong the whole l ength of the muscl e fi ber. These receptors, call ed fetal
receptors, have a subuni t (see Fi g. 16-7). When the endpl ate devel ops, receptors tend to cl uster
at the neuromuscular juncti on and l eave onl y few receptors in the extrajuncti onal areas. As
maturati on continues, the subuni t i s substi tuted by an subuni t, whi ch i s characteri sti c of the
adult-type, juncti onal receptor.
11, 12
In humans, the switch occurs i n the l ast weeks of pregnancy.
Mai ntenance of adul t receptors at the endpl ate depends on the i ntegri ty of nerve suppl y. A few -
FIGURE 16-7. Two types of ni cotinic receptors i n muscl e. Both have the same fi ve subuni ts,
except for a substi tution of the for the subuni ts. The acetyl chol ine bindi ng si tes are
represented by a shaded oval area. They are on the subuni t, at the and or interface,
respectively. Accordi ng to some authors, the order of the and is i nverted.
type, extrajuncti onal receptors sti ll persist in adults, but can prol iferate i n cases of denervati on.
Both types of receptor have slightl y different sensi ti vi ties to agoni st and antagoni st drugs.
12
Both
have two bindi ng si tes for acetylchol ine, located on the subunit, at the i nterface between the
and the or or subunits, respecti vel y.
16

The mai n acti on of nondepol ari zi ng neuromuscul ar bl ocki ng drugs i s to bl ock the postsynapti c
acetyl chol i ne receptor by bi ndi ng to at l east one of the two subuni ts, thus preventi ng
access by acetylchol ine. Under normal ci rcumstances, onl y a smal l fracti on of avai lable receptors
must bind to acetylchol ine to produce suffi cient depol ari zati on to trigger a muscl e contraction. In
other words, there i s a wide margi n of safety. Thi s impli es that neuromuscul ar bl ocki ng drugs
must be bound to a l arge number of receptors before any bl ockade i s detectabl e. Ani mal studi es
suggest that 75% of receptors must be occupi ed before twi tch hei ght decreases in the presence of
d-tubocurari ne, and blockade is complete when 92% of receptors are occupi ed.
17
The actual
number depends on speci es and type of muscl e, and humans mi ght have a reduced margi n of
safety compared wi th other speci es.
18
So, i t i s futi l e to correl ate receptor occupancy data obtai ned
in cats wi th certai n cl i ni cal tests i n humans, such as hand gri p and head l i ft, which i nvolve
di fferent muscle groups. However, the general concept that a l arge proportion of receptors must
be occupi ed before bl ockade becomes detectabl e, and that measurabl e blockade occurs over a
narrow range of receptor occupancy, remains appl i cabl e to cl inical practi ce. Because i t must
overcome the margi n of safety, the i ni ti al dose of neuromuscular blocki ng agent i s greater than
maintenance doses.
Acetyl chol i ne i s hydrol yzed rapi dl y by the enzyme acetyl chol i nesterase, whi ch i s present i n the
fol ds of the endplate as wel l as embedded i n the basement membrane of the synaptic cl eft. The
presence of the enzyme i n the synaptic cleft suggests that not al l the acetylchol i ne released
reaches the endpl ate; some i s hydrol yzed en route.
14

P r esynapt i c Event s
The rel ease of acetylchol ine normall y decreases duri ng hi gh-frequency sti mul ati on because the
pool of readil y rel easabl e acetyl choli ne becomes depl eted faster than i t can be repl eni shed. Under
normal circumstances, the reduced amount rel eased i s wel l above what is requi red to produce
muscle contraction because of the high margin of safety at the neuromuscul ar juncti on. However,
duri ng partial nondepolarizing bl ockade thi s decrease i n transmitter output produces fadea
progressi ve decrease i n muscl e response wi th each sti mulus. Nondepol arizing neuromuscular
bl ocking drugs probably accentuate the fade by bl ocki ng presynapti c ni cotinic receptors, which
di ffer structural l y from postsynapti c receptors.
19
The function of the presynaptic receptors i s to
sustain acetyl chol i ne mobi l izati on

in the face of conti nuing sti mul ati on, i n other words to provi de posi tive feedback. Nondepolarizing
agents have a greater affi ni ty for presynaptic than postsynapti c receptors. Onl y smal l doses of
nondepol ari zi ng rel axants are needed to bl ock presynaptic receptors.
20
Whatever the exact
mechani sm of fade, i t remai ns a key property of nondepol ari zi ng neuromuscul ar bl ocki ng drugs
and is useful for moni toring purposes.
NEUROMUSCULAR BLOCKING AGENTS
Neuromuscul ar bl ocking drugs i nteract with the acetyl chol i ne receptor either by depol ari zi ng the
endplate or by competi ng with acetylchol ine for bi ndi ng sites. The former mechani sm i s
characteri sti c of depol ari zi ng drugs and the l atter of nondepolari zi ng agents. The onl y depol ari zi ng
agent stil l i n use i s succi nylchol ine. Al l others are of the nondepol ari zi ng type.
P har macol ogi cal Char act er i st i cs of Neur omuscul ar Bl ocki ng
Agent s
The effect of neuromuscular blocking drugs i s measured as the depressi on of adductor muscl e
contracti on (twitch) fol lowi ng el ectrical sti mulation of the ul nar nerve. The value i s compared with
a control value, obtained before i njection of the drug. Each drug has onset, potency, and recovery
P.426
characteri sti cs.
Potency of each drug i s determi ned by constructi ng dose-response curves, whi ch descri be the
rel ati onship between twitch depressi on and dose (Fi g. 16-8). Then, the effecti ve dose 50, or ED
50
,
whi ch i s the medi an dose corresponding to 50% twi tch depressi on, i s obtai ned. A more cl inicall y
rel evant value, the ED
95
, correspondi ng to 95% bl ock, i s more commonl y used. For exampl e, the
ED
95
for vecuronium is 0.05 mg/kg, which means that hal f the patients wi ll achi eve at least 95%
bl ock of singl e twitch (compared wi th the prevecuroni um value) wi th that dose, and hal f the
subjects wi l l reach l ess than 95% block. Rocuroni um has an ED
95
of 0.3 mg/kg. Therefore, i t has
one-si xth the potency of vecuroni um because 6 ti mes as much rocuroni um has to be given to
produce the same effect. The ED
95
of known neuromuscular blocki ng agents vary over two orders
of magni tude (Tabl e 16-2).
TABLE 16-2 Potency, Onset Time, Duration, and Recovery Index of Neuromuscular
Blocking Agents
AGENT
ED
95

(mg/kg)
ONSET
TIME
(min)
DURATION TO
25% RECOVERY
(min)
RECOVERY INDEX
(2575%
RECOVERY) (min)
ULTRASHORT-DURATION AGENTS
Succi nylchol i ne 0.3 11.5 68 24
GW280430A
a
0.19 1.7 68 2.5
SHORT-DURATION AGENTS
Mi vacurium 0.08 34 1520 710
Rapacuroni um
b
0.75 11.5 1525 57
INTERMEDIATE-DURATION AGENTS
Atracuri um 0.20.25 34 3545 1015
Ci satracuri um 0.05 57 3545 1215
Rocuronium 0.3 1.53 3040 812
Vecuroni um 0.05 34 3545 1015
LONG-DURATION AGENTS
Al curoni um
b
0.25 35 6090 3040
Doxacuri um 0.025 510 40120 3040
d-Tubocurari ne
b
0.5 24 60120 3045
Gal lami ne
b
2 1.53 60120 3060
Metocuri ne
b
0.3 35 60150 4060
Pancuroni um 0.07 24 60120 3040
Pi pecuronium
b
0.05 35 90130 3545
Typical values for the average young adul t pati ent. Onset and durati on data depend on
dose. The val ues presented are the best esti mates avail able for twi ce the ED
95
and are
measured at the adductor pol l ici s. Actual values may vary markedly from one i ndi vi dual
to the next, and may be affected by age, other medi cations, and/or di sease states. The
categori es under whi ch the drugs are cl assi fi ed are somewhat arbi trary.
a
Being i nvestigated at the ti me of writi ng.
b
No l onger used or very l i mi ted use in North Ameri ca.
FIGURE 16-8. Exampl e of a dose-response rel ati onshi p. The actual numbers are
approxi mately those for rocuronium. The ED
50
is the dose correspondi ng to 50% bl ockade and
ED
95
the dose correspondi ng to 95% bl ockade.
Onset time, or ti me to maxi mum bl ockade, can be shortened if the dose i s increased. When two or
more drugs are compared, i t i s meani ngful to compare only equi potent doses, and usual ly,
cl i ni cal ly rel evant doses (2 ED
95
) are consi dered.
Durati on of action is the ti me from i njecti on of the neuromuscular blocki ng agent to return of 25%
twi tch hei ght (compared wi th control). Duration increases wi th dose, so compari sons are normal l y
made with 2 ED
95
doses. The 25% twi tch hei ght figure was chosen because rapid reversal can
normal ly be achi eved at that l evel. Categori es were proposed for neuromuscul ar blocki ng drugs
according to thei r durati on of acti on (see Tabl e 16-2).
21
Same duration agents may have markedly
di fferent onsets.
Recovery index i s the time i nterval between 25% and 75% twi tch hei ght. It provi des information
about the speed of recovery once return of twitch i s mani fest. It i s someti mes preferred to
duration of action, because i t does not depend heavi l y on the dose gi ven. The val ues for ED
95
,
onset ti me, durati on of acti on, and recovery i ndex depend on whi ch muscl e i s used to make
measurements. For consistency' s sake, the adductor pol li ci s has been retai ned as the gol d
standard, not because of its physi ologi cal si gnifi cance, but because i t i s most commonl y moni tored
and data on i t are most abundant.
The pharmacol ogi cal characteristics of neuromuscular blocki ng agents are compl eted by an
assessment of i ntubati ng condi ti ons, which do not al ways paral lel twi tch hei ght at the adductor
pol li cis. Intubati ng condi ti ons depend on paral ysi s of central l y l ocated muscles, but al so on type
and quanti ty of narcoti c and hypnoti c drug gi ven for i nducti on of anesthesi a. To decrease
vari abi l ity between studi es, cri teri a to grade i ntubating conditi ons as excel l ent, good, poor, or
impossibl e i n a scoring system were adopted by a group of experts who met in Copenhagen in
1994.
22

DEPOLARIZING DRUGS: SUCCINYLCHOLINE
Among drugs that depol ari ze the endplate, only succi nylchol ine i s sti ll used cl i ni cal ly.
Decamethoni um, a depol ari zi ng drug wi th a slow onset and i ntermediate durati on, has been
repl aced by nondepolari zi ng al ternati ves. However, succi nylchol ine sti l l

enjoys some populari ty, despi te a l ong l i st of undesi red effects, because it i s the onl y ultrarapi d
onset, ul trashort durati on neuromuscul ar blocking drug avai labl e.
Neur omuscul ar Ef f ect s
The effects of succi nylchol ine at the neuromuscul ar junction are not compl etel y understood. The
drug depol ari zes presynapti c, postsynapti c, and extrajuncti onal receptors. However, when the
receptor i s i n contact wi th any agoni st, including acetyl chol i ne, for a prol onged time, i t ceases to
respond to the agonist. Normall y, thi s desensi ti zation process does not take place because of the
rapi d breakdown of acetylchol ine (<1 msec). However, succi nylchol ine remai ns at the endpl ate for
much longer, and desensi ti zation can develop. Another possi bl e mechani sm i s the i nacti vation of
sodium channel s in the juncti onal and peri juncti onal area, whi ch occurs when the membrane
remai ns depol ari zed. Thi s i nacti vation prevents the propagati on of the acti on potenti al .
Wi thi n 1 mi nute after succi nyl chol ine i njecti on and before paralysi s is mani fest, some di sorganized
muscul ar acti vi ty i s observed frequentl y. This phenomenon is cal l ed fasciculati ons and is
probabl y a result of depol ari zati on of the nerve termi nal produced by acti vati on of presynapti c
receptors. The effecti veness of smal l doses of nondepolari zi ng drugs in reducing the i ncidence of
fasciculati ons suggests that the presynapti c receptors are rel ati vel y sensi ti ve to these drugs.
20

Succi nylchol i ne has yet another neuromuscul ar effect. In some muscl es, li ke the masseter and to a
lesser extent the adductor poll i ci s, a sustained i ncrease in tension that may l ast for several
mi nutes can be observed. The mechanism of acti on of thi s tensi on change i s uncertai n but i s most
P.427
li kel y medi ated by acetylchol ine receptors because i t i s bl ocked by l arge amounts of
nondepol ari zi ng drugs.
23
The i ncrease i n masseteri c tone, whi ch i s probably al ways present to
some degree but greater i n some susceptive individual s, may lead to imperfect i ntubati ng
condi ti ons i n a smal l proporti on of pati ents. Masseter spasm may be an exaggerated form of thi s
response.
Char act er i st i cs of Depol ar i zi ng Bl ockade
After i njection of succi nylchol ine, single-twi tch hei ght i s decreased. However, the response to
hi gh-frequency sti mul ati on i s sustained: mi ni mal train-of-four and tetani c fade is observed. The
bl ock i s antagoni zed by nondepolari zi ng agents so that the ED
95
i s i ncreased by a factor two i f a
smal l dose of nondepol ari zi ng drug i s gi ven before.
24
Succinyl chol i ne bl ockade i s potenti ated by
inhi bitors of acetyl chol inesterase, such as neosti gmi ne and edrophoni um.
25

Phase II Block
After admi ni strati on of 7 to 10 mg/kg, or 30 to 60 minutes of exposure to succi nylchol ine, trai n-
of-four and tetani c fade become apparent. Neosti gmi ne or edrophoni um can antagoni ze thi s bl ock,
whi ch has been termed nondepol ari zi ng, dual , or Phase II bl ock. The onset of Phase II bl ock
coincides wi th tachyphylaxi s, as more succinyl chol i ne i s requi red for the same effect.
26

P har macol ogy of Succi nyl chol i ne
Succi nylchol i ne i s rapi dly hydrolyzed by plasma chol i nesterase (al so cal l ed pseudochol i nesterase),
with an el iminati on hal f-li fe

of <1 mi nute in pati ents.
27
Because of the rapi d di sappearance of succi nylchol ine from pl asma, the
maxi mum effect i s reached qui ckly. Subparal yzi ng doses (up to 0.3 to 0.5 mg/kg) reach their
maximal effect within ~1.5 to 2 mi nutes at the adductor pol l ici s,
24
and within 1 minute at more
central muscl es, such as the masseter and the larynx. Wi th l arger doses (1 to 2 mg/kg), abol i ti on
of twi tch response can be reached even more rapi dl y.
The mean dose produci ng 95% bl ockade (ED
95
) at the adductor pol l i ci s i s 0.30 to 0.35 mg/kg wi th
opi oi dni trous oxide anesthesi a.
28
In the absence of ni trous oxi de, the ED
95
is i ncreased to 0.5
mg/kg.
29
These values are doubl ed if d-tubocurari ne, 0.05 mg/kg, i s given as a defascicul ati ng
agent.
24
The ti me until ful l recovery is dose dependent and reaches 10 to 12 mi nutes after a dose
of 1 mg/kg.
28

Si de Ef f ect s
Cardiovascular
Si nus bradycardi a wi th nodal or ventri cular escape beats (or both) may occur, especial ly i n
chi l dren, and asystol e has been descri bed after a second dose of succi nylchol ine i n both pedi atri c
and adul t pati ents. These parasympatheti c effects can be attenuated with atropi ne or
glycopyrrolate.
30
Succinyl chol i ne i ncreases catechol ami ne release, and thi s effect may expl ain, i n
part, why bradycardi a does not occur more frequentl y. The mechani sm for the enhanced
bradycardic effect of a second dose is not known.
Anaphylaxis
Succi nylchol i ne has been incri mi nated as the tri gger of al l ergi c reacti ons more often than any
other drug used i n anesthesi a. Successive studi es conducted i n France i ndi cate that the number of
reported events i s decreasing, correspondi ng to the gradual replacement of succi nylchol ine by
nondepol ari zi ng drugs.
31
The i nci dence of anaphyl acti c reacti ons to succinyl chol i ne i s di ffi cul t to
establ i sh, but i s probably of the order of 1:5,000 to 1:10,000.
Fasciculations
P.428
The preval ence of fasci cul ati ons i s hi gh (60 to 90%) after the rapi d i njecti on of succinyl choli ne,
especial ly i n muscul ar adul ts. Al though thi s i s a beni gn si de effect of the drug, most cl i ni ci ans
prefer to prevent fasci culations. In thi s respect, a small dose of a nondepol ari zi ng neuromuscul ar
bl ocki ng drug i s gi ven 3 to 5 minutes before succi nyl chol i ne i s effecti ve. When the drug was
avai labl e, d-tubocurari ne 0.05 mg/kg was used for this purpose. Rocuronium is an acceptable
al ternative, as l ong as appropri ate doses (0.03 to 0.04 mg/kg, that i s, 10% of the ED
95
) are
gi ven.
32
In one study, rocuroni um, 0.03 mg/kg, decreased the i nci dence of fasci cul ati ons from 90
to 10%.
33
A dose of 0.06 mg/kg l eads to an unacceptabl y hi gh i nci dence of symptoms of
neuromuscul ar weakness, such as bl urred vi si on, heavy eyeli ds, voi ce changes, difficulty
swal lowi ng, or even dyspnea, i n the awake pati ent.
34
Atracuri um 0.02 mg/kg is al so effecti ve.
Pancuroni um, vecuroni um, cisatracuri um, and mivacuri um are not as effecti ve as defasci cul ants.
After these nondepolarizing drugs, the dose of succi nylchol ine must be increased from 1 mg/kg to
1.5 or even 2 mg/kg because of the antagonism between depol arizing and nondepol ari zi ng
drugs.
24
Other drugs, such as di azepam, l idocai ne, fentanyl , calci um, vi tamin C, magnesium, and
dantrol ene, have all been used to prevent fasci culations. The resul ts are no better than with
nondepol ari zi ng rel axants, and they may have undesirable effects of thei r own. Sel f-tami ng, the
administrati on of smal l (10-mg) doses of succi nylchol i ne 1 minute before the intubati ng dose,
does not appear to be effecti ve
33
and has l argely been abandoned.

Muscle Pains
General i zed aches and pai ns, si mi l ar to the myalgi a that fol l ows vi ol ent exerci se, are common 24
to 48 hours after succinyl chol i ne admini stration. They occur in 1.5 to 89% of pati ents receivi ng
succi nyl choli ne and are more common i n young, ambul atory pati ents.
35
The i ntensi ty of muscl e
pai ns i s not al ways correl ated wi th the intensi ty of fasci cul ati ons, but the methods that have been
shown effective to prevent fasci cul ati ons usual ly prevent muscl e pai ns. For exampl e, a
precurarizati on dose of a nondepol ari zi ng neuromuscul ar bl ocki ng agent is effective. Li docaine (1
to 1.5 mg/kg), especi all y in conjuncti on wi th precurari zati on, has al so been shown to be of
value.
35
Cal ci um, vi tamin C, benzodi azepi nes, magnesi um, and dantrol ene have been tri ed wi th
inconcl usive resul ts.
35

Intragastric Pressure
Succi nylchol i ne i ncreases i ntragastric pressure, and this effect i s blocked by precurari zati on.
However, succi nyl choli ne causes even greater increases i n l ower esophageal sphi ncter pressure.
Thus, succi nyl choli ne does not appear to i ncrease the ri sk of aspirati on of gastric contents unl ess
the lower esophageal sphi ncter is i ncompetent.
Intraocular Pressure
Intraocul ar pressure i ncreases by 5 to 15 mm Hg after i njection of succi nylchol ine. The mechani sm
is unknown but occurs after detachment of extraocul ar muscle, suggesti ng an intraocul ar etiol ogy.
Precurarizati on wi th a nondepolari zi ng bl ocker has li ttl e or no effect on thi s increase. This
background i nformati on has l ed to the wi despread recommendation to avoid succi nylchol ine i n
open eye i njuri es. However, i t must be appreciated that other factors, such as i nadequate
anesthesia, el evated systemi c blood pressure, and i nsuffici ent neuromuscul ar bl ockade duri ng
l aryngoscopy and tracheal i ntubati on, mi ght i ncrease i ntraocul ar pressure more than
succi nyl choli ne. In additi on, there i s l ittle evidence that the use of succi nyl chol ine has led to
bl i ndness or extrusi on of eye content.
36

Intracranial Pressure
Succi nylchol i ne may increase i ntracranial pressure (ICP), and this response is probabl y di mi ni shed
by precurari zation.
37
Most of thi s change may be a resul t of an i ncrease in PCO
2
produced by
fasciculati ons. Agai n, l aryngoscopy and tracheal intubati on wi th i nadequate anesthesi a or muscl e
rel axation are l ikely to increase ICP even more than succi nyl choli ne.
Hyperkalemia
Serum potassi um i ncreases by 0.5 to 1.0 mEq/L after i njecti on of succi nylchol ine. Thi s i ncrease is
not prevented compl etel y by precurari zati on. In fact, only l arge doses of nondepol arizing bl ockers
rel iabl y abol i sh thi s effect.
38
Subjects with preexi sti ng hyperkalemia, such as patients i n renal
fai l ure, do not have a greater i ncrease in potassi um l evel s, but the absol ute l evel mi ght reach the
toxi c range. Succinyl chol i ne i s safe in normokalemi c renal fai l ure pati ents.
39
However, severe
hyperkalemia, occasi onall y leading to cardi ac arrest, has been descri bed i n pati ents after major
denervation injuri es, spi nal cord transecti on, peripheral denervati on, stroke, trauma, extensive
burns, and prol onged i mmobi l i ty wi th di sease, and may be rel ated to potassi um loss vi a a
proli ferati on of extrajuncti onal receptors.
38
Hyperkalemia has been reported wi th myotoni a and
muscle dystrophies, and cardi ac arrests have been reported i n chi l dren before the di agnosi s of the
di sease was made.
38

Severe hyperkal emi a after succinyl chol i ne resul ting i n cardi ac arrest has al so been observed i n
acidotic hypovol emi c pati ents.
Abnormal Plasma Cholinesterase
Pl asma chol i nesterase acti vi ty can be reduced by a number of endogenous and exogenous causes,
such as pregnancy, li ver di sease, uremi a, malnutriti on, burns, pl asmapheresis, and oral
contracepti ves. These conditi ons usual ly l ead to a sl i ght, cli nicall y uni mportant i ncrease in the
duration of action of succi nylchol ine.
40
Plasma chol i nesterase acti vi ty i s reduced by some
anti choli nesterases (e.g., neosti gmi ne) so that the durati on of succi nyl choli ne given after
neostigmine, but not after edrophonium, i s i ncreased.
25

A small proporti on of pati ents have a geneti cal ly determi ned inabi l i ty to metabol i ze
succi nyl choli ne. Ei ther plasma choli nesterase i s absent or an abnormal form of the enzyme i s
present. Onl y pati ents homozygous for the condi tion (approxi mately 1:2,000 i ndi vi dual s) have
prolonged paral ysis (3 to 6 hours) after usual doses of succi nylchol ine (1 to 1.5 mg/kg). In
heterozygous pati ents (1:30 cases), the duration of action is onl y sl i ghtly prol onged compared
with normal i ndi vi dual s. Tradi ti onal methods for i dentifyi ng pl asma chol i nesterase phenotype
invol ve measurement of enzyme acti vi ty wi th a substrate and i nhibiti on wi th di bucai ne, fl uori de,
and chl ori de. These tests are onl y capabl e of i dentifying some enzyme variants. The complete
amino acid sequence of plasma choli nesterase has now been determi ned usi ng molecul ar geneti cs
techniques. The chol inesterase gene i s located on chromosome 3 at q26,
40
and 20 mutati ons i n the
coding regi on of the plasma choli nergi c gene have been i denti fi ed. Al though whol e bl ood or fresh
frozen plasma (FFP) can be gi ven to accel erate succi nyl choli ne metaboli sm i n pati ents wi th l ow or
absent pl asma chol inesterase, the best course of action i s probabl y mechani cal venti l ati on of the
lungs until ful l recovery of neuromuscul ar functi on can be demonstrated. Neosti gmi ne and
edrophoni um are unpredi ctable i n the reversal of abnormall y prol onged succi nyl choli ne blockade
and are best avoi ded.
Cl i ni cal Uses
The mai n i ndicati on for succi nylchol ine i s to facil i tate tracheal intubati on. In adults, a dose of 1.0
mg/kg yi el ds 75 to 80% excell ent i ntubation condi tions withi n 1 to 1.5 mi nutes after an i nducti on
sequence that i ncl udes a hypnoti c (propofol or thi opental ) and a moderate dose narcoti c.
41
The
dose must be i ncreased to 1.5 to 2.0 mg/kg if a precurari zi ng dose of nondepolari zi ng blocker has
been used.
Succi nylchol i ne i s especi al ly i ndi cated for the rapid sequence induction, when a pati ent presents
with a ful l stomach and the possibi l ity of aspi rati on of gastri c contents. In thi s situation, manual
ventil ati on of the lung is avoided i f possi bl e to reduce the probabi li ty of aspi rati on because of
excessive pressure in the stomach. Thus, the ideal neuromuscul ar bl ocking agent has both a fast
onset, to reduce the ti me between i nducti on and intubati on of the airway, and a rapi d recovery, to
al low return of normal breathi ng before the pati ent becomes hypoxic. The durati on of acti on of
succi nyl choli ne, given at a dose of 1 mg/kg, i s short enough so that i n the majority of properl y
P.429
preoxygenated pati ents resume respiratory efforts (5 to 6 mi nutes) before hypoxi a can be
detected.
42
It has been argued that thi s i s vali d onl y i n rel ati vel y heal thy subjects and not i n al l
cases. As a resul t, a lower dose has been suggested. However, a dose of 0.6 mg/kg results in
substantial ly fewer pati ents wi th excell ent i ntubating conditi ons, and the decrease i n duration is
modest.
41
For maintenance of rel axati on, typi cal i nfusi on rates are ~50 to 100 g/kg/mi n.
26

However, the avai l abi l ity of short and intermedi ate nondepol ari zi ng drugs makes succi nyl choli ne
infusi ons obsolete.
Chi l dren are sli ghtl y more resi stant to succi nyl choli ne than adults,
43
and doses of 1 to 2 mg/kg
are required to faci li tate i ntubati on. In i nfants, 2 to 3 mg/kg may be requi red. Precurari zati on i s
not necessary i n pati ents younger than 10 years because fasci culations are uncommon i n thi s age
group. Bradycardi a i s common i n chi ldren unless atropi ne or glycopyrrol ate i s given.
30

Succi nylchol i ne, at a dose of 4 mg/kg, i s the only effecti ve intramuscul ar neuromuscul ar bl ocking
agent i n chi ldren with difficult i ntravenous access and provi des adequate i ntubati ng condi tions i n
about 4 minutes. However, this route of admi ni stration shoul d not be the method of choi ce.
44

NONDEPOLARIZING DRUGS
Nondepolari zing neuromuscul ar bl ocking drugs bi nd to the postsynapti c receptor i n a
competiti ve fashi on, by bi ndi ng to one of the subuni ts of the receptor (see Fi g. 16-7).
12

Char act er i st i cs of Nondepol ar i zi ng Bl ockade
The fade observed i n response to hi gh-frequency sti mul ati on (>0.1 to 0.15 Hz) is characteri sti c of
nondepol ari zi ng blockade. Wi th EMG recordi ngs, fade i s rel ati vel y constant i n the range 2 to 50
Hz.
45
Mechanical fade is greater wi th 100 Hz than wi th 50 Hz.
46
Tetani c sti mulation is fol lowed by
posttetanic facil i tation, whi ch i s an i ncreased response to any sti mul ation appl i ed soon after the
tetanus. The intensi ty and durati on of thi s effect depend on the frequency and durati on of the
tetanic stimul ati on. Wi th a 50-Hz tetanus of 5-second durati on, twi tch responses have been found
to fal l withi n 10% of their pretetanic val ues i n 1 to 2 mi nutes, and i n most cases i n 1 mi nute (Fi g.
16-9).
Fi nal ly, nondepol arizing bl ockade can be antagoni zed wi th anti chol inesterase agents such as
edrophoni um, neosti gmi ne, or pyridosti gmi ne. It i s also antagoni zed by depol ari zi ng agents, such
as succinyl chol i ne, provided that the nondepol ari zi ng bl ockade i s i ntense and that the
succi nyl choli ne dose is too smal l to produce a bl ock of i ts own.
P har macoki net i cs
As i s the case for other drugs used i n anesthesi a, the el iminati on hal f-li fe of neuromuscul ar
bl ocking agents does not al ways correl ate with durati on of acti on because terminati on of acti on
sometimes depends on redi stributi on i nstead of eli mi nation. However, knowl edge of the kineti cs of
the drug hel ps us understand the behavior of the drug i n special situations (prol onged
administrati on, di sease of the organs of el i mi nation, and so on).
Several mechani sms can expl ai n the vari ous categori es of durations of action li sted in Tabl e 16-3:
1. All l ong-acti ng drugs al l have a l ong (1 to 2 hours) el imi nati on hal f-li fe and depend on l i ver
and/or ki dney functi on for termi nati on of action.
2. Intermedi ate-duration drugs ei ther have an intermedi ate eli mi nation hal f-li fe (atracuri um
and ci satracuri um); or they have l ong eli mi nation hal f-li ves (1 to 2 hours) but depend on
redi stri buti on rather than eli mi nation for termi nati on of effect (vecuronium and rocuroni um)
(Fi g. 16-10).
3. Short-duration drugs have ei ther short el i mi nation half-li ves (the active isomers of
mivacurium) or long

el i mi nation half-li fe but extensi ve redi stributi on (rapacuroni um).
4. Ul trashort-duration drugs have a very short el i mi nati on hal f-li fe (succi nyl choli ne).
FIGURE 16-9. Characteri sti cs of nondepolari zi ng bl ockade. Trai n-of-four responses are equal
before admini stration of vecuronium (arrow). For a gi ven twi tch depressi on, fade i s l ess
duri ng onset (top trace) than recovery (bottom trace). A 50 Hz- tetanus was appl i ed duri ng
recovery. Tetani c fade is seen, with posttetanic faci li tati on, that is a greater trai n-of-four
response after than before the train.
P.430
P.431
TABLE 16-3 Typical Pharmacokinetic Data for Neuromuscular Blocking Agents in
Adults, Except where Stated
DRUG VOLUME OF
DISTRIBUTION
(L/kg)
CLEARANCE
(mL/kg/min)
ELIMINATION
HALF-LIFE (min)
ULTRASHORT-DURATION AGENTS
Succi nylchol i ne 0.04 37 0.65
SHORT-DURATION AGENTS
Mi vacurium
Transtrans 0.05 29 2.4
Cistrans 0.05 46 2.0
Ciscis 0.18 7 30
Rapacuroni um 0.2 7 100
INTERMEDIATE-DURATION AGENTS
Atracuri um 0.14 5.5 20
Ci satracuri um
Adults 0.12 5 23
Intensive
care
0.26 6.5 25
Rocuronium
Adults 0.3 3 90
Intensive
care
0.7 3 330
Vecuroni um 0.4 5 70
LONG-DURATION AGENTS
Doxacuri um 0.2 2.5 95
d-Tubocurari ne
Adults 0.3 13 90
El derl y 0.3 0.8 270
Neonates 0.7 1.1 300
Infants 0.5 1.0 300
Children 0.3 1.5 90
Pancuroni um 0.3 1.8 140
FIGURE 16-10. Representative concentrati ons at the neuromuscular juncti on for si x
representati ve drugs, after bolus doses of 2 ED
95
. Concentrations at the neuromuscul ar
juncti on l ag somewhat behi nd plasma concentrati ons. The level correspondi ng to 25%
recovery i s i ndi cated. The curves were moved up or down so that the 25% l evel matched.
Succi nylchol i ne and the active mi vacuri um i somers have a rapi d el i mi nati on. Pancuroni um
The vol ume of distri buti on of all these agents i s approxi matel y equal to extracell ul ar flui d (ECF)
vol ume (0.2 to 0.4 L/kg) (see Tabl e 16-3). Drugs with short eli minati on hal f-li ves (succi nyl choli ne
and mivacurium) have even smaller vol umes of di stri buti on because they are degraded before
di stri bution is compl ete. In infants, i n whom the ECF vol ume, as a proporti on of body weight, i s
increased, the vol ume of di stri buti on paral l el s ECF vol ume cl osel y.
Onset and Dur at i on of Act i on
Onset and durati on of acti on of neuromuscul ar bl ocki ng drugs are determi ned by the time requi red
for drug concentrati ons at the si te of acti on to reach, and return bel ow, a cri ti cal l evel ,
respectively. For durati on, thi s level i s determi ned chiefly by pl asma concentrations, at l east for
intermedi ate- and long-duration drugs. However, onset time (2 to 7 minutes) l ags behi nd peak
pl asma concentrati ons (<1 mi nute). Thi s del ay refl ects the ti me requi red for drug transfer
between plasma and neuromuscul ar juncti on and is represented quanti tati vel y by a rate constant
(k
eo
). Thi s rate constant corresponds to hal f-ti mes of 5 to 10 mi nutes for most nondepolari zi ng
drugs and i s determi ned by al l the factors that modify access of the drug to, and i ts removal from,
the neuromuscul ar junction. These i nclude cardiac output, di stance of the muscl e from the heart,
and muscl e bl ood fl ow. Thus, onset times are not the same i n al l muscles because of different
bl ood fl ows. If metabol ism or redi stri buti on i s very rapid, the onset ti me i s accelerated. This
probabl y pl ays a rol e only for succi nyl chol ine and mivacurium. Fi nal l y, potent drugs have a slower
onset of acti on than l ess potent agents (Fi g. 16-11).
47
Thi s is because a l arge proportion of
receptors must be occupi ed before bl ockade can be observed. Bl ockade of these receptors wi ll
occur faster, and onset wil l be more rapi d, i f more drug mol ecules are avai labl e, that i s, i f

potency i s l ow. Tabl e 16-2 shows that onset tends to be slower i f a drug i s potent, that i s if ED
95

is smal l.
has a l ong hal f-li fe and recovery occurs duri ng the eli minati on phase. Ci satracuri um has an
intermedi ate terminal hal f-li fe, and recovery al so occurs duri ng the el iminati on phase.
Rocuronium and vecuronium have an el imati on hal f-li fe comparable to that of pancuroni um.
However, an i mportant redi stributi on occurs before, and 25% recovery occurs during that
redi stri buti on process. As a resul t, both rocuroni um and vecuroni um have a durati on of acti on
comparabl e to that of ci satracuri um.
P.432
I ndi vi dual Nondepol ar i zi ng Agent s
Since 1942, nearl y 50 nondepol ari zi ng neuromuscular bl ocki ng agents have been introduced into
cl i ni cal anesthesi a. Thi s section covers only those drugs currently avail able i n North America and
Europe, plus a few others of hi stori cal i nterest. The first agent to undergo cli ni cal i nvesti gati on
was Intocostri n, or d-tubocurari ne, the puri fi ed and standardi zed product of curare obtai ned from
the plant Chondodendrum tomentosum.
1
d-Tubocurari ne has been almost compl etely repl aced by
more modern syntheti c analogues.
d-Tubocurarine
The ED
95
of d-tubocurari ne i s 0.5 mg/kg. At that dose, the durati on of acti on i s typi cal of a l ong-
duration agent (see Tabl e 16-2).
48

Pharmacology. The mol ecul e undergoes mi ni mal metabol ism so that 24 hours after i ts
administrati on about 10% of the compound i s found in the uri ne and 45% i n the bi l e. Li ke most
other neuromuscul ar bl ocking drugs, i t is not extensi vely (30 to 50%) protei n bound. Excreti on i s
impai red in renal fai l ure wi th an i ncrease i n el i mi nati on hal f-li fe.
49

Cardiovascular Effects. Hypotensi on frequentl y accompani es the admini stration of d-
tubocurari ne even at doses l ess than ED
95
. The mechani sm i nvol ved i s mai nl y hi stami ne release,
and skin fl ushing i s frequently observed. Autonomi c gangli oni c blockade may al so pl ay a mi nor
role i n the production of hypotension.
Age. Pharmacoki netic studi es have been performed i n al l age groups, and the resul ts are hel pful
in understanding the behavi or of all nondepol ari zi ng agents i n patients at the extremes of age.
The potency of d-tubocurari ne on a mg/kg basi s does not vary greatl y with age. Infants
demonstrate greater bl ockade than ol der chil dren or adul ts i f the same concentration of d-
tubocurari ne is appl ied. However, this i ncreased sensiti vi ty of the neuromuscular juncti on i n
infants is conceal ed by the increased vol ume of distri buti on (see Tabl e 16-3),
50
and thi s
FIGURE 16-11. Neuromuscular blockade as a function of ti me for four neuromuscular
bl ocking agents. Onset i s faster for the less potent succinycholi ne and rocuronium than for
the more potent vecuronium and ci satracuri um. Reproduced from Kopman et al .
47

phenomenon has al so been observed wi th other neuromuscul ar bl ocking agents. The onset of
acti on i s more rapi d i n the young as a resul t of a more rapid ci rculation ti me. However, the
decreased gl omerul ar fil tration rate (GFR) i n the very young and the very old results in an
increase i n T
1/2
and prol onged durati on of acti on.
50

Burns. Pati ents wi th massi ve burns demonstrate resi stance to d-tubocurari ne and other
nondepol ari zi ng drugs that i s dependent on the si ze of the burn and the ti me si nce i njury.
51

Resi stance is associated wi th hi gher concentrati ons of the free drug to produce a gi ven degree of
twi tch depressi on compared with nonthermall y i njured pati ents. As i n denervati on injury, there i s
an i ncrease i n the number of acetyl choli ne receptors i n muscles cl ose to the si te of i njury, and
less so i n more di stant muscl es.
52

Clinical Use. The l ong durati on and cardiovascular effects of d-tubocurari ne have restri cted i ts
use and consti tuted a stimul us for the producti on of alternati ve agents. Ini tial ly, thi s led to the
introducti on of pancuroni um, whi ch repl aced the hypotensi on of d-tubocurari ne wi th hypertensi on
and tachycardi a. More recentl y, drugs of i ntermedi ate durati on (atracuri um, ci satracuri um,
vecuroni um, and rocuroni um) wi th vi rtual l y no cardi ovascul ar effects have al most el i mi nated the
use of d-tubocurari ne. When avail able, d-tubocurari ne has been mainly confi ned to be used as a
precurarizati on (3 mg/70 kg) before succinyl choli ne to reduce fasciculations and muscl e pains.
Rocuronium has l argel y replaced d-tubocurari ne for thi s indicati on.
Alcuronium
Although i t has never been avai labl e in North Ameri ca, al curoni um sti ll enjoys li mi ted use i n some
countries. The ED
95
is approxi mately 0.2 to 0.25 mg/kg. Intubati ng doses are usual l y l i mi ted to
0.3 mg/kg because of the l ong durati on of acti on. Al though it was i ntroduced as an intermedi ate-
duration drug, i ts recovery i ndex (37 minutes) makes it a long-acti ng neuromuscul ar bl ocking
agent.
53

Atracurium
Atracuri um i s a bi squaternary ammoni um benzyl isoqui nol ine compound. It was devel oped in an
attempt to produce a short-acti ng muscl e rel axant that was independent of the l i ver and the
kidney for termi nation of i ts acti on. It is a mi xture of 10 i somers of different potencies. In
humans, atracuri um is degraded vi a two metaboli c pathways. One of these pathways is the
Hofmann reacti on, a nonenzymati c degradati on the rate of whi ch i ncreases as temperature and/or
pH i ncreases. The second pathway is nonspeci fic ester hydrol ysis. The enzymes i nvol ved i n this
metaboli c pathway are a group of tissue esterases, which are distinct from plasma or acetyl
chol i nesterases. The same group of enzymes is i nvol ved i n the degradati on of esmolol and
remi fentani l . It has been esti mated that two-thirds of atracuri um is degraded by ester hydrolysi s
and one-thi rd by Hofmann reacti on.
54
Subjects with abnormal pl asma chol inesterase have a
normal response to atracuri um.
The end products of the degradati on of atracuri um are l audanosi ne and acryl ate fragments.
Laudanosi ne has been reported as causing seizures in ani mals, but at doses l argely exceeding the
cl i ni cal range. No del eterious effect of laudanosine has been demonstrated concl usi vel y i n
humans.
55
Laudanosi ne i s excreted by the ki dney. Acryl ates have the potential to i nhi bit cell
growth, and this has been demonstrated i n vi tro.
56
However, the concentrati ons and exposure
ti mes requi red to obtai n thi s effect are much greater than what i s obtained normal l y i n cl i ni cal
practi ce.
Pharmacology. Atracuri um i s an intermedi ate-duration drug, wi th a terminal hal f-li fe of
approxi mately 20 mi nutes. Termi nati on of effect occurs duri ng the eli mi nation phase of the drug.
Because degradati on does not depend on an end-organ functi on, duration of action is not
dependent on renal or hepati c function. It does not i ncrease wi th age.
The ED
95
of atracuri um is 0.2 to 0.25 mg/kg. The onset of action of equi potent doses i s simil ar for
atracurium, pancuroni um, d-tubocurari ne, and vecuroni um. It i s sl ower than succi nylchol ine. As
with any neuromuscul ar bl ocki ng agent, onset time can be reduced i f the dose i s i ncreased, but i t
is not recommended to exceed 0.5 mg/kg, because of hypotensi on and hi stami ne release. The
duration of action is al so dose related. The ti me to 25% first twi tch recovery after 0.5 mg/kg i s
approxi mately 30 to 40 mi nutes.
Cardiovascular Effects. Atracuri um rel eases hi stami ne if large doses (2 ED
95
or greater) are
administered, with hypotensi on and tachycardi a as frequent mani festati ons. Si mi lar changes occur
after the use of d-tubocurari ne or metocuri ne but at l ower equi potent doses. The most obvi ous
cl i ni cal mani festation of hi stami ne rel ease is ski n fl ushi ng. Bronchospasm may al so occur. These
responses can be avoi ded by sl ow i njecti on over 1 to 3 minutes or by pretreatment wi th H
1
and H
2

receptor bl ockade. Anaphyl acti c reacti ons to atracuri um have been descri bed, but they do not
appear to be more frequent than after other neuromuscular bl ocki ng drugs.
31

Special Situations. Dosage requirements are simi lar in the el derl y, younger adul ts, and chi l dren,
presumabl y refl ecti ng the organ i ndependence of atracuri um' s el imi nati on. Si mi l arl y, no

dosage adjustment i s requi red i n i ndi vi dual s wi th renal or hepati c fai l ure. As with other
nondepol ari zi ng agents, the dose must be i ncreased i n burn pati ents, partl y because of i ncreased
protei n bi ndi ng, partl y because of up-regul ati on of receptors, causi ng resi stance at the endpl ate.
In the obese patient, the dose of atracuri um, as for al l neuromuscul ar blocki ng agents, shoul d be
cal cul ated based on l ean body mass.
Clinical Uses. To obtai n adequate intubati ng condi tions, relativel y large doses must be used (0.5
mg/kg), and l aryngoscopy shoul d be attempted onl y after 2 to 3 mi nutes. Cardiovascul ar
mani festati ons of histamine rel ease are often seen at that dose, and perfect intubati ng condi tions
are seen i n onl y half the pati ents (see Fi g. 16-3).
7
Increasi ng the dose may improve i ntubating
condi ti ons, but at the expense of greater cardiovascular effects. For i ntubation, there has been a
tendency to repl ace atracurium by agents, such as rocuronium, with a shorter onset ti me and
more cardiovascular stabil i ty. Atracuri um i s, however, conveni ent and versati l e for maintenance of
rel axation, either as a conti nuous i nfusi on (5 to 10 g/kg/mi n) or as i ntermi ttent i njections (0.05
to 0.1 mg/kg every 10 to 15 mi nutes).
Cisatracurium
In an attempt to increase the margi n of safety between the neuromuscul ar bl ocking dose and the
hi stami ne-rel easing dose, a potent i somer of atracurium, ci satracurium, was identi fi ed. Li ke
atracurium, i ts cardiovascul ar effects are mani fest at doses exceeding 0.4 mg/kg, but i ts ED
95

(0.05 mg/kg) i s much l ower. As a resul t, manifestati ons of hi stami ne rel ease are not seen i n
practi ce. The metabol i sm of cisatracuri um i s si mi l ar to that of atracurium, but i t seems that the
rel ati ve i mportance of Hofmann el iminati on i s somewhat greater than for atracuri um, and the rol e
of ester hydrol ysi s is correspondi ngl y l ess.
57
The end products of metabol ism, laudanosine and
acrylate fragments are the same as for atracurium.
Pharmacology. Because ci satracurium i s a potent drug, i ts onset time i s longer than that of
atracurium and longer sti l l than that of rocuronium. For example, equi potent doses of
ci satracurium (0.092 mg/kg) and rocuroni um (0.72 mg/kg) had onset ti mes of 4 minutes and 1.7
mi nutes, respecti vel y.
58
The el i mi nati on hal f-li fe (22 to 25 minutes) i s simil ar to that of
atracurium,
59
so that the durati on of acti on for 2 ED
95
doses (0.1 mg/kg) is 30 to 45 mi nutes.
However, in an attempt to accelerate onset, the recommended dose was i ncreased to 0.15 mg/kg.
Thi s is wel l below the threshold for histami ne release, but the durati on of acti on i s prol onged to
45 to 60 mi nutes.
Because the doses requi red to obtai n paral ysis are consi derably less for ci satracurium than for
atracurium, l ess laudanosine and l ess acryl ate byproducts are produced.
56
Peak concentrati ons of
laudanosine have been found to be five ti mes l ess with equi potent doses of ci satracuri um. Thus,
the concerns rai sed by the potenti al toxi c effects of these metabol ites are vi rtual l y el iminated.
Special Situations. As for atracuri um, there i s no need to adjust dosage i n the el derl y, chi l dren,
or i nfants, when compared wi th young adul ts. The experi ence i n burn and obese pati ents is
l i mi ted, but the same pri nci ples that are val i d for atracurium are expected to appl y.
P.433
Side Effects. In contrast to atracurium, ci satracuri um is devoi d of hi stami ne-rel easing properti es
even at high doses (8 ED
95
). It i s al so devoi d of cardi ovascul ar effects. However, anaphyl actic
reacti ons have been descri bed.
31

Clinical Use. Ci satracuri um may be used to faci l i tate tracheal i ntubation at doses equi val ent to 3
to 4 times the ED
95
(0.15 to 0.2 mg/kg) when manual venti l ati on i s possi bl e after induction of
anesthesia and when the durati on of the procedure i s expected to exceed 1 hour. Durati on i s
shorter wi th l ower doses, but onset ti me i s prol onged and i ntubati ng conditi ons are less i deal .
Neuromuscul ar bl ockade i s easi l y maintai ned at a stable level by conti nuous intravenous i nfusion
of ci satracurium (1 to 2 g/kg/mi n) at a constant rate and does not change wi th ti me, suggesti ng
the l ack of a si gni fi cant cumul ati ve drug effect and l ack of dependence on renal and/or hepati c
cl earance mechani sms.
60
The rate of recovery i s i ndependent of the dose of ci satracuri um and the
duration of the admi ni strati on.
Because ci satracuri um does not depend on end-organ functi on for i ts eli mi nation, the drug
appears sui tabl e for administrati on i n the i ntensive care unit (ICU). The infusion rates to keep
patients paral yzed i s greater than in the operati ng room (typi cal l y 5 g/kg/min), with wide
interindividual vari abi l ity.
61
It i s l ikel y that prol onged exposure of the receptors to a
neuromuscul ar bl ocki ng agent causes some up-regul ati on, with a correspondi ng requirement for a
hi gher dose.
Doxacurium
Doxacurium is a l ong-acti ng bisquaternary ammoni um compound that is devoi d of hi stami ne-
rel easing or cardi ovascul ar si de effects. It has a prol onged eli mi nation hal f-li fe (1 to 2 hours) and
depends on the ki dney and the l i ver for its di spositi on. Thus, durati on of action i s prol onged i n the
el derl y and i n subjects wi th i mpai red renal or hepati c functi on. Doxacuri um i s al so a weak
substrate for pl asma chol i nesterase. The ED
95
for doxacuri um i s 25 g/kg (see Tabl e 16-2).
62

Doxacurium has a l i mi ted place in cli nical practi ce because of i ts very sl ow onset and l ong
duration of action. Neverthel ess, i t may be useful i n pati ents with ischemic heart di sease who are
undergoing prolonged anesthesi a or long-term mechanical venti lati on of the lungs. The slow onset
ti me, prol onged durati on of action, and slow recovery make doxacuri um unsuitable for facil i tating
tracheal i ntubati on or for providi ng skeletal muscle rel axation during bri ef surgi cal procedures.
When i nfused for several days to pati ents i n the ICU, recovery after stopping the i nfusi on
exceeded 10 hours.
Gallamine
Gal lami ne was i ntroduced in 1948 and has onl y historical interest. It i s a low potency
nondepol ari zi ng drug (ED
95
= 2 mg/kg) and i t has a l ong duration of action. Gal l amine produces
si gni fi cant tachycardi a because of a vagol ytic effect, even at doses associated wi th i ncompl ete
bl ockade at the adductor pol li cis. It i s effecti ve when used to prevent succinyl chol i ne-induced
fasciculati ons.
GW280430A
The new compound call ed GW280430A i s a nondepolarizing drug and belongs to the class of
asymmetric mixed-onium chlorofumarates. Its main degradati on pathway i nvol ves cystei ne i n the
pl asma and i s i ndependent of pl asma chol i nesterase. The ED
95
in humans i s 0.19 mg/kg.
63

Cardi ovascul ar effects are observed at doses exceedi ng 3 ED
95
, and are most probabl y rel ated to
hi stami ne rel ease. At doses anti cipated to be requi red for tracheal i ntubati on (0.4 to 0.6 mg/kg),
onset at the adductor pol li cis i s 1.5 mi nutes and durati on to 25% T1 recovery is 8 to 10 mi nutes,
maki ng thi s drug comparabl e to succi nylchol ine i n durati on of acti on. At the time of wri ti ng, this
compound was sti ll an investi gati onal drug.
Metocurine
Metocuri ne, produced by methyl ati on of two hydroxy groups of d-tubocurari ne, i s twi ce as potent
as the parent compound and produces l ess histamine rel ease. Its ED
95
is approxi mately 0.3
mg/kg.
48
Its durati on of acti on i s comparabl e to that of d-tubocurari ne, making i t a l ong-acti ng
agent.

Metocuri ne causes less hi stami ne rel ease and cardiovascular effects than equi potent doses of d-
tubocurari ne. Because of thi s, metocuri ne enjoyed a bri ef peri od of popul ari ty before the
introducti on of atracuri um and vecuroni um. Metocuri ne and pancuronium combi ned were found to
be synergi sti c wi th opposi ng cardiovascular effects, and the mi xture was recommended for use in
patients with severe cardi ovascul ar di sease.
64
However, the introducti on of shorter durati on
al ternatives without cardi ovascul ar effects has made metocuri ne obsol ete.
Mivacurium
Mi vacurium is a benzyl isoqui noli ne deri vati ve with an i ntermedi ate onset and short durati on of
acti on that i s hydrol yzed by pl asma chol i nesterase, li ke succi nyl chol ine.
65
Contrary to
succinylcholine, however, mivacurium produces nondepol ari zi ng blockade. The drug i s presented
as a mi xture of three isomers. Two, the cistrans and transtrans, have short hal f-li ves, but the
ci sci s isomer has a much l onger hal f-li fe (see Tabl e 16-3). The cisci s isomer accounts for onl y
6% of the mi xture, has l ess than one-tenth the potency of the other i somers and thus contributes
li ttl e i f anything to neuromuscul ar bl ock duri ng anesthesi a. The pharmacology of mi vacuri um i s
governed l argel y by the behavi or of the transtrans and cistrans isomers.
Pharmacology. Under steady-state nitrous oxidenarcoti c anesthesi a, the ED
95
of mi vacuri um i s
0.08 mg/kg (see Tabl e 16-2). However, there i s evi dence that mivacuri um i s less effective when
gi ven at inducti on of anesthesia than during stabl e anesthesi a.
66
Thi s mi ght be because cardi ac
output i s decreased and/or peri pheral bl ood fl ow mi ght be i ncreased after i nduction of anesthesi a.
Decreasi ng cardi ac output tends to increase the effect of short-acti ng drugs because a bol us dose
is di luted in a small er volume, produci ng greater pl asma concentrati ons. In any event, doses that
are twice the ED
95
mg/kg determi ned under steady-state anesthesi a are associ ated wi th poor
intubati ng condi ti ons. In 9 out of 9 pati ents, a dose of 0.15 mg/kg provi ded unacceptabl e
condi ti ons.
67
These condi tions are markedl y improved i f the dose i s increased to 0.2 or 0.25
mg/kg but were not as good as with succi nyl chol ine.
67
Onset ti me i s surpri si ngl y long for a drug
whose active isomers have a termi nal hal f-li fe of l ess than 2 mi nutes. At 2 to 3 ED
95
, twitch
di sappears in 2.5 to 4 mi nutes.
65
Thi s long onset time i s probabl y the resul t of the high potency of
mi vacuri um. For all neuromuscul ar blocki ng agents, a direct rel ationship between onset ti me and
potency has been demonstrated. Drugs with a low ED
95
, expressed i n mol es/kg, have a l onger
onset time.
47
On the other hand, recovery to 25% does not depend heavi l y on dose, bei ng i n the
range of 15 to 25 mi nutes for doses of 0.15 to 0.25 mg/kg. The i nfusi on rate to mai ntai n blockade
constant does not vary wi th ti me, and recovery i s as rapi d after many hours of i nfusi on than after
a bol us dose, suggesti ng that the sl owl y el iminated ci sci s metabol ite contri butes very li ttl e to the
overal l neuromuscular effect.
Side Effects. Like atracuri um, mi vacurium rel eases hi stami ne in a dose-rel ated fashi on. At doses
of 0.15 mg/kg or less, the drug has vi rtual l y no cardi ovascul ar effects. Hypotension and
tachycardi a are seen frequentl y when doses are i ncreased to 0.2 mg/kg or more. Cutaneous si gns,
such as erythema and fl ushi ng, are also observed frequentl y wi th large doses. They can be seen i n
isol ati on or be accompanied by cardi ovascul ar changes. These hi stami ne-rel ated effects are short
li ved (2 to 3 mi nutes) and shoul d not normal l y be considered a mani festation of anaphyl axis,
whi ch i s a rare event. Bronchospasm i s rare, but may be seen more frequently wi th mi vacuri um
than wi th other neuromuscul ar bl ocki ng agents.
68
Manifestati ons of hi stami ne rel ease may be
decreased i f the drug i s ei ther gi ven slowl y (i n more than 30 seconds) or i n di vi ded doses (0.15
mg/kg fol l owed 30 seconds l ater by 0.1 mg/kg).
Special Situations. In i nfants and chi ldren the ED
95
is approxi mately the same as i n adul ts, but
onset of bl ock and recovery are more rapid.
69
Cardi ovascul ar effects are not as i mportant as in
adults, so doses up to 0.3 mg/kg have been used. Durati on to 25% recovery i s shorter (10
mi nutes) in infants and chi l dren than i n adul ts.
69
The i nfusi on rate requi red to mai ntai n blockade
is greater i n chi ldren than i n adults.
70
In the el derl y, the ED
95
i s the same as i n younger adul ts.
P.434
However, duration of action is prol onged by a few mi nutes and the i nfusi on rate to mai ntain
neuromuscul ar bl ockade i s decreased.
71

Burns. In burn pati ents, upregul ati on of the receptors, and to a l esser extent i ncreased protei n
bi nding, causes a resi stance to all nondepol ari zi ng neuromuscul ar bl ocki ng agents. Thus, a l arger
dose of the drug i s normall y requi red. However, for mi vacuri um, the si tuati on i s different because
pl asma chol i nesterase acti vi ty i s decreased i n burn pati ents. The net effect i s ei ther a normal or
even an enhanced effect of usual doses.
72

Reversal. Admi ni strati on of anti chol inesterase agents after mivacuri um has been controversi al for
two mai n reasons. Fi rst, neosti gmi ne, but not edrophoni um, i nhi bits plasma chol i nesterase.
Therefore, the breakdown of mi vacuri um may be sl ower i n the presence of neosti gmi ne. In fact,
neostigmine has been shown to del ay recovery if gi ven duri ng i ntense neuromuscul ar bl ock,
presumabl y when hi gh concentrations of mi vacurium are sti ll present.
73
However, if neosti gmi ne i s
gi ven when si gns of spontaneous recovery are present (two twi tches or more present), the rate of
recovery i s accel erated. Edrophoni um does not interfere wi th pl asma chol inesterase activity and
was found to accelerate recovery, even when gi ven when blockade is profound (one twi tch in the
trai n-of-four).
73
Al so, mivacurium reversal has been suggested to be unnecessary because
spontaneous recovery is rapi d and its avoi dance may reduce the i nci dence of side effects such as
postoperative nausea and vomi ting. However, thi s may result in residual block on arrival in the
recovery room, particul arl y if large doses of mivacuri um are used up to the end of anesthesi a.
Plasma Cholinesterase. Mi vacuri um i s metabol i zed by pl asma chol i nesterase somewhat more
sl owly than succinyl choli ne. The condi ti ons associ ated wi th a decrease plasma choli nesterase
acti vi ty known to affect succi nylchol ine metabol ism al so al ter mivacuri um durati on of acti on. For
example, a moderate i ncrease i n the duration of action of mi vacuri um can be seen i n postpartum
patients. Patients homozygous for atypi cal plasma chol i nesterase may show very prol onged bl ock.
Clinical Use. Mivacuri um is well sui ted to surgi cal procedures requi ri ng bri ef muscl e relaxation,
parti cul arl y those in whi ch rapid recovery is requi red, such as ambul atory and l aparoscopic
surgery. However, it i s not recommended for rapid sequence inducti on. Because of i ts sl ow onset,
condi ti ons for tracheal i ntubation are unsatisfactory unless l arge bol us doses, at l east 0.2 mg/kg,
are given and a del ay of at least 2 mi nutes i s al l owed before i ntubation i s attempted.
67
However,
by usi ng two doses of 0.15 and 0.1 mg/kg separated by 30 seconds, good to excel lent intubati ng
condi ti ons have been achieved in almost 90% of pati ents, an onset si mi l ar to that of
succi nyl choli ne.
74
Smal l doses of mi vacuri um (0.04 to 0.08 mg/kg) have been suggested to
faci li tate insertion of a laryngeal mask ai rway.
75
Condi ti ons and success rate are usuall y better
than i n the absence of neuromuscul ar bl ocking agent. The rapid recovery makes it necessary to
moni tor neuromuscul ar acti vi ty conti nuously duri ng i ts administrati on, whi ch i s accompli shed more
easil y by constant i nfusion (5 to 7 g/kg/mi n i n young and mi ddl e-aged adul ts) than by
intermi ttent bol us i njecti on. This i nfusi on rate has to be i ncreased i n chi l dren and reduced i n the
el derl y.
76
In chi l dren, mi vacuri um has a faster onset of action and more rapid

recovery than i n adul ts, so the drug can be used for intubati on and mai ntenance of relaxation for
short procedures.
69, 70

Pancuronium
Pancuroni um bel ongs to a seri es of bi squaternary ami nosteroi d compounds. It i s metabol ized to a
3-OH compound, which has one-half the neuromuscul ar bl ocking acti vi ty of the parent compound.
The ED
95
of pancuroni um i s 0.07 mg/kg. The durati on of acti on i s l ong, being 1.5 to 2 hours after
a 0.15 mg/kg dose. Clearance i s decreased i n renal and hepati c fai l ure, demonstrati ng that
excreti on i s dependent on both organs. The onset of action is more rapid i n i nfants and chi l dren
than i n adul ts and recovery is sl ower i n the elderly.
Cardiovascular Effects. Pancuroni um i s associ ated wi th i ncreases in heart rate, bl ood pressure,
and cardiac output, particul arl y after large doses (2 ED
95
). The cause is uncertai n but includes a
vagol ytic effect at the postgangli oni c nerve termi nal , a sympathomimeti c effect as a resul t of
bl ocking of muscarinic receptors that normal l y exert some braki ng on gangli oni c transmi ssi on, and
P.435
an i ncrease i n catechol ami ne release. Pancuroni um does not rel ease hi stami ne.
Clinical Use. The sl ow onset of acti on of pancuroni um l i mi ts i ts useful ness i n faci li tating tracheal
intubati on. Admi ni strati on i n di vi ded doses, wi th a smal l dose gi ven 3 mi nutes before i nducti on of
anesthesi a (pri mi ng pri nci pl e), produces a smal l but measurabl e accelerati on, but the
intermedi ate- and short-acti ng compounds are more sui table when succinyl chol i ne i s
contrai ndi cated. In pati ents wi th myocardi al ischemi a, tachycardi a shoul d be avoi ded. However,
pancuroni um has enjoyed popul ari ty i n cardiac anesthesi a because i t counteracts the bradycardi c
effect of hi gh doses of opioids. Wi th the i ncreased tendency toward earl y extubati on i n cardi ac
surgery, the appropriateness of pancuroni um i n thi s setti ng must be reeval uated. The use of
pancuroni um i nstead of rocuroni um i s associated wi th a greater incidence of muscul ar weakness i n
the recovery room after cardi ac surgery,
77
and reversal should be consi dered seri ously. The
conti nued popul ari ty of pancuroni um i s dependent on cost: generi c pancuroni um i s cheaper than
other nondepolarizing rel axants. Its use i s associ ated wi th a high incidence of residual bl ock in the
postanesthesia care uni t (PACU), at l east i n adults (see Tabl e 16-1).
8, 78
Pancuroni um
neuromuscul ar bl ock is more di ffi cul t to reverse than that of the intermedi ate duration agents.
79

Pipecuronium
In an effort to obtai n a pancuronium wi thout cardi ovascul ar si de effects, pi pecuronium was
devel oped. Its ED
95
is sl ightl y less (0.05 mg/kg) than that of pancuronium, and i t is vi rtual l y
without any cardi ovascular effects. However, pi pecuronium soon became obsol ete because i t had
the drawbacks of l ong-acti ng agents (di ffi cul ty to reverse, resi dual paralysi s, l ack of versati l ity),
and the absence of cardi ovascul ar effects was al so seen wi th the shorter acti ng vecuroni um and
rocuroni um.
Rapacuronium
Rapacuroni um i s al so an aminosteroid compound that was i ntroduced for cl ini cal use i n 1999. It
was withdrawn i n 2001 because of rare, but severe cases of bronchospasm after intubati on. Bei ng
less potent than rocuroni um, i t had a more rapid onset of acti on. Fol l owing 1.5 mg/kg, good to
excel l ent intubati on condi ti ons were produced at 60 seconds, cl i ni cal durati on (25% T
1
recovery)
occurs i n 17 mi nutes and spontaneous recovery to train-of-four rati o of 0.7 occurs i n 35
mi nutes.
80
The i ntubating conditi ons were not as good as wi th succi nylchol ine and the duration of
acti on was l onger. Rapacuroni um i s metabol ized to a 17-OH deri vati ve (ORG 9488) that has twi ce
the neuromuscul ar blocki ng acti vi ty of the parent compound and i s excreted slowl y via the
ki dneys.
Rapacuroni um produces mi l d dose-rel ated tachycardi a and hypotension, and these cardiovascular
changes do not appear to be because of hi stami ne rel ease. Mi ld to moderate increases i n ai rway
pressure and bronchospasm were observed i n more patients gi ven rapacuroni um than
succi nyl choli ne.
80
The mechanism for this effect is not a hypersensiti vi ty or al lergic reaction, but
is most li kel y rel ated to the effect of rapacuronium on M2 and M3 muscari ni c receptors in the
lung. Activati on of the postsynaptic M3 receptors by acetylchol ine produces brochosconstriction in
the lungs, and the effect is termi nated by presynapti c M2 receptors that counteract thi s effect.
Rapacuroni um has the potenti al to bl ock both receptors, but i t has a greater affinity for the M2
receptor. The concentrati ons requi red for M2 bl ockade are well withi n the cli nical range, whi l e
much more i s requi red for M3 i nhibi ti on. The net effect i s that i f M2 receptors are blocked
sel ecti vely, for exampl e, i n suscepti bl e individuals, bronchoconstricti on by acti vati on of the M3
receptors i s unopposed.
81
Other neuromuscular blocki ng agents, such as vecuronium and
ci satracurium, have simil ar differenti al effects on the M2 and M3 receptors, but at concentrati ons
hi gher than encountered cl i ni cal l y.
81

Rocuronium
Rocuronium i s an ami nosteroi d compound wi th structural simil ari ty wi th vecuroni um and
pancuroni um. Its duration of action i s comparabl e to that of vecuronium, but onset i s shorter.
Pharmacology. Plasma concentrati ons of rocuronium decrease rapi dl y after bol us injecti on
because of hepatic uptake.
82
Thus, the duration of action of the drug i s determi ned chi efl y by
redi stri buti on, rather than by i ts rather l ong termi nal eli minati on hal f-li fe (1 to 2 hours) (see Fi g.
16-10). Metabol ism to 17-deacetyl rocuroni um is a very mi nor el i mi nati on pathway. Most of the
drug is excreted unchanged in the uri ne, bi l e, or feces.
82

Wi th an ED
95
of 0.3 mg/kg, rocuroni um has one-si xth the potency of vecuroni um, a more rapi d
onset, but a si mi lar durati on of acti on and si mi l ar pharmacoki neti c behavi or. Wi th equi potent
doses, rocuroni um onset at the adductor pol li cis was much faster than that of ci satracuri um,
atracurium, and vecuronium (see Fi g. 16-11).
47
After doses of 0.6 mg/kg (2 ED
95
) maximal
bl ock occurs in 1.5 to 2 mi nutes. In a multi center study of 349 pati ents, intubati ng condi ti ons at
60 seconds after 0.6 mg/kg rocuroni um were good to excel l ent i n 77% of cases. To obtain results
si mi l ar to those after 1 mg/kg succinyl choli ne, the dose of rocuroni um had to be increased to 1.0
mg/kg, whi ch provi ded 92% good or excel l ent condi tions.
83
However, the durati on of acti on i s
longer than for succi nylchol ine, ranging between 30 to 40 mi nutes for a 0.6 mg/kg dose to
approxi mately 60 mi nutes after 1 mg/kg i n adults. Thus, rocuronium is an intermedi ate-duration
drug.
As for other nondepol ari zi ng agents the onset of action of rocuronium i s more rapid at the
di aphragm and adductor l aryngeal muscl es than at the adductor pol l i ci s,
84
probabl y a resul t of a
greater blood fl ow to central l y l ocated muscles. Laryngeal adductor muscl es are important in
anesthesia because they cl ose the vocal cords and i nsuffi ci ent rel axati on prevents easy passage of
the tracheal tube. Laryngeal adductor muscl es are resi stant to the effect of rocuroni um, and the
pl asma concentrati on required for equi val ent blockade i s greater at the l arynx than at the
adductor pol l i ci s.
85
The same i s true of the diaphragm, whi ch is resi stant to the effect of
rocuroni um and other neuromuscul ar bl ocking agents. Recovery is faster at the diaphragm and
larynx than at the adductor pol l i ci s.
84

Cardiovascular Effects. No hemodynamic changes (bl ood pressure, heart rate, or ECG) were
seen in humans, and there were no i ncreases i n plasma hi stami ne concentrati ons after doses of up
to 4 ED
95
(1.2 mg/kg).
86
Only sli ght hemodynami c changes are observed during coronary artery

bypass surgery. Anaphylacti c reacti ons have been descri bed, and i t has been cl ai med that these
events occur more frequentl y wi th rocuroni um than wi th other neuromuscul ar bl ocki ng agents.
31

However, it now appears that many of these reports mi ght not be a true anaphyl acti c reaction to
rocuroni um, because up to 50% of the general popul ati on show a posi tive i ntradermal or pick test
to the drug.
87
Cl early, many pati ents who were investi gated for a possibl e anaphylacti c reacti on
were fal sel y label ed al l ergi c to the drug, because of the hi gh rate of fal se-positi ve tests. It is
possi bl e that overdiagnosis has pl ayed a rol e in the relativel y hi gh inci dence of rocuronium
anaphyl axi s reported i n Norway (29 cases i n 150,000 administrati ons, or 1:5,000)
88
or i n France,
31
whi l e reports from other Nordi c countri es suggest a much l ower i nci dence (7 cases i n 800,000
administrati ons or l ess than 1:100,000).
88
Current evi dence suggests that wi thholdi ng rocuronium
because of the fear of anaphyl acti c reactions i s unjustified.
Special Situations. The potency of rocuronium has been reported to be sl i ghtly greater i n women
than in men, the ED
95
being 0.27 and 0.39 mg/kg, respecti vel y, with an i ncreased durati on i n
women.
89
Some ethni c groups are more sensi ti ve to the drug. Chi nese subjects l i vi ng i n Vancouver
were found to be more sensi tive than Caucasi ans.
90
Chi l dren (2 to 12 years ol d) requi re more
rocuroni um and duration of action is l ess. Onset of acti on i s shorter i n the pediatri c than i n the
adul t popul ati on. For exampl e, a dose of 1.2 mg/kg provi des an onset ti me (39 seconds)
comparabl e to that of succi nyl choli ne, 2 mg/kg, and mean duration of action is 41 mi nutes.
91

Thus, the recommended doses are 0.9 to 1.2 mg/kg i n thi s age group. Rocuronium i s more potent
in infants than in older children.
92
Doses of 0.6 mg/kg have a longer durati on i n neonates (<1
month) than i n infants (5 to 12 months), so a reduced dosage (0.45 mg/kg) i s recommended.
93

Rocuronium may be used for rapi d-sequence inducti on as succi nyl chol i ne i s rel ati vel y
contrai ndi cated because of the possi bl e presence of undi agnosed muscl e dystrophy i n pedi atri c
patients, especi all y in boys.
38

In elderl y pati ents, the ED
95
is si mi l ar to that found in younger adults, but the duration of action
P.436
i s prol onged sl i ghtl y.
94
Rocuroni um has an i ncreased termi nal half-li fe i n renal fai lure patients,
probabl y because of i ts parti al renal el i mi nation, but thi s transl ates i nto very mi nor, i f any,
prolongation of block.
95
In hepatic di sease, the sl ower uptake and eli mi nation of rocuronium by
the li ver tends to prol ong the durati on of action of the drug, but this i s compensated to some
extent by the l arger vol ume of di stri buti on.
96

Clinical Use. The rapi d onset and i ntermedi ate durati on of acti on makes this agent a potenti al
repl acement for succi nylchol ine i n condi ti ons where rapi d tracheal intubati on i s i ndi cated.
However, large doses (>1 mg/kg) are requi red with a prolonged duration of action. Contrary to
succi nyl choli ne, the opti on to wait for spontaneous breathi ng to resume before hypoxia i s mani fest
does not exi st wi th rocuroni um. To shorten the onset ti me, the pri mi ng pri nci pl e, whi ch i nvol ves
the admini stration of a smal l dose of rocuroni um usual l y 3 minutes before i nducti on, has been
advocated. Unfortunatel y, the optimal primi ng dose, that i s the l argest dose that wi ll not produce
symptoms of weakness in the awake pati ent, i s rather smal l . As wi th defascicul ati ng doses before
succi nyl choli ne, i t i s not recommended to admi ni ster more than 0.1 ED
95
,
32
whi ch, i n the case of
rocuroni um, amounts to 0.03 mg/kg. Such a smal l dose has mi ni mal effects on onset ti mes
provi ded by much larger doses (0.6 to 1.0 mg/kg). However, pri mi ng mi ght have an effect i f the
intubati ng dose is smal l (0.45 mg/kg). A ti mi ng pri nci ple has been described in whi ch 0.6 mg/kg
rocuroni um i s given before the induction agent, whi ch i s admi ni stered at the onset of ptosis.
Consi dering that loss of consciousness does not occur i mmedi ately after i njection of the induction
agent, thi s techni que i s not recommended. Rocuroni um and thi opental do not mi x. They form a
precipi tate when they are i n the same intravenous l ine. If thi opental is used for i nducti on of
anesthesia, the li ne must be fl ushed careful l y before rocuroni um i s given.
Except in countri es where i t is not avail able, rocuroni um has repl aced vecuroni um as an
intermedi ate-duration rel axant because of i ts more rapi d onset. Ini tial doses of 0.6 mg/kg i v wi l l
usuall y produce good i ntubating condi tions withi n 90 seconds. Durati on of acti on i s 30 to 40
mi nutes. Smal l er doses (typi cal l y 0.45 mg/kg) have a shorter duration of action, but time to
intubati on must be i ncreased. Subsequent doses of 0.1 to 0.2 mg/kg wil l provi de cl i ni cal
rel axation for 10 to 20 mi nutes. Al ternati vely, rocuroni um mi ght be gi ven by conti nued i nfusi on,
ti trated with the hel p of a nerve stimul ator. Infusi on rates are i n the range 5 to 10 g/kg/mi n.
60

Recovery after infusi ons i s sl ower than after bolus doses.
97

Vecuronium
Vecuroni um i s an i ntermedi ate-duration aminosteroid neuromuscul ar rel axant wi thout
cardi ovascul ar effects. Its ED
95
is 0.04 to 0.05 mg/kg. Its durati on and recovery characteristics
are comparabl e to those of rocuronium. However, i ts onset of acti on i s sl ower.
Pharmacology. Vecuroni um i s a monoquaternary ammoni um compound produced by
demethyl ati on of the pancuroni um molecul e. The demethyl ati on reduces the acetyl chol i ne-li ke
characteri sti cs of the mol ecule and increases i ts l i pophil i ci ty, whi ch encourages hepatic uptake.
Vecuroni um undergoes spontaneous deacetylation to produce 3-OH, 17-OH, and 3,17-(OH)
2

metaboli tes. The most potent of these metabol ites, 3-OH vecuronium, about 60% of the acti vi ty of
vecuroni um, i s excreted by the ki dney, and may be responsi bl e, i n part, for prol onged paral ysi s i n
patients i n the intensive care uni t.
98
Like rocuronium, vecuronium has been found less potent and
with a shorter durati on of acti on i n men than i n women, probabl y because of a greater vol ume of
di stri bution in men.
Durati on of action of vecuronium, li ke that of rocuronium, is governed by redistri bution, not by
el i mi nation (see Fi g. 16-10). Attempts have been made to speed the onset of action by usi ng the
pri mi ng pri nci pl e, that i s by admi ni stering a small , subparal yzing dose several mi nutes before the
pri nci pal dose i s gi ven. For vecuronium, the best results have been obtai ned wi th a pri mi ng dose
of 0.01 mg/kg, fol lowed 3 to 4 minutes later by 0.1 mg/kg. However, the i ntroduction of
rocuroni um, whi ch has a more rapi d onset of acti on, i s l ikel y to make this practice obsol ete.
Cardiovascular Effects. Vecuroni um usual ly produces no cardi ovascul ar effects with cl i ni cal
doses. It does not induce histamine rel ease. Bradycardi a has been descri bed wi th hi gh-dose opi oi d
anesthesia, and this might be the refl ection of the opi oid effect. All ergi c reacti ons have been
descri bed, but no more frequentl y than after the use of other neuromuscular blocki ng drugs.
31

Clinical Use. The cardi ovascul ar neutral i ty and i ntermediate durati on of acti on make vecuroni um
a sui tabl e agent for use in pati ents wi th i schemi c heart di sease or those undergoi ng short,
ambul atory surgery. Care shoul d be taken when vecuroni um i s admini stered immedi atel y after
thi opental because a precipi tate of barbi turic aci d may be formed that may obstruct the
intravenous cannula.
Large doses, 0.1 to 0.2 mg/kg, with or wi thout pri ming, can be used to faci l i tate tracheal
intubati on i nstead of succinyl chol i ne. For maintenance of rel axati on, vecuroni um may be gi ven
using i ntermittent bol uses, 0.01 to 0.02 mg/kg, or by continuous i nfusion at a rate of 1 to 2
g/kg/mi n. However, the rate of spontaneous recovery of neuromuscul ar functi on i s sl ower after
administrati on by i nfusi on than by i ntermi ttent boluses.
99
Vecuroni um has now largel y been
repl aced by the more rapi d rocuroni um.

DRUG INTERACTIONS
Interactions between neuromuscul ar bl ocki ng drugs and several anestheti c and nonanesthetic
drugs have been suggested. Al though some interacti ons have been confi rmed, many remain as
isol ated case reports or theoreti cal possi bil i ti es. Onl y some of these i nteracti ons wi ll be di scussed
here.
Anest het i c Agent s
Inhalational Agents
The anestheti c vapors potenti ate neuromuscular blockade in a dose-rel ated fashi on. Studi es
attempti ng to quanti fy the magni tude of thi s effect have l ed to confl i cti ng resul ts, because the
ti me factor i s al so important. The ol der hal ogenated agents halothane, enflurane, and i sofl urane
may take 2 hours or more to equi l ibrate with muscle, so i n practi ce the potenti ating effect of
these vapors might not be i mmedi atel y apparent. At simi lar MAC, enflurane appears to potenti ate
nondepol ari zi ng bl ockade more than does isofl urane, which in turn potentiates to a greater extent
than hal othane. The newer agents sevofl urane and desfl urane equi l ibrate more rapi dl y wi th
muscle, but the effect may be measurabl e onl y after 30 minutes or more. For exampl e, the
duration of action of a bol us dose of mi vacuri um gi ven at i nducti on of anesthesi a is not altered by
the presence of sevoflurane (1 MAC). However, the infusi on rate requi red to mai ntai n block
decreases by 75% over the next 1.5 hours, compared wi th no change under propofol
anesthesia.
100
The degree of potenti ation increases wi th the concentrati on of sevoflurane.
70

Recovery rate is l onger in the presence of sevofl urane, even i f the i nfusi on rate of mi vacuri um was
less.
70
There is evidence that desflurane mi ght have a greater potentiating effect on the
neuromuscul ar juncti on than sevofl urane.
101

The mechanism of action of potentiation by hal ogenated agents is uncertai n, but it appears that
they produce thei r effects at the neuromuscular juncti on. Isofl urane and sevofl urane i nhibi t
current through the ni coti nic receptor at the neuromuscul ar juncti on, and thi s i nhi biti on i s dose
dependent.
102

Intravenous Anesthetics
Although some sl i ght potenti ati on of neuromuscul ar bl ockade has been demonstrated with high
doses of most i v i nducti on agents in ani mal s, cl i ni cal doses of drugs such as midazolam,
thi opental , propofol, fentanyl , and ketamine have l i ttl e or no neuromuscul ar effect i n humans.
Local Anesthetics
Li docai ne, procai ne, and other l ocal anestheti c agents produce neuromuscul ar bl ockade i n their
own right as wel l as potentiating the effects of depol ari zi ng and nondepolari zi ng neuromuscul ar
bl ocking drugs. However, these data were obtai ned in vi tro, wi th concentrations of l ocal
P.437
anesthetics rarely obtained systemi cal l y i n practi ce.
Interactions between Nondepolarizing Blocking Drugs
Combinati ons of two nondepol ari zi ng neuromuscul ar bl ocki ng drugs are ei ther addi ti ve or
synergi sti c, dependi ng on whi ch two drugs are i nvol ved. Addi ti on occurs when the total effect
equal s that of equi potent doses of each drug. For i nstance, pancuroni um and vecuroni um have an
addi ti ve i nteracti on.
103
An ED
95
of either pancuroni um (0.07 mg/kg) or vecuroni um (0.05 mg/kg)
yiel ds 95% bl ockade. Hal f the ED
95
of pancuronium (0.035 mg/kg) admi ni stered wi th hal f the ED
95

of vecuroni um (0.025 mg/kg) wi l l al so produce 95% block. However, some combi nations are
synergi sti c, that is thei r combi ned effect i s greater than i f an equi potent dose of either one of the
consti tuents i s given al one. For example, ci satracurium (ED
95
= 0.05 mg/kg) and rocuronium (ED
95

= 0.3 mg/kg) wil l produce a greater bl ockade than equi potent amounts of each drug gi ven al one.
To get 95% bl ock, not one-hal f but approximatel y one-fourth the ED
95
of each drug needs to be
gi ven together, that i s cisatracuri um, 0.0125 mg/kg wi th rocuroni um, 0.075 mg/kg.
104
General ly,
combi nations of chemicall y si mi l ar drugsfor exampl e, pancuroni umvecuroni um, d-tubocurari ne
metocurine, and atracuri ummi vacuri umhave addi tive effects. Combinati ons of dissimi lar agents
tend to show potentiati on, but the rul e i s not al ways fol lowed. For example, mi vacuri um and
ci satracurium show synergism,
104
whi l e vecuroni um and atracurium show very l ittle, if any. The
first such synergi sm was demonstrated for pancuroni ummetocurine combinati ons, and the
mi xture has less cardiovascular effects than either drug alone for the same neuromuscul ar bl ock.
64

The use of combi nati ons may be recommended to reduce cost, and this mi ght be advocated for
ci satracuriumrocuroni um mixtures, whi ch show synergism. Another reason to use mixtures of
drugs i s to take advantage of the properti es of two drugs. For exampl e, synergism occurs between
mi vacuri um and rocuroni um, and the mi xture retai ns the fast onset of rocuroni um, whi l e havi ng
the short durati on of acti on of mi vacurium.
105

The mechanism by which two drugs produce a greater effect than either one al one is unknown,
except i n rare cases. For exampl e, synergi sm i s expected between mi vacuri um and pancuroni um,
because of the i nhibi tion of plasma chol i nesterase that pancuronium produces, thus accentuating
the effect of mi vacuri um. However, such a si mpl e mechanism i s absent i n most cases.
Admi ni strati on of a combi nation of rel axants does not affect the degree of protei n bi ndi ng of
ei ther drug. Surpri si ngl y, when drug mi xtures are appl i ed to receptors i n vi tro, no potenti ati on i s
observed.
106
Perhaps the i nteracti on occurs via presynapti c receptors or some other, unknown,
mechanism.
Interactions of a di fferent nature occur when admi ni strati on of a nondepolari zi ng agent is fol lowed
by i njection of another nondepolarizing agent. Usuall y, the durati on of acti on of the second agent
is that of the first drug given. For example, if mi vacuri um, a short-acti ng agent, is gi ven after
mi vacuri um, i t has a duration of action of 12 minutes. However, i f the same dose of mi vacurium,
0.05 mg/kg, i s given after rocuroni um, i ts duration of action is prol onged to 42 minutes.
107
On the
contrary, i f mi vacuri um i s the fi rst drug, rocuroni um has a short durati on of acti on. Thus,
swi tchi ng from a l ong- or i ntermedi ate-duration agent to a shorter duration drug to obtai n
paral ysi s of short durati on at the end of a case wi l l not provi de paralysi s of short durati on. The
reason why the characteristics of the fi rst agent given are determinant i s that the si ze of the
l oadi ng dose i s greater than that of the maintenance dose, so that even when the second dose i s
gi ven, the majori ty of receptors is sti l l occupi ed by the fi rst drug.
NondepolarizingDepolarizing Interactions
Depol ari zi ng and nondepol ari zi ng rel axants are mutual l y antagoni sti c. When d-tubocurari ne or
other nondepolari zi ng agents are given before succi nyl choli ne to prevent fasci culations and muscl e
pai n, the succi nylchol ine i s less potent and has a shorter durati on of acti on.
24
The exception is
with pancuronium, because i t i nhi bits pl asma chol inesterase. Mixtures of succi nylchol ine wi th
mi vacuri um or atracuri um demonstrate antagoni sm.
108
However, nondepolari zing drugs are
somewhat more effecti ve when admini stered after the effect of succi nylchol ine has worn off,
compared with no prior succi nyl chol ine. Final l y, the response to a small dose of succi nylchol ine at
the end of an anestheti c in which a nondepol ari zi ng agent has been used i s di fficult to predict. It
may ei ther antagonize or

potenti ate the bl ockade, dependi ng on the degree of nondepol ari zi ng bl ock. Antagoni sm i s more
li kel y i f bl ockade i s deep and potenti ati on i f bl ockade i s shall ow. If an anti choli nesterase agent
has been given, then the effect of the succi nyl chol i ne i s potenti ated because of inhi bi ti on of
pl asma chol i nesterase.
Antibiotics
Neomyci n and streptomyci n are the most potent of the aminogl ycosi des i n depressi ng
neuromuscul ar function.
109
The pol ymi xi ns al so depress neuromuscul ar transmi ssi on.
109
These
anti bi otics are not used frequentl y any more. Other aminogl ycosi des (e.g., gentami ci n, netil mi ci n,
tobramyci n) al so potenti ate nondepol ari zi ng neuromuscul ar bl ockade. They prol ong the acti on of
steroidal neuromuscular agents, but thei r effect on benzyli soquinol i ne compounds i s l ess
apparent.
110
The l i ncosami nes cli ndamyci n and l i ncomycin have prejunctional and postjuncti onal
effects, but prolongati on of bl ockade by cl i ndamyci n is unl i kely to occur cl i ni cal ly unl ess l arge
doses are used.
111
The penici ll i ns, cephalosporins, tetracycl ines, and erythromyci n are devoid of
neuromuscul ar effects at cl inicall y rel evant doses.
111
Metroni dazol e does not appear to have
cl i ni cal ly significant effects at the neuromuscular juncti on.
Anticonvulsants
Acute admi nistrati on of phenytoin produces augmentation of neuromuscul ar bl ock.
112
Resi stance to
pancuroni um, metocuri ne, vecuroni um, and rocuroni um, but not to atracuri um or mi vacuri um, has
been demonstrated i n pati ents receiving chronic anti convul sant therapy with carbamazepi ne or
phenytoin.
113, 114
A least part of the phenomenon has a pharmacoki netic origi n. In pati ents wi th
chroni c carbamazepi ne therapy, the cl earance of vecuroni um was found to be increased and its
termi nal half-li fe decreased.
114

Cardiovascular Drugs
Beta-bl ocking drugs and calci um channel antagoni sts have been found to have neuromuscul ar
effects i n vitro, but in practice, the duration of action of neuromuscul ar bl ocking agents is not
al tered i n patients taking these drugs chroni cal l y.
115
Ephedri ne gi ven at i nducti on of anesthesi a
has been found to accel erate onset of acti on of rocuroni um whi l e esmol ol prolongs onset ti me.
116

The mechani sm for thi s effect i s probabl y by al teration of drug deli very to the site of acti on by
changes i n cardiac output. The accel eration of onset by ephedri ne has not been found i n al l
studi es.
Miscellaneous
Metocl oprami de i nhi bi ts pl asma chol i nesterase and thus prol ongs the action of succi nylchol ine and
mi vacuri um. Inconsistent interacti ons have been descri bed for di ureti cs, di goxi n, and
corti costeroi ds, probabl y because these drugs induce chronic fluid and electrolyte shifts, the
magni tude of whi ch depends on the condi ti on bei ng treated. Magnesi um at doses used for
anti arrhythmic treatment or preeclampsi a has profound potentiation effects on depol ari zi ng and
nondepol ari zi ng bl ockade.
117

ALTERED RESPONSES TO NEUROMUSCULAR BLOCKING AGENTS
I nt ensi ve Car e Uni t
Neuromuscul ar bl ocking agents are useful i n the ICU to facil i tate mechani cal venti l ati on. It is
essential to provide sedati on to pati ents who receive paralyzi ng agents, to prevent di scomfort
associated wi th the i nabi li ty to move. Enthusiasm for the l i beral use of neuromuscul ar blocking
agents i n the ICU has waned consi derabl y over the past decade or so, because of several reports
of criti cal ly i ll patients who demonstrated resi dual weakness for unexpectedl y l ong peri ods after
di sconti nuati on of a neuromuscul ar blocking agent. In some, recovery took several months.
P.438
Pancuroni um and vecuroni um have been used most frequentl y, but recent descripti ons of si mil ar
syndromes after atracurium and cisatracuri um
118
suggest that the frequency of reports of
weakness refl ects the popul ari ty of the drugs rather than a particular associ ati on wi th steroi d-
based compounds. El ectromyographi c (EMG) studi es have shown vari able l esions from myopathy to
axonal degenerati on of motor and sensory fi bers. The pi cture i s compli cated by the syndrome of
criti cal i ll ness neuropathy, whi ch occurs i n patients with sepsi s and multi organ fai lure, even i n
individual s not gi ven neuromuscul ar bl ocki ng agents. Admi ni strati on of corticosteroids i s also
consi dered a ri sk factor.
119
Symptoms i ncl ude fai l ure to wean from mechani cal venti lation, li mb
weakness, and i mpaired deep tendon reflexes, but sensory functi on i s usual ly not affected. There
are no control l ed cli ni cal studi es to al l ow the several i ni ti ati ng factors to be i denti fi ed and
matched with particul ar syndromes. In the absence of more defi ni tive studi es, i t is recommended
to admi ni ster neuromuscul ar bl ocking agents onl y to pati ents who cannot be managed otherwi se,
to l imit the duration of admini stration to a few days or l ess, and to use onl y the dose that is
necessary.
120

Studies i n ICU pati ents in whom the admi nistrati on of relaxant was adjusted accordi ng to stri ct
neuromuscul ar monitori ng criteri a have shown consi derable vari ati on i n the requi rement for
neuromuscul ar bl ocki ng agent to maintai n the same effect among patients and a wi de wi thi n-
patient pharmacoki netic variabi li ty.
121, 122
Vecuroni um and rocuroni um have been associ ated with
prolonged recovery ti mes. For exampl e, a mean of 3 hours was found between the end of
rocuroni um i nfusion and a train-of-four rati o of 0.7.
122
With ci satracuri um, thi s i nterval was
shorter (approximatel y 1 hour) and l ess vari abl e.
121
Drug requirement is variable from patient to
patient, is usuall y greater than i n the operati ng room, and tends to increase with ti me. These
reports suggest the need for more careful moni tori ng of neuromuscul ar bl ock i n ICU pati ents,
al though the opti mal method and l evel of block to be achieved are uncertai n. It i s suggested to
ti trate neuromuscul ar blocki ng agents to the mi ni mum i nfusion rate that wil l opti mi ze
oxygenati on.
Myast heni a Gr avi s
Myastheni a gravi s i s an autoi mmune disease i n which ci rculating anti bodi es produce a functional
reduction in the number of acetyl choli ne receptors.
10, 16
The l esion i s postsynaptic: the number of
acetylchol ine quanta i s normal and thei r content i s ei ther normal or increased.
Diagnosis and Management
The hal lmark of myastheni a gravi s is fatigue. Presentati on i s extremel y vari ed, but typi cal l y,
ocul ar symptoms, such as di pl opi a and ptosi s, occur fi rst. Bul bar i nvol vement i s usual l y seen next.
Patients may go on to have extremi ty weakness and respiratory diffi culti es.
10
The characteri sti c
EMG fi ndi ng in myastheni a gravi s is a vol tage decrement to repeated sti mulation at 2 to 5 Hz. Thi s
findi ng is al so characteristic of nondepol ari zi ng blockade i n nonmyasthenic i ndi vi dual s.
Edrophoni um, 2 to 8 mg, produces bri ef recovery from myasthenia gravis and can be used as a
di agnosti c test. Final l y, up to 80% of patients have an i ncreased ti ter of the acetylchol i ne receptor
anti body.
10

Treatment is l argel y symptomatic. Anti choli nesterase agents such as pyridosti gmi ne are used to
increase neurotransmi ssi on

at the neuromuscular juncti on. Corticosteroi ds and i mmunotherapy, wi th azathiopri ne, mi ght
produce l ong-term improvement. Pl asmapharesi s mi ght be effective by el i mi nati ng the circul ati ng
anti body. Finall y, many myastheni cs have an associ ated thymoma, and surgi cal removal of the
thymus may be indicated.
10

Response to Neuromuscular Blocking Agents
Patients with myastheni a gravi s are usual ly resi stant to succi nylchol ine, wi th l arger than usual
doses requi red to produce compl ete bl ockade. Thi s effect mi ght be offset by the i nhi bi ti on of
pl asma chol i nesterase activity provi ded by pyri dostigmine. Sensi ti vi ty to nondepolari zi ng
P.439
neuromuscul ar bl ocki ng drugs is i ncreased to a vari abl e extent, dependi ng on the severi ty of the
di sease. The ED
95
of vecuronium was found to be decreased by more than half in myasthenic
patients, and the response of the orbi culari s ocul i i s depressed even more than that of the
adductor pol l i ci s, refl ecti ng some degree of ocular involvement.
123

Management of Anesthesia
Traditi onal l y, neuromuscular bl ocki ng drugs have been avoided in the pati ent wi th myasthenia
gravi s by the use of inhal ational vapors wi th or wi thout local anesthesi a. More recentl y, there
have been several reports of the successful use of smal l , titrated doses of atracuri um,
mi vacuri um, vecuroni um, or rocuroni um, admini stered under careful neuromuscul ar moni tori ng.
Mi vacurium mi ght have a prol onged durati on i n myastheni c pati ents, especi al l y those who have
been treated with an antichol inesterase agent preoperati vel y, as pl asma chol i nesterase i s i nhi bi ted
by pyri dosti gmi ne. In addi ti on, the effect of reversal drugs mi ght be l ess than expected because
myastheni c patients al ready receive drugs that produce chol i nesterase i nhibi tion. Thus, it i s
preferabl e to conti nue mechani cal venti l ati on until spontaneous recovery i s mani fest.
Two problems remai n after thymectomy: postoperative anti chol inesterase therapy and predi cti ng
the need for mechani cal support of venti lation. In most patients, the dose of anti chol i nesterases is
reduced for 1 to 2 days after surgery. The need for mechani cal venti l ati on of the l ungs usual ly
correlates with preoperative l ung function tests.
Myot oni a
Myotoni a i s characterized by an abnormal delay in muscl e rel axati on after contraction. Several
forms have been descri bed: myotoni c dystrophy (dystrophia myotoni ca, myotoni a atrophica,
Stei nert' s di sease), myotoni a congenita (Thomsen' s di sease), hyperkal emi c peri odi c paral ysi s, and
paramyotoni a congenita.
Diagnosis
Repeated nerve sti mulation l eads to a gradual but persi stent increase i n muscl e tensi on. The EMG
is pathognomonic; myotoni c after-di scharges are seen i n peri pheral muscl e, consisting of rapi d
bursts of potenti al produced by tappi ng the muscl e or moving the needle. They produce typical
di ve-bomber sounds on the l oudspeaker.
The characteristic response to succi nylchol ine i s a sustai ned, dose-rel ated contracture that may
make venti l ati on diffi cult for several mi nutes. Muscl e membrane fragil i ty may be responsi bl e for
the exaggerated hyperkalemia that i s produced after succinyl chol i ne.
38
Most case reports suggest
that the response to nondepolari zi ng drugs is normal . However, myotoni c responses have been
observed after reversal with neostigmi ne.
Anesthesia
Succi nylchol i ne i s best avoided. Short- or i ntermedi ate-duration nondepolari zi ng agents may be
used in usual doses with careful neuromuscul ar moni toring. Reversal agents are best avoi ded.
Muscul ar Dyst r ophy
The muscular dystrophi es are a group of many di seases, wi th vari abi l i ty in presentati on and
typical age at onset of symptoms. The most common of these i s the Duchenne-type muscul ar
dystrophy (DMD), an X-li nked heredi tary di sease that usual ly becomes apparent i n chil dhood.
Other types of muscul ar dystrophy i ncl ude Becker, l i mb-gi rdl e, fasci ohumeral , Emery-Drei fuss,
nemal ine rod, and ocul opharyngeal dystrophy. There have been several reports of cardiac arrest
after admini stration of succi nylchol ine i n chi l dren, often associ ated wi th hyperkal emi a.
Resuscitati on was found to be difficult, and several of these cases were fatal .
38
The most l i kel y
explanation for these adverse events i s previ ousl y undi agnosed, l atent, muscul ar dystrophy. In
1993, the number of such reports encouraged Burroughs Wel l come, the manufacturer of Anecti ne
(succinyl chol i ne), to state that succi nyl choli ne [i s] contrai ndi cated i n chi l dren and adol escents
except when used for emergency tracheal i ntubation. After further di scussi on the
recommendation was modifi ed to a warni ng.
Most case reports descri be a normal response to nondepol arizing agents, such as vecuroni um,
atracurium, and mi vacuri um, al though there have been sporadi c instances of increased sensi ti vi ty.
There are li ttl e data on the response to antichol i nesterases. There is considerabl e controversy
over whether DMD pati ents are suscepti bl e to mal i gnant hyperthermi a (MH).
Anesthesia
Succi nylchol i ne shoul d be avoided in pati ents wi th muscular dystrophy, especi al l y i f onset of
symptoms occurred i n chi l dhood or adol escence. The possi bi li ty of l atent or unrecognized DMD i n
young males (less than 10 years ol d) may be a reason to avoi d succinyl choli ne in thi s pati ent
popul ati on. Careful ti trati on of short- or i ntermediate-duration nondepolari zi ng agents shoul d be
done. Reversal agents do not appear to be contrai ndi cated.
Upper Mot or Neur on Lesi ons
Patients with hemi pl egia or quadri plegi a as a result of central nervous system lesi ons show an
abnormal response to both depol ari zi ng and nondepolari zi ng agents. Hyperkal emi a and cardi ac
arrest have been descri bed after succi nyl chol i ne, probabl y as a resul t of extrajuncti onal receptor
spread. Hyperkalemia i s typicall y seen if the drug i s gi ven between from 1 week to 6 months after
the l esi on, but may be seen before and after that ti me peri od.
38
There is resi stance to
nondepol ari zi ng neuromuscul ar bl ocking drugs below the level of the lesi on. In hemi plegi c
patients, moni tori ng of the affected si de shows that the block i s less intense and recovery i s more
rapi d than on the unaffected si de. However, the apparentl y normal si de al so demonstrates some
resistance to nondepolarizing drugs.

Simil ar findi ngs have been reported after a stroke, wi th a greater resi stance on the affected side.
Bur ns
As a resul t of the prol iferati on of extrajunctional receptors, succi nylchol ine produces severe
hyperkal emi a i n pati ents with burns, and thi s may l ead to cardi ac arrest. The magni tude of the
probl em depends on the extent of the i njury. It may appear as early as 24 to 48 hours after the
burn i njury and usual l y ends with heali ng.
38
Resi stance to the effects of nondepol ari zi ng
neuromuscul ar bl ocki ng agents i s mani fest, even in muscl es that are apparentl y not affected by
the burn.
51, 52
Mivacuri um requirements may be decreased i n burn pati ents, because of the lower
pl asma chol i nesterase acti vi ty.
124

Mi scel l aneous
Denervated muscl e demonstrates potassi um release after succi nylchol ine and resi stance to
nondepol ari zi ng rel axants. Contractures i n response to succinyl chol i ne have al so been observed i n
amyotrophic l ateral scl erosi s and mul tipl e scl erosis. Succi nylchol ine i s usual ly avoi ded i n several
neurol ogic di seases, incl uding Fri edri ch' s ataxi a, pol yneuri tis, and Parki nson' s disease, because of
isol ated reports of hyperkalemia.
MONITORING NEUROMUSCULAR BLOCKADE
Why Moni t or ?
Deep level s of paralysi s are usually desi red duri ng anesthesi a to faci l itate tracheal intubati on and
to obtain an i mmobil e surgical fi el d. However, compl ete return of respiratory functi on must be
P.440
attai ned before the trachea i s extubated. Admi ni strati on of neuromuscular blocki ng drug must be
i ndi vi dual i zed because blockade occurs over a narrow range of receptor occupancy,
18
and because
there i s consi derable interi ndi vi dual vari abi l ity in response. Thus, i t is i mportant for the cl i ni cian
to assess the effect of neuromuscul ar bl ocki ng drugs wi thout the confoundi ng infl uence of vol ati l e
agents, i ntravenous anesthetics, and opi oi ds. To test the functi on of the neuromuscul ar juncti on, a
peri pheral nerve i s sti mulated electri cal ly, and the response of the muscl e is assessed.
St i mul at or Char act er i st i cs
The response of the nerve to el ectri cal sti mul ati on depends on three factors: the current appl i ed,
the durati on of the current, and the posi ti on of the el ectrodes. Sti mulators should del i ver a
maxi mum current i n the range of 60 to 80 mA. Most sti mul ators avai l abl e for cl i ni cal use are
desi gned to provide constant current, i rrespecti ve of impedance changes because of drying of the
el ectrode gel , cool i ng, decreased sweat gl and functi on, and so forth. However, thi s constant
current feature does not hold for hi gh i mpedances (>5 k). Thus, el ectrodes shoul d be fi rml y
appl ied to the ski n. A current di splay moni tor on the stimul ator is an asset, because accidental
di sconnecti on can be identi fi ed easi l y by a current approachi ng 0 mA. The duration of the current
pul se should be long enough for all axons i n the nerve to depol ari ze but short enough to avoid the
possi bi li ty of exceedi ng the refractory period of the nerve. In practice, pulse durati ons of 0.1 to
0.2 msec are acceptabl e. At least one electrode shoul d be on the ski n overl yi ng the nerve to be
stimul ated. If the negati ve el ectrode i s used for thi s purpose, the threshol d to supramaxi mal
stimul ati on i s l ess than for the posi tive electrode.
13
However, the difference is not large in
practi ce. The positi on of the other el ectrode i s not cri ti cal , but i t shoul d not be pl aced i n the
vici ni ty of other nerves. There is no need to use needle electrodes. Si lversi l ver chlori de surface
el ectrodes, used to moni tor the electrocardi ogram, are adequate for peri pheral nerve sti mul ati on,
without the ri sk of bl eeding, i nfecti on, and burns. In practi ce, appl yi ng these el ectrodes al ong the
course of a nerve gives the best results (Fi g. 16-12).
FIGURE 16-12. El ectrode pl acement to obtai n contracti on of the adductor poll i ci s muscl e.
The traditi onal method i s to sti ck the el ectrodes over the course of the ulnar nerve at the
wri st, wi th the negative electrode distal (ri ght). An al ternate method is to posi ti on the
el ectrodes over the adductor pol l i ci s (left), the negative electrode on the palm of the hand,
the posi ti ve i n the same locati on, but on the dorsum of the hand. The devi ce fi xed to the
thumb is an accel erometer.
Moni t or i ng Modal i t i es
Different stimul ati on modali ties were i ntroduced i nto cl i ni cal practi ce to take advantage of the
characteri sti c features of nondepol arizing neuromuscul ar bl ockade: fade and posttetani c
faci li tati on wi th high-frequency sti mulation. Thus, the foll owing di scussi on refers mostl y to
nondepol ari zi ng block.
Single Twitch
The simplest way to sti mulate a nerve i s to apply a si ngl e sti mulus, at i nterval s of >10 seconds.
The ampl itude of

response i s compared wi th a control, prebl ockade twi tch hei ght. The si ngl e-twi tch modali ty i s
useful to construct dose-response curves and to evaluate onset ti me. However, because a control
val ue is requi red, the cl i ni cal useful ness of this mode of stimul ati on i s li mited.
Tetanus
When stimul ati on i s appl i ed at a frequency of 30 Hz, the mechani cal response of the muscle i s
fusi on of i ndi vi dual twitch responses. In the absence of neuromuscul ar bl ocki ng drugs, no fade i s
present and the response is sustai ned. Duri ng nondepol ari zi ng bl ockade, the mechani cal response
appears as a peak, fol lowed by a fade (see Fi g. 16-9). The sensi tivity of tetani c stimul ati on i n the
detecti on of resi dual neuromuscular blockade is greater than that of si ngl e twi tch, that is, tetani c
fade mi ght be present whi l e twi tch hei ght i s normal . Most nerve sti mulators provi de a 5-second
trai n at a frequency of 50 Hz. Thi s frequency was adopted because at >100 Hz, some fade may be
seen even i n the absence of neuromuscul ar bl ocki ng drugs. However, more fade is seen with 100-
Hz than 50-Hz frequenci es, and 100-Hz, 5-second trains are most useful i n the detection of
resi dual bl ock.
46
With tetani c stimul ati on, no control prerelaxant response is requi red, as the
degree of muscl e paralysi s can be assessed by the degree of fade fol l owi ng tetani c stimul ati on.
However, the mai n di sadvantage of thi s mode of sti mulati on i s posttetani c faci l itati on (see Fi g.
16-9), the extent of which depends on the frequency and durati on of the tetani c sti mul ati on. For a
50-Hz tetanus appl i ed for 5 seconds, the durati on of thi s i nterval appears to be at l east 1 to 2
mi nutes.
125
If single-twi tch sti mul ati on i s performed during that ti me, the response i s spuriousl y
exaggerated.
Train-of-Four
Wi th 2-Hz stimul ati on, the mechani cal or el ectri cal response decreases li ttl e after the fourth
stimul us, and the degree of fade i s si mi l ar to that found at 50 Hz.
45
Thus, appl yi ng train-of-four
stimul ati on at 2 Hz provi des more sensi ti vi ty than si ngl e twi tch and approxi matel y the same
sensi ti vi ty as tetani c sti mulati on at 50 Hz. In addi tion, this relatively l ow frequency al lows the
response to be evaluated manual l y or vi sual l y. Moreover, the presence of a smal l number of
impul ses (4) eli mi nates the probl em of posttetani c faci l i tati on. Train-of-four sti mul ati on can be
repeated every 12 to 15 seconds. There i s a fai rly close rel ati onship between single-twi tch
depressi on and trai n-of-four response, and no control i s required for the latter.
126
Duri ng
recovery, the second twi tch reappears at 80 to 90% single-twi tch bl ock, the thi rd at 70 to 80%,
and when bl ockade i s 65 to 75%, al l four twi tches become visi ble.
127
Then, the trai n-of-four rati o,
the hei ght of the fourth twitch to that of the fi rst twitch, is l i nearl y related to fi rst twi tch hei ght
when blockade is <70%. When si ngl e-twi tch hei ght has recovered to 100%, the train-of-four rati o
is ~70%.
Posttetanic Count
During profound neuromuscular blockade, there i s no response to si ngle-twi tch, tetani c, or trai n-
of-four sti mul ati on. To esti mate the time required before the return of a response, one may use a
techni que that depends on the pri ncipl e of posttetani c faci l itati on. A 50-Hz tetanus i s appl i ed for 5
seconds, fol l owed by a 3-second pause and by sti mulati on at 1 Hz. The train-of-four and tetani c
P.441
responses are undetectable, but faci l itati on produces a certai n number of visi ble posttetanic
twi tches (Fi g. 16-13). The number of vi sibl e twi tches correlates i nversely wi th the ti me required
for a return of si ngle-twi tch or trai n-of-four responses.
128
For i ntermedi ate-duration drugs, the
ti me from a posttetanic count of 1 to reappareance of twi tch is 10 to 20 mi nutes.
Double-Burst Stimulation
Train-of-four fade may be di ffi cul t to eval uate by vi sual or tacti l e means duri ng recovery from
neuromuscul ar bl ockade. Irrespective of experi ence, i t i s di fficul t for anesthesi ol ogi sts to detect
trai n-of-four fade when actual train-of-four rati o i s 0.4 or greater, meaning that residual paralysi s
can go undetected.
129
Thi s shortcomi ng can be overcome, to a certai n extent, by appl yi ng two
short tetanic sti mulations (three i mpul ses at 50 Hz, separated by 750 msec), and by eval uating
the rati o of the second to the first response. The doubl e-burst sti mul ati on ratio correl ates closel y
with the train-of-four rati o, but i s easi er to detect manual l y.
129
At least 12 to 15 seconds must
el apse between two consecuti ve double-burst sti mul ati ons.
Recor di ng t he Response
Visual and Tactile Evaluation
When el ectrical sti mul ati on i s appli ed to a nerve, the easi est and least expensi ve way to
assess the response i s to observe or feel the response of the muscl e. This method is easi l y
adaptabl e to any superfici al muscl e. However, seri ous errors in assessment can be made. In the
case of evaluati ng the response of the adductor pol li cis to ul nar nerve sti mul ati on, the train-of-
four count can be made rel i ably duri ng a surgi cal procedure,
127
but the quanti tati ve assessment of
trai n-of-four ratio i s diffi cult to make duri ng recovery. Several investi gati ons suggest that train-
of-four rati os as l ow as 0.3
129
can remai n undetected. The detection rate for tetani c fade (50 Hz)
is no better.
130
With double-burst sti mul ati on, fade can be detected rel iabl y up to trai n-of-four
rati os i n the range of 0.5 to 0.6.
129
With 100-Hz tetanic sti mul ati on, fade mi ght be detected at
trai n-of-four rati os of 0.8 to 1.0
46
and may be seen i n individuals wi th no neuromuscul ar bl ock.

Measurement of Force
A force transducer can overcome the shortcomi ngs of one' s senses. If appli ed correctly, the devi ce
FIGURE 16-13. Posttetanic count (PTC). During profound bl ockade, no response i s seen to
trai n-of-four (TOF) or tetanus. However, because there is posttetani c facil i tati on, some
twi tches (i n the case earl ier, 9) can be seen after tetanic stimul ati on. In the example above,
the PTC is 9.
provi des accurate and rel i abl e responses, displ ayed as ei ther a digi tal or an anal og signal on a
moni tor. Force measurement can be measured after single-twi tch, tetanus, train-of-four, double-
burst, or posttetanic sti mul ati on. However, the avail abil i ty of tetanus and doubl e-burst sti mul ati on
is superfl uous i f accurate recording of the train-of-four response can be made. Unfortunately,
transducers are expensi ve, bul ky, cumbersome, and can be appl i ed to only one muscl e, usual l y
the adductor pol l i ci s.

Electromyography
It i s possibl e to measure the el ectrical instead of the mechanical response of the muscl e. One
el ectrode should be posi ti oned over the neuromuscul ar junction, which is usual l y cl ose to the
mi dporti on of the muscle, and the other near the inserti on of the muscl e. A thi rd, neutral
el ectrode can be l ocated anywhere else. Theoreti cal l y, any superfici al muscl e can be used for EMG
recordings. In practice, such recordi ngs are l i mi ted to the hypothenar emi nence, the fi rst dorsal
interosseous, and the adductor pol l ici s muscl es, whi ch are suppl ied by the ulnar nerve. Most EMG
recording devi ces compute the area under the EMG curve duri ng a speci fi ed time wi ndow (usual l y
3 to 18 msec) after the sti mul us i s appl i ed.
131
Thi s integrated EMG response is considered a better
representati on of the overal l muscul ar acti vi ty than the measurement of peak response. There i s
usuall y good correl ati on between EMG and force of the adductor pol l i ci s i f the EMG si gnal i s taken
from the thenar emi nence. The si gnal obtai ned from the hypothenar emi nence is l arger and l ess
subject to movement arti facts, but i t can underesti mate the degree of paral ysis when compared
wi th the adductor pol l ici s.
132

Accelerometry
Accordi ng to Newton' s l aw, accel erati on i s proportional to force i f mass remai ns unchanged. The
device i s usual ly attached to the ti p of the thumb (see Fi g. 16-12) and a digi tal readout i s
obtai ned. The setup is sensi ti ve to i nadvertent di spl acement of the thumb and, in the absence of
neuromuscul ar bl ocki ng drugs, trai n-of-four rati os >100% can be obtained.
133
In spite of these
shortcomi ngs, accelerometers have become increasingl y popular because they are easy to use, are
less cumbersome, can be used on muscl es other than the adductor pol l i cis, and are relatively
inexpensive. The use of accelerometry i s hel pful in the diagnosis of resi dual paral ysis
134
and can
reduce the i nci dence of the condi ti on.
135

Displacement
A vari ety of devi ces have been proposed that i nclude a piezoel ectri c wafer that responds to motion
or di spl acement. They are desi gned for the adductor pol li cis. A thorough eval uation of these
devi ces has not been made, but data i ndicate that there are sl i ght, but cl i ni cal ly i nsigni ficant
di fferences between the resul ts such displ acement trasnducers and mechanomyography provide.
136

Phonomyography
A contracting muscl e emi ts low frequency sounds. Trai n-of-four response and fade can be heard
with a stethoscope placed over the adductor pol l i ci s muscl e. A quanti tative response can be
obtai ned wi th speci al mi crophones sensiti ve to frequencies (2 Hz) bel ow the threshol d of the
human ear. An excell ent correl ati on between phonomyography and force measurement has been
found at several muscl es, incl udi ng the adductor pol l i ci s and the corrugator superci l ii .
84
At the
time of writing, no commercial devices usi ng phonomyography were avai l abl e.
Choi ce of Muscl e
Muscl es do not respond in a uni form fashion to neuromuscular blocki ng drugs. After admi ni strati on
of a neuromuscul ar bl ocki ng agent, differences can be measured wi th respect to onset ti me,
maxi mum bl ockade, and durati on of acti on. It is not practi cal to moni tor the muscl es of
physi ol ogi cal importance, for exampl e, the abdomi nal muscl es duri ng surgery, or the respi ratory
and upper ai rway muscl es postoperati vely. A better approach i s to choose a moni toring site that
P.442
has a response si mi lar to the muscle of interest. For exampl e, moni toring the response of the
faci al nerve around the eye i s a good i ndi cator of i ntubating conditi ons, and the use of the
adductor pol l i ci s duri ng recovery reflects upper ai rway muscl e functi on. Another strategy is to
stick to one monitori ng si te, such as the adductor pol l ici s, and i nterpret the informati on provi ded
from knowl edge of the di fferent responses between muscl es (Fi g. 16-14).
Adductor Pollicis
The adductor pol l ici s is accessi bl e duri ng most surgi cal procedures. It i s suppl i ed by the ul nar
nerve, which becomes superfici al at the wrist where a negative electrode can be posi ti oned. The
positi ve el ectrode i s appl i ed a few centi meters proxi mal ly (see Fi g. 16-12). The force of
contracti on of the adductor poll i ci s can be measured easi ly, and i t has become a standard i n
research. After injecti on of a dose that produces l ess than 100% blockade, the ti me to maximal
bl ockade i s l onger than in central ly l ocated muscl es.
137, 138
The adductor poll i ci s i s rel ati vely
sensi ti ve to nondepolari zi ng neuromuscul ar bl ocking drugs, and duri ng recovery i t i s bl ocked more
than some respiratory muscl es such as the di aphragm,
137
laryngeal adductors,
138
and abdomi nal
muscles (see Fi g. 16-14).
139
There

is evi dence that recovery of the adductor pol l ici s and of upper airway muscles occurs more or l ess
si multaneously (see Fi g. 16-14).
140

The adductor pollicis can al so be sti mul ated by applying electrodes directl y over i t. Thi s can be
accompl i shed by pl aci ng the two electrodes i n the space l yi ng between the base of the first and
second metacarpal s, on the palmar and dorsal aspects on the hand, respecti vel y (see Fi g. 16-12).
Such a stimul ati on avoi ds the confounding movement of hypothenar muscl es. Direct muscle
stimul ati on with this el ectrode posi tion does not normal l y occur, because neuromuscul ar blocking
agents abol i sh the response compl etel y.
141

Other Muscles of the Hand
FIGURE 16-14. Approxi mate ti me course of twitch height after rocuronium, 0.6 mg/kg, at
di fferent muscles. Di aphragm: di aphragm; l arynx: l aryngeal adductors (vocal cords); CS:
corrugator superci li i (eyebrow); abd: abdomi nal muscles; OO: orbi cularis ocul i (eyeli d); GH:
geniohyoi d (upper airway); AP: adductor pol l i ci s (thumb). The data are taken or inferred
from Pl aud et al ,
142
Dhonneur et al ,
166
Ki rov et al ,
139
and d' Honneur et al .
140

P.443
Ul nar nerve sti mulati on al so produces fl exi on and abducti on of the fi fth finger, whi ch usual l y
recovers before the adductor pol l i ci s, the discrepancy i n fi rst twitch or train-of-four rati o being of
the order of 15 to 20%.
132
Rel yi ng on the response of the fifth fi nger mi ght overestimate recovery
from blockade. Abducti on of the index fi nger al so resul ts from stimul ati on of the ul nar nerve
because of contraction of the fi rst dorsal i nterosseous, the sensi ti vi ty of whi ch i s comparabl e to
that of the adductor pol li cis. The hypothenar emi nence (near the fi fth fi nger) and the fi rst dorsal
interosseous are parti cul arl y well sui ted for EMG recordi ngs.
132
Sti mul ati on i n the hand (see Fi g
16-12) el i mi nates contracti on of the hypothenar muscles, but may evoke movement of the first
dorsal i nterosseous.
Muscles Surrounding the Eye
There seem to be major differences i n the response of muscl es innervated by the facial nerve and
located around the eye, and these di fferences have i ntroduced some confusi on i n the li terature.
The orbi cul aris ocul i essenti al l y covers the eyel i d, and i ts response to neuromuscul ar blocking
agents is si mi l ar to that of the adductor poll i ci s.
142
However, it i s customary to observe the
movement of the eyebrow, and recordi ngs at that site are si mi lar to that of the l aryngeal
adductors (see Fi g 16-14).
142
Onset of bl ockade i s more rapi d and recovery occurs sooner than at
the adductor pol li cis. Thus, faci al nerve sti mulation with inspection of the response of the eyebrow
(whi ch most l i kel y represents the effect of the corrugator supercil i i, not the orbi culari s oculi ) i s
i ndi cated to predi ct i ntubati ng condi ti ons and to moni tor profound blockade. The faci al nerve can
be sti mul ated 2 to 3 cm posteri or to the lateral border of the orbit. There i s no need to use
stimul ati ng currents greater than 20 to 30 mA.
Muscles of the Foot
The posteri or ti bial nerve can be stimul ated behind the i nternal mall eolus to produce flexion of the
bi g toe by contracti on of the flexor hal luci s. The response of this muscl e i s comparabl e to that of
the adductor pol l ici s. Sti mul ati on of the external peroneal nerve produces dorsi fl exi on, but the
sensi ti vi ty of the muscl es i nvol ved has not been measured.
Cl i ni cal Appl i cat i ons
Monitoring Onset
The qual ity of intubati ng condi tions depends chi efl y on the state of rel axati on of muscl es of the
jaw, pharynx, l arynx, and respi ratory system. Onset of acti on i s faster in all these muscl es than i n
the hand or foot because they are cl oser to the central ci rcul ati on and they recei ve a greater
bl ood fl ow. Among these central muscl es, the diaphragm and especi al l y the laryngeal adductors
are the most resistant to nondepol arizing agents. Data on l aryngeal muscl es are important not
onl y because easy passage of the tracheal tube can be performed i f vocal cords are relaxed, but
al so because al l other muscl es can be presumed to be bl ocked if the resi stant l aryngeal muscl es
are bl ocked. The rel ati onshi p between onset ti me i n laryngeal and hand muscl es depends on dose.
At relatively low doses (e.g., rocuronium, 0.3 to 0.4 mg/kg), onset time is sl ower at the adductor
pol li cis than at the laryngeal muscles. If the dose i s increased (e.g., rocuroni um, 0.6 to 1.0
mg/kg), onset i s faster at the adductor pol l ici s because these doses produce 100% bl ockade at the
adductor poll i ci s wi thout blocki ng l aryngeal muscl es completely (see Fi g. 16-14).
143
Onset ti me
decreases consi derably i n any muscl e i f the dose gi ven i s suffici ent to reach 100%. Fi nal l y, i f the
dose i s l arge enough to bl ock the laryngeal muscles compl etel y, onset ti me agai n becomes shorter
at the l arynx. It i s not surprisi ng that moni toring the adductor pol l ici s muscl e predi cts i ntubating
condi ti ons poorly. Facial nerve stimul ati on wi th visual observati on of the response over the
eyebrow gi ves better resul ts because the response of the corrugator superci li i is cl ose to that of
the vocal cords. Train-of-four fade takes l onger to devel op than si ngl e-twitch depressi on (see Fi g.
16-9), and during onset, trai n-of-four sti mul ati on does not have any advantages over si ngl e-
twi tch sti mulation at 0.1 Hz.
Monitoring Surgical Relaxation
Adequate surgi cal rel axati on i s usuall y obtained when fewer than two or three visi ble twitches are
observed at the adductor poll i ci s. However, thi s criteri on might prove i nadequate in certai n
ci rcumstances when profound rel axati on i s requi red owing to the discrepancy between the
adductor poll i ci s and other muscles. In this case, the posttetanic count can be used at the
adductor pol l i ci s,
128
provi ded that this type of sti mulation is not repeated more often than every 2
to 3 minutes. A sui tabl e al ternative i s sti mul ati on of the faci al nerve wi th observati on of the
response over the eyebrow, whi ch recovers at the same rate as such resi stant muscl es as the
di aphragm.
137, 142

Monitoring Recovery
Complete return of neuromuscular function should be achi eved at the concl usi on of surgery unl ess
mechani cal venti l ation is pl anned. Thus, moni tori ng is useful i n determini ng whether spontaneous
recovery has progressed to a degree that al lows reversal agents to be gi ven and to assess the
effect of these agents.
The effectiveness of anti choli nesterase agents depends di rectl y on the degree of recovery present
when they are administered. Preferabl y, reversal agents shoul d be gi ven onl y when four twitches
are vi si bl e,
144
whi ch corresponds to a fi rst-twi tch recovery of >25%. For thi s assessment, usi ng
the adductor pol li cis i s preferable. The presence of spontaneous respi ration is not a sign of
adequate neuromuscul ar recovery. The di aphragm recovers earl i er than the much more sensi tive
upper ai rway muscl es, such as the geni ohyoi d, which recovers, on average, at the same ti me as
the adductor pol l i ci s.
140
To prevent upper ai rway obstructi on after extubati on, i t i s preferable to
use the adductor pol l ici s to monitor recovery, i nstead of the more resi stant muscles of the
hypothenar emi nence or those around the eye.
Fi nal ly, the adequacy of recovery shoul d be assessed. Tradi tional ly, a train-of-four rati o of
0.7 was considered to be the threshol d below whi ch resi dual weakness of the respi ratory
muscles coul d be present. There i s abundant evi dence that si gni fi cant weakness may occur up to
trai n-of-four val ues of 0.9. Awake vol unteers gi ven mi vacurium fai l ed to perform the head-l i ft test
when the train-of-four rati o at the adductor poll i cis decreased bel ow 0.62, but needed a trai n-of-
four ratio of

at l east 0.86 to hol d a tongue depressor between thei r teeth (Fi g. 16-15).
145
Thi s suggests that
the head-li ft test does not guarantee full recovery, and that the upper ai rway muscl es used to
retai n a tongue depressor are very sensi ti ve to the resi dual effects of neuromuscul ar blocki ng
drugs. Furthermore, i mpai rment i n swal lowi ng and l aryngeal aspi ration of a pharyngeal fl ui d was
observed at trai n-of-four rati os as high as 0.9 in volunteers gi ven vecuroni um (see Fi g. 16-4).
146

P.444
Anestheti zed patients appear consi derabl y more sensiti ve to the venti latory effects of
neuromuscul ar bl ocki ng drugs than are awake pati ents. Whereas tidal volume and end-ti dal CO
2

are preserved in awake pati ents recei vi ng rel ati vel y hi gh doses of neuromuscular bl ocki ng
drugs,
147
anestheti zed adul ts have a decreased ti dal vol ume and i ncreased PCO
2
wi th doses of
pancuroni um as low as 0.5 mg.
148
In consci ous volunteers, admi ni strati on of smal l doses of
vecuroni um to maintai n trai n-of-four at l ess than 0.9 l eads to severe i mpai rment of the venti l atory
response to hypoxi a (Fi g. 16-16).
149
The response to hypercapnia is mai ntained, and this i ndi cates
that the response to hypoxi a is not a result of respi ratory muscl e weakness.
149

Taken together, the results of these investi gati ons i ndi cate that normal respi ratory and upper
ai rway functi on does not return to normal unl ess the train-of-four rati o at the adductor poll i cis i s
0.9 or more. However, it has become apparent that human senses fai l to detect ei ther a trai n-of-
four or 50-Hz tetanic fade when the trai n-of-four rati o i s as l ow as 0.3.
129, 130
With double-burst
stimul ati on, detecti on fai lures may occur at trai n-of-four ratios of 0.5 to 0.6.
129
Compared with
the train-of-four, the abi l i ty to detect fade i s not improved by usi ng tetani c sti mulation at 50 Hz
for 5 seconds. However, in one study fade coul d be detected vi sual l y at train-of-four rati os of 0.8
to 0.9 by using 100-Hz tetanic sti mulation.
46
It i s uncl ear, however, whether fade i nduced by
inhalational agents al one can be seen. Because of the presence of posttetani c faci li tati on, 50- or
100-Hz stimul i shoul d not be appl i ed more often than every 2 mi nutes. Because of the l imi tati ons
of one' s senses, it has been advocated that quanti tati ve assessment of the trai n-of-four rati o be
made routinely.
9
Mechanographi c and EMG equi pment gi ve rel i abl e val ues of train-of-four rati o,
but the use of thi s equi pment is li mited by si ze, cost, and conveni ence. Accel erometers are l ess
FIGURE 16-15. Correlati on between train-of-four responses at the adductor pol li ci s and
certai n cl inical tests of neuromuscul ar recovery. Vol unteers were gi ven mi vacuri um and were
asked to lift their head for 5 seconds (head lift), lift thei r l eg for 5 seconds (l eg l i ft), or hol d
a tongue depressor between their teeth agai nst force (tongue depressor). The mi nimum
trai n-of-four rati o (and SD) when each of these tests was passed i s indi cated. Data from
Kopman et al.
145

FIGURE 16-16. Response to hypoxi a i s i mpai red duri ng recovery from vecuronium bl ockade.
Normal response i s an i ncrease in minute volume (MV) or ti dal vol ume (TV) (control ). These
increases are decreased si gni fi cantl y when vecuronium produces a train-of-four rati o of 0.7
at the adductor pol l i ci s. They return to near normal val ues at a trai n-of-four rati o >0.9. Data
from Eri ksson et al .
149

bul ky and cheaper, but they can overesti mate the val ue of trai n-of-four rati o duri ng recovery.
133

It has been suggested that a train-of-four rati o of 1.0 obtai ned by accel erometry must be obtained
before neuromuscul ar functi on can be consi dered compl ete.
150
Monitori ng devices based on the
measurement of displ acement or sound may prove to have more rel i abl e trai n-of-four rati os than
accel erometry. In one study, a transmi ssi on module sensi ti ve to bendi ng and deformation was
found to yi eld trai n-of-four rati o values comparabl e to mechanomyography duri ng the recovery
peri od.
136

In response to the shortcomi ngs of vi sual or tactil e eval uati ons, another approach to recovery i s
to wai t unti l suffi cient spontaneous recovery is present and gi ve reversal agents systemati cal ly.
Kopman et al
151
suggested that neosti gmi ne be gi ven at a train-of-four count of 2 or greater i f the
neuromuscul ar bl ocki ng agent is ci satracuri um or rocuronim. Compl ete recovery took l onger than
expected, as some pati ents sti ll had trai n-of-four rati os less than 0.9 after 30 mi nutes. In any
event, cli ni ci ans must be aware of the li mi tati ons of the tests they are usi ng and complete thei r
eval uations with cl i ni cal tests.
Fact or s Af f ect i ng t he Moni t or i ng of Neur omuscul ar Bl ockade
Many drugs i nterfere wi th neuromuscular functi on and these are deal t wi th el sewhere. However,
certai n si tuati ons make the i nterpretation of data on neuromuscular functi on di ffi cul t. Central
hypothermia may slow the metabol ism of neuromuscul ar bl ocki ng agents and prol ong bl ockade. If
the extremi ty where moni tori ng is performed i s col d, the degree of bl ock wi l l be accentuated.
Thus, i f only the moni tored hand is cold, wi thout central hypothermi a, the degree of paral ysi s wi l l
appear to be i ncreased. Resi stance to nondepolari zi ng neuromuscul ar bl ocking drugs occurs wi th
nerve damage, i ncl udi ng peri pheral nerve trauma, cord transecti on, and stroke. In thi s case,
moni tori ng of the i nvol ved l i mb woul d tend to underesti mate the degree of muscl e paralysi s. The
level of paral ysis shoul d al so be adjusted for the type of pati ent, as well as the type of surgery.
For example, it i s not necessary to paral yze frail i ndi vi dual s or patients at the extremes of age to
the same extent as young muscul ar adults. The same appl ies to patients with debi l i tati ng muscul ar
di seases.
Neuromuscul ar moni tori ng by i tsel f does not guarantee adequate rel axation duri ng surgery and
compl ete recovery postoperati vel y. The surgi cal fi eld may be poor i n spi te of ful l paralysi s of the
hand, because of difference in response between muscl es.

Resi dual paral ysi s mi ght occur because of excess neuromuscular blocki ng agents given, earl y
administrati on of reversal , or an abnormal response of the patient. The effect of the
neuromuscul ar bl ocki ng drug i s the same whether or not monitori ng i s used. Neuromuscul ar
moni tori ng can hel p i n the diagnosis of i nadequate skeletal muscle relaxation during surgery or
insuffi cient recovery after surgery, but does not, i n i tsel f, treat these condi tions.
ANTAGONISM OF NEUROMUSCULAR BLOCK
In most ci rcumstances, al l efforts shoul d be made to ensure that the pati ent l eaves the operating
room wi th uni mpaired muscl e strength. Speci fi cal l y, respi ratory and upper ai rway muscl es must
functi on normal l y, so the pati ent can breathe, cough, swal l ow secreti ons, and keep hi s or her
ai rway patent. Two strategi es can be adopted to achi eve thi s goal . The first i s to ti trate
neuromuscul ar bl ocki ng agents carefull y, so that no resi dual effect i s mani fest at the end of
surgery. The second i s to accel erate recovery by gi vi ng a reversal drug. Thi s second opti on i s
probabl y safer, but both strategi es requi re careful assessment of bl ockade.
Assessment of Neur omuscul ar Bl ockade
Spontaneous breathi ng can resume even i f rel ati vel y deep degrees of paralysi s are sti l l present.
Spontaneous venti l ati on, adequate to prevent hypercapnia, can be mai ntained despite
consi derable measurable skel etal muscl e weakness if a patent ai rway is ensured. The abil i ty to
perform maneuvers such as vi tal capaci ty, maximum vol untary venti lation, and forced expi ratory
flow rate recovers at less intense level s of paral ysi s because it requi res a greater strength.
147

P.445
Such tests are, however, diffi cult to perform in everyday practi ce, parti cul arly when the patient i s
recoveri ng from general anesthesi a. Moreover, the weakest point i n the respi ratory system is the
upper ai rway. When given vecuroni um, swall owi ng was i mpaired and laryngeal aspi rati on occurred
when the TOF rati o was 0.9 or l ess.
146
These probl ems are di ffi cul t to di agnose when a tracheal
tube is i n place. Consequentl y, several i ndi rect i ndi ces, whi ch are easi er to measure, have been
correlated wi th the more speci fi c tests of lung and upper ai rway function.
Clinical Evaluation
Several crude tests have been suggested, incl uding head l i ft for 5 seconds, tongue protrusion, and
the abi l ity to l ift the legs off the bed to determi ne recovery of neuromuscul ar functi on. Pavl i n et
al
147
correl ated the maximum inspiratory pressure (MIP) wi th tests of skeletal muscle strength and
of ai rway musculature in consci ous volunteers recei vi ng d-tubocurari ne. As the dose was
increased, head l i ft and l eg rai sing were affected fi rst. Then, the abi l ity to swal l ow, touch teeth,
and mai ntai n a patent airway was i mpaired. Hand gri p strength was decreased markedl y by then.
Nevertheless, as long as the mandibl e was el evated by an observer, the PETCO
2
was normal even
when al l the tests were fai l ed. From these data, i t was concl uded that abi l ity to mai ntain head l ift
for 5 seconds usuall y indicates suffici ent strength to protect the ai rway and support ventil ati on.
147

However, Kopman et al have shown, i n vol unteers, that the most sensi ti ve test i s the abi l ity to
cl amp the jaws shut and prevent removal of a wooden spatula.
145
Thi s correl ated wi th a TOF ratio
measured at the adductor pollicis of >0.86, whereas head lift and l eg l i ft coul d be performed at
more i ntense l evels of paral ysi s (TOF approximately 0.6) (see Fi g. 16-15). All subjects compl ained
of vi sual symptoms until TOF >0.9. Pressure measurements i n the upper esophagus have been
shown to be decreased (see Fi g. 16-4) and laryngeal aspi rati on detected at a TOF rati o <0.9.
146, 152

Thus, i t appears that a normal head li ft or leg l i ft i s i nsuffi cient to guarantee normal upper ai rway
functi on. The abi l ity to resi st removal of an object (such as a tongue depressor or a tracheal tube)
from the mouth by closing the teeth probabl y correlates better with adequate upper airway
function.
Evoked Responses to Nerve Stimulation
The cli nical tests descri bed above are usuall y unobtai nabl e i n the pati ent recoveri ng from
anesthesia. Furthermore, i t i s preferabl e to assess the degree of recovery before emergence.
Evoked responses to nerve stimul ati on are then appropriate. The target i s a TOF >0.9, consi deri ng
that upper airway functi on does not recover completely until the trai n-of-four rati o at the adductor
pol li cis i s at least 0.9. Even at that level, some subjects show some si gns of weakness.
134

Wi th the introducti on of short- and i ntermediate-duration nondepolari zi ng agents i nto cli ni cal
practi ce, the use of reversal agents has been considered by some as opti onal . The deci sion to omi t
pharmacol ogical reversal of neuromuscular bl ockade must be made careful ly, because the
presence of resi dual paral ysi s may be missed. As menti oned earl i er, manual and tactil e evaluati on
of neuromuscul ar bl ockade by trai n-of-four or 50-Hz tetanic sti mulation may fai l to detect
fade.
129, 130
Doubl e-burst sti mul ati on is more sensiti ve, but becomes unrel i abl e at train-of-four
rati os i n the 0.6 to 0.9.
129
The most sensi ti ve test i s the abi li ty to maintai n sustai ned contracti on
to 100-Hz tetanus for 5 seconds. Fade is detected when TOF rati o i s as hi gh as 0.8 to 0.9.
46

Tetani c sti mulati on at 100 Hz is pai nful and must be performed onl y i n adequately anestheti zed
patients.
Because of the li mi tati ons of the vi sual and tacti l e esti mate of the train-of-four response duri ng
recovery, objecti ve measurement has been advocated.
9
Accel eromyographi c recordi ngs mi ght be
the most practical, because accel erometers are cheap and easy to use. However, i t must be
appreci ated that the TOF rati o obtained wi th accel erometry is greater than that measured with
mechanomyography and may exceed 1.0. An accelerographi c TOF ratio of 1.0 has been proposed
as the equival ent of a mechanomyographic TOF of 0.9.
150

Resi dual P ar al ysi s
Several studi es have demonstrated that residual neuromuscul ar bl ockade i s frequent i n
patients i n the recovery room after surgery. Viby-Mogensen et al found i n 72 adul t pati ents given
long-acti ng agents that the trai n-of-four rati o was 0.7 in 30 (42%) patients, and that 16 of the 68
patients (24%) who were awake were unabl e to sustain head l ift for 5 seconds.
8
In that study, the
patients recei ved appropri ate doses of neosti gmi ne. Si mi lar resul ts have been obtai ned in Sweden,
Austral i a, Canada, and the Uni ted States (see Tabl e 16-1).
153
The i nci dence of train-of-four ratio
0.7 is reduced from about 30% to l ess than 10% i f the i ntermedi ate agents atracurium or
vecuroni um are substi tuted for the l ong-acti ng drugs and i f reversal i s gi ven.
153
Recovery from
mivacurium is even more rapi d. However, the actual i nci dence of resi dual paral ysi s was certai nl y
underesti mated i n these studi es because of the criteri on used (trai n-of-four rati o of 0.7).
Recentl y, there has been a trend for a greater incidence of residual paral ysis, even wi th
intermedi ate-duration drugs. Thi s can be expl ained by two factors. The threshol d for residual
paral ysi s has been rai sed from a trai n-of-four rati o of 0.7 to 0.8 and then to 0.9.
134
However, the
most i mportant reason for hi gh incidence of residual paral ysis seems to be omission of reversal . In
one study, thi s i nci dence was 42% after vecuroni um, usi ng the 0.7 cri terion.
154

Clinical Importance
Resi dual paral ysi s in the recovery room has been shown to be associ ated wi th si gni fi cant
morbi dity. In 1997, Berg et al studi ed nearl y 700 general surgical pati ents who randomly received
pancuroni um, vecuroni um, or atracurium to produce surgi cal rel axati on.
155
In pati ents who had
recei ved pancuroni um, the i nci dence of postoperati ve parti al paralysi s, defi ned by a trai n-of-four
rati o <0.7, was fi ve ti mes that in pati ents receiving either of the two i ntermediate-acti ng drugs
(26 versus 5%). In additi on, the i nci dence of atel ectasi s demonstrated on chest radi ographs taken
2 days l ater was greater i n pati ents who had recei ved pancuroni um and who had not attai ned a
trai n-of-four rati o of 0.7 (16%) than in those who exceeded thi s threshold (4.8%).
155
Intense
resi dual bl ock has been demonstrated i n patients after cardi ac surgery, and choosi ng rocuronium
over pancuronium has been associ ated with fewer symptoms of weakness and a shorter ti me to
extubati on.
156

Rever sal Agent s
So far, the onl y compounds that have been wi del y used to reverse the effect of neuromuscul ar
bl ocking agents are the antichol inesterase drugs. The pharmacol ogi c princi pl e i nvol ved i s
inhi biti on of acetyl choli ne breakdown to increase i ts concentration of acetyl chol i ne at the
neuromuscul ar juncti on, thus ti l ti ng the competi ti on for receptors in favor of the neurotransmi tter.
Other drugs such as surami n and 34 aminopyri di ne are not as effecti ve, or more toxi c, or both.
At the ti me of wri ting, a chel ati ng agent, ORG25696, desi gned to ri d the organi sm of rocuroni um,
was i nvesti gated for its abi l ity to reverse neuromuscul ar bl ockade.
Anticholinesterases: Mechanism of Action
Neosti gmi ne, edrophoni um, and pyri dosti gmi ne inhi bi t acetyl chol i nesterase, but this may not be
the only mechanism by which blockade i s antagoni zed. Thi s i nhibi ti on i s present at al l choli nergi c
synapses i n the peri pheral nervous system. Thus, the anti chol i nesterases have potent
parasympathomi meti c acti vi ty, whi ch i s attenuated or abol i shed by the admini stration of an
anti muscari ni c agent, atropi ne or gl ycopyrrol ate. Neosti gmi ne, edrophoni um, and pyri dosti gmi ne
are quaternary ammoni um compounds, whi ch do not penetrate the bl ood-brai n barri er wel l . Thus,
al though these agents have the abi li ty to affect chol inergi c functi on i n the central nervous system,
the concentrations i n the brai n are usual ly too small for such an effect. Physosti gmi ne i s an
anti choli nesterase that can cross the blood-brain barrier easi ly. For thi s reason, it i s not used to
reverse neuromuscul ar bl ockade. Neosti gmi ne injected i ntrathecal l y i s a good analgesi c, but
produces nausea and vomi ti ng.
Neosti gmi ne and pyri dosti gmi ne are attached to the ani onic and esteratic si tes of the
acetylchol inesterase molecul e and produce l onger l asti ng inhi bi ti on than edrophoni um.
Neosti gmi ne and pyri dosti gmi ne are inactivated by the i nteracti on wi th the enzyme, whereas
P.446
edrophonium is unaffected.
153

Inhi biti on of acetyl choli nesterase resul ts i n an i ncreased amount of acetyl chol i ne reachi ng the
receptor and in a l onger ti me for acetyl chol i ne to remai n in the synapti c cl eft. Thi s causes an
increase i n the si ze and durati on of the end plate potential s.
157
There is evi dence that some of the
effects of neosti gmi ne are not the result of chol i nesterase i nhi biti on.
157
Anti chol i nesterases al so
have presynapti c effects. In the absence of neuromuscul ar bl ocking drugs, they potentiate the
normal twi tch response in a way si mi lar to succinyl chol i ne, probabl y as a resul t of the generati on
of acti on potenti al s that spread anti dromi cal l y.
20
A cei l ing effect, that is, the i nabi l ity for l arge
doses to produce an increasi ng effect, has been demonstrated in vi tro.
Neostigmine Block
Large doses of antichol inesterases, greater than those used cl i ni cal l y, may produce neuromuscular
bl ockade. Fade of both EMG and mechani cal responses has been observed during tetani c
stimul ati on after cl ini cal doses of neosti gmi ne but not edrophoni um were gi ven to reverse
neuromuscul ar blockade.
158
Paradoxi cal l y, thi s neosti gmi ne effect is antagonized wi th small doses
of nondepol ari zi ng blocki ng agents. The mechani sm i nvol ved i s uncertai n. There are no cl inical
reports of postoperati ve weakness attri buted to reversal agents, and thi s may be because al l
patients who received the antichol inesterase also had been gi ven some neuromuscul ar bl ocking
agent.
Potency
Dose-response curves have been constructed for edrophonium, neosti gmi ne, and pyri dosti gmi ne.
During a constant infusi on of neuromuscul ar blocking drugs, the curves are obtai ned by pl otting
the peak effect versus the dose of reversal agent. In thi s si tuati on, neosti gmine was found to be
approxi mately 12 times as potent as edrophoni um.
159
However, the curves are not parall el , that of
edrophoni um bei ng fl atter. Thi s i ndicates that edrophoni um i s effecti ve over a narrower range of
bl ockade and less effecti ve against deep bl ockade. Thi s was veri fi ed when neostigmi ne and
edrophoni um were used to reverse atracuri um blockade. More neosti gmi ne and edrophoni um were
requi red to reverse deep (99%) than moderate (90%) bl ock, but the di fference was greater for
edrophoni um.
160
There is no difference i n the dose-response rel ati onshi p of antichol inesterases if
vecuroni um i s infused i nstead of pancuroni um, but there i s a marked shi ft to the l eft for the
curves obtai ned during vecuronium block if the reversal agent is given duri ng spontaneous
recovery.
161
Thi s indi cates that anti chol inesterase-assi sted recovery i s the sum of two
components: (1) spontaneous recovery from the neuromuscular blocki ng agent i tsel f, whi ch
depends on the pharmacoki neti c characteri sti cs of the drug, and (2) assi sted recovery, whi ch is a
functi on of the dose and type of antichol inesterase agent given.
Pharmacokinetics
Foll owi ng bol us i v i njection, the pl asma concentrati on of the anti chol inesterases decreases rapidl y
duri ng the fi rst 5 to 10 minutes and then more sl owly.
153
Vol umes of di stri buti on are i n the range
of 0.7 to 1.4 L/kg and the el iminati on hal f-li fe i s 60 to 120 minutes. The drugs are water-solubl e,
ioni zed compounds so that thei r pri nci pal route of excretion is the kidney. Their cl earances are i n
the range of 8 to 16 mL/kg/min, whi ch is much greater than the GFR because they are acti vel y
secreted i nto the tubul ar l umen. Their clearance i s reduced markedl y in pati ents in renal fail ure.
Pharmacodynamics
The onset of acti on of edrophoni um (1 to 2 minutes) to peak effect i s much more rapi d than that
of neostigmi ne (7 to 11 mi nutes) or pyridosti gmi ne (15 to 20 mi nutes) (Fi g. 16-17).
159
The reason
for the di fferences i s uncertai n, but may be rel ated to the different rates of bi ndi ng to the
enzyme. The durati on of action (1 to 2 hours) is si mi lar to thei r eli mi nation half-li fe. Even when
used to reverse bl ockade produced by l ong-acti ng agents, duration of action of anti chol inesterase
agents i s comparabl e to or most often exceeds that of the neuromuscul ar bl ocking drug. Wel l -
documented recurari zati on has not been reported. In practi ce, cases of apparent reparal ysi s in the
recovery room are incomplete reversal that was initi al l y thought to be compl ete. Either manual or
visual assessment i s performed usi ng the trai n-of-four or tetanus mode, whi ch can yi el d to gross
underevaluati on of resi dual paralysi s, or respi ratory functi on appeared adequate when the tracheal
tube was i n pl ace, but once extubated, the pati ent cannot mai ntai n a patent ai rway.
Fact or s Af f ect i ng Rever sal
Several factors modi fy the rate of recovery of neuromuscul ar activity after reversal .
Intensity of Block
The more intense the block at the time of reversal , the l onger the recovery of neuromuscul ar
acti vi ty (Fi g. 16-18).
160
In addi ti on, neosti gmi ne is more effecti ve than edrophoni um or
pyri dosti gmi ne i n antagoni zi ng i ntense (90%) blockade.
160
When reversal i s administered after
spontaneous recovery to
25% T
1
has occurred, recovery i s rapi d and the ti me from reversal to
TOF 0.9 i s usual ly onl y a few mi nutes, al though recovery after

pancuroni um may not be compl ete.
79
Thus, it has been recommended that reversal should not be
attempted unti l T
1
25% when four twi tches to TOF sti mul ation are vi sibl e. Attempted reversal at
only two twi tches may take 30 mi nutes or more to reach TOF = 0.9.
151

FIGURE 16-17. Reversal of pancuroni um bl ockade at 10% twitch recovery. Reversal i s given
at time zero. Edrophonium is faster then neosti gmine, which is faster than pyrodosti gmi ne.
Redrawn from Ferguson et al .
167

P.447
It i s someti mes argued that reversal can be attempted earl i er, for instance when there i s only one
or no twi tch vi si bl e foll owi ng trai n-of-four sti mulation, because time has to be spent anyway
wai ting for al l four twi tches to reappear. Several studies dealt wi th the problem of total ti me
between injecti on of the neuromuscul ar bl ocki ng agent unti l compl ete recovery, wi th the reversal
agent gi ven at di fferent l evel s of spontaneous recovery. Bevan et al
162
admini stered l arge doses of
neostigmine (0.07 mg/kg) after rocuronium and vecuronium and measured ti me until train-of-four
rati o was 0.9. Neosti gmi ne decreased the ti me to recovery, no matter when i t was gi ven.
However, ti me from i njecti on to ful l reversal was not less when neosti gmine was given 5 minutes
after rocuroni um (42.1 mi nutes) than at 25% recovery (28.2 mi nutes) (Fi g. 16-19).
162
In addi ti on,
gi vi ng the reversal agent too earl y leads to a period of bl i nd paral ysi s, because neosti gmi ne-
assi sted recovery i s characteri zed by an earl y, rapi d phase, fol l owed by sl ower recovery. As a
resul t, the i nterval between a trai n-of-four rati o of 0.4 to 0.9, that i s, the ti me when fade i s
di fficul t to detect, is l i kely to be much longer wi th earl y neosti gmi ne admi ni strati on. Thus, there is
little advantage in attempting earl y reversal.
FIGURE 16-18. Neosti gmi ne i s more effecti ve at greater degree of recovery from rocuroni um
bl ockade. Ti me to reach a trai n-of-four rati o of 0.8 after various doses of neostigmine. Thi s
ti me i s l ess i f neostigmine i s given at 25% than at 10% first-twi tch recovery. Notice a ceil i ng
effect for neosti gmi ne at doses greater than 0.035 mg/kg. A dose of 0 i ndi cates no reversal
gi ven. Data from McCourt et al .
168

Dose
Over a certai n dose range, the degree and rate of reversal depends directl y on dose.
163
However,
al l anti chol inesterase agents demonstrate a cei li ng effect (see Fi g. 16-18). Usuall y, there i s no
added benefi t i n giving doses exceeding 0.07 mg/kg neostigmine, or 1.0 mg/kg edrophoni um.
Choice of Neuromuscular Blocking Agent
Recovery of neuromuscul ar acti vi ty after reversal is dependent on the rate of spontaneous
recovery as wel l as the accel erati on i nduced by the reversal agent. Consequentl y, the overall
recovery of intermedi ate-acti ng agents (atracuri um, vecuroni um, mivacurium, rocuroni um)
following the same dose of anti chol inesterase is more rapi d and more complete than after
pancuroni um, d-tubocurari ne, or gal l amine.
79
Thi s is probabl y why residual paral ysis i s more
frequent wi th l onger acti ng neuromuscul ar bl ocking agents. After prol onged infusi ons, recovery i s
sl ower than after i ntermittent bol us admi ni strati on.
97
Thi s i s especi al l y true of drugs that depend
on redi stributi on for termi nati on of action, such as rocuronium and vecuronium.

Age
Recovery of neuromuscul ar acti vi ty occurs more rapidl y wi th small er doses of antichol inesterases
in i nfants and chi l dren than i n adults (Fi g. 16-20).
162
Resi dual weakness in the recovery room is
found l ess frequently i n chi l dren than i n adults. The effecti veness of reversal has not been studied
extensi vel y i n the elderly. Al though the eli mi nati on of antichol inesterases i s reduced in thi s age
group, thi s i s counterbal anced by the tendency for neuromuscul ar bl ockade to wear off more
sl owly. Thi s i s especial ly true of steroi d neuromuscular blocki ng agents, such as vecuroni um and
FIGURE 16-19. Time from i njecti on of rocuronium unti l recovery to train-of-four rati o of 0.9
in adul ts. Reversal with neosti gmi ne was ei ther not gi ven (spont), or gi ven at 25, 10, or 1%
twi tch recovery, or gi ven 5 minutes after rocuronium, when there was no twitch. Times from
rocuroni um i njection to 1% fi rst twi tch, 25% fi rst twitch and trai n-of-four rati o of 0.9 are
i ndi cated. Neosti gmi ne was opti mal when gi ven at 10 to 25%. Gi vi ng it earl y had no
advantage. Data from Bevan et al .
162

P.448
rocuroni um, whi ch have a sl ower recovery i ndex in the el derl y.
Drug Interactions
Drugs that potenti ate neuromuscul ar bl ockade can slow reversal or produce recurari zation if given
after anti choli nesterase administration. Halogenated agents, when continued after neostigmi ne
administrati on, prolong ti me to full reversal . Even when they are di sconti nued at the ti me of
anti choli nesterase drug administration, reversal time i s not reduced si gnifi cantly, probably
because wash out of the vapor from muscl e ti ssue takes ti me. Care must be taken i f
aminogl ycosi de antibi oti cs or magnesium must be given shortl y after reversal agents.
117

Renal Failure
Antichol inesterases are actively secreted i nto the tubular lumen so that thei r cl earance i s reduced
in renal fai l ure.
153
Thus, durati on of action of neosti gmi ne and edrophoni um i s increased i n renal
fai l ure, at l east to a comparabl e extent as durati on of acti on of the neuromuscular blocki ng agent.
No cases of recurari zati on have been reported.
Ant i chol i nest er ases: Ot her Ef f ect s
Cardiovascular
Antichol inesterases provoke profound vagal stimul ati on. The ti me course of the vagal effects
paral l el s the reversal of block: rapi d for edrophoni um and sl ower for neosti gmi ne. However, the
bradycardia and bradyarrhythmi as can be prevented wi th anti chol i nergi c agents. Atropine has a
rapi d onset of acti on (1 minute), durati on of 30 to 60 mi nutes, and crosses the

bl ood-brain barrier. Its ti me course makes it appropriate for use i n combinati on wi th
edrophoni um,
159
whereas gl ycopyrrol ate (onset 2 to 3 minutes) i s more suitabl e with neostigmi ne
or pyri dosti gmi ne. Because gl ycopyrrolate does not cross the bl ood-brai n barri er, i t i s bel i eved
that the i nci dence of memory defi ci ts after anesthesi a i s l ess than that after atropine. If atropine
FIGURE 16-20. Same graph as i n Fi gure 16-19, but i n chil dren 2 to 12 years old.
Spontaneous recovery from rocuronium blockade i s more rapi d, as wel l as neosti gmi ne-
assi sted recovery. Data from Bevan et al.
162

P.449
i s gi ven wi th neosti gmi ne, the dose i s approxi matel y hal f that of neosti gmine (atropine 20 g/kg
for neosti gmi ne 40 g/kg). Such a combinati on l eads to an i ni ti al tachycardi a foll owed by a sl ight
bradycardia. Wi th gl ycopyrrol ate, the dose i s one-fourth to one-fifth that of neosti gmi ne. Atropi ne
requi rements are l ess with edrophoni um than wi th nesotigmine (atropi ne 7 to 10 g/kg versus
edrophoni um 0.5 mg/kg).
Other Cholinergic Effects
Antichol inesterases produce i ncreased sali vation and bowel moti l i ty. Al though atropi ne bl ocks the
former, i t appears to have l ittle effect on peri stal si s. Some reports cl ai m an i ncrease in bowel
anastomotic l eakage after the reversal of neuromuscul ar bl ockade. Others have hel d the use of
anti choli nesterases to be responsi bl e for an i ncreased i nci dence of vomiting after ambul atory
surgery. In a recent meta-anal ysi s, it was concl uded that neosti gmi ne (2.5 mg or more in adul ts)
was associated wi th a hi gher i ncidence of nausea and vomi ting than no reversal .
164
Thi s concl usi on
is heavi l y affected by two studies showi ng a l arge effect, whi le al l other studies showed no effect.
The meta-anal ysi s suggested that l ower doses (1.5 mg or less) were not associ ated with a greater
inci dence of nausea and vomi ti ng. Si nce then, two more studies fai led to show any rel ati onshi p
between admini stration of neosti gmi ne and an i ncreased i nci dence of postoperati ve nausea and
vomiti ng. Thi s emeti c effect has not been found for edrophoni um. At any rate, possibl e nausea and
vomiti ng i s preferable to signs and symptoms of respi ratory paralysi s.
Respiratory Effects
Antichol inesterases may cause an i ncrease in airway resi stance, but anti chol inergi cs reduce thi s
effect. Several other factors, such as pai n, the presence of an endotracheal tube, or l i ght
anesthesia, may predi spose to bronchoconstricti on at the end of surgery so that it i s diffi cult to
incri mi nate the reversal agents.
Cl i ni cal Use
Several reversal regi mens have been proposed and are effecti ve. In general , the more i ntense the
bl ock, the greater the dose of anti chol i nesterase that i s required. However, there does not seem
to be any advantage i n gi vi ng more than the equi val ent of neosti gmi ne 0.07 mg/kg. Neostigmine
is preferred to edrophoni um for intense bl ock, but the rapi d acti on of edrophoni um has the
advantage of all owing the extent of reversal to be assessed i n the operati ng room. Pyri dosti gmi ne
has a sl ow onset of acti on, and does not appear to accelerate reversal of short- and intermedi ate-
duration drugs to a great extent.
ORG 25969
A new method of reversing neuromuscular blockade has been advocated recently by the
introducti on of a cyclodextri n, ORG 25969, which, at the ti me of writi ng, was sti l l in the
investi gati onal stage i n humans.
165
The compound i s made up of ei ght sugars arranged i n a ri ng.
It has a hi gh affi ni ty for rocuroni um, wi th whi ch i t forms a compl ex, and the compl ex i s excreted.
ORG 25969 has less affi ni ty for other steroi dal neuromuscul ar blocking agents l i ke vecuroni um and
pancuroni um, and apparentl y no affi ni ty for other endogenous steroi dal compounds. It does not
bi nd benzyli soquinol i ne-type neuromuscul ar bl ocki ng agents. The abi l i ty to produce a rapi d return
of twi tch height even at deep levels of paral ysis and the lack of si de effects make thi s compound a
promi si ng new development in anesthesi a.
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muscle paral ysi s after rocuronium: Less residual block when accel eromyography i s used. Acta
136. Dahaba AA, Von Kl obucar F, Rehak PH, Li st WF: The neuromuscul ar transmission modul e
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137. Donati F, Meistelman C, Plaud B: Vecuroni um neuromuscul ar bl ockade at the di aphragm,
the orbiculari s oculi , and adductor pol l ici s muscl es. Anesthesi ol ogy 73:870, 1990
138. Donati F, Meistelman C, Plaud B: Vecuronium neuromuscular blockade at the
adductor muscles of the larynx and adductor pollicis. Anesthesiology 74:833, 1991
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di aphragm to mi vacuri um: An electromyographi c study. Anesthesi ol ogy 95:1323, 2001
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reflects rocuronium neuromuscular blockade at the laryngeal adductor muscles.
143. Wri ght PM, Cal dwel l JE, Mi ll er RD: Onset and durati on of rocuronium and succi nylchol ine
at the adductor pol l i ci s and l aryngeal adductor muscles i n anesthetized humans.
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149. Eriksson LI, Lennmarken C, Wyon N, Johnson A: Attenuated ventilatory response
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antagonists of pancuronium. Anesthesi ol ogy 53:390, 1980
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after intermedi ate-acti ng neuromuscul ar blocki ng drugs. Anaesthesia 56:312, 2001
Local Anestheti cs
Chapter 17
Local Anesthetics
Spencer S. Liu
Raymond S. Joseph Jr.
KEY POINTS
Local anesthetics block the generati on, propagati on, and osci ll ati ons of
el ectrical impul ses i n electri cal ly exci table ti ssue.
Mol ecular and geneti c studi es indi cate that l ocal anestheti cs primari ly work by
bi ndi ng to a modul ated receptor l ocated on the interior of the sodi um channel.
In addi ti on to sodium channel block, mechanisms of acti on of both peri pheral
and central neural bl ock may i nvol ve decremental conducti on, parti al bl ock of
information carryi ng electri cal osci ll ati ons, and i nteracti ons wi th other
neurotransmitters such as GABA.
In general , the more potent and l onger acti ng agents are more l i pi d sol ubl e,
have i ncreased protei n bi ndi ng, l ess systemi c absorpti on, but more potenti al for
systemi c toxi city.
All currentl y avai labl e l ocal anesthetics are racemi c mixtures wi th the excepti on
of li docaine (achi ral ), l evobupi vacai ne (l = S), and ropi vacai ne (S). It appears
that S i somers have nearl y equal effi cacy but less potenti al for systemi c
toxi ci ty.
Effi cacy for cl inical use of l ocal anesthetics may be increased by addi ti on of
epi nephri ne, opi oi ds, and al pha-2 adrenergic agoni sts. The val ue of
al kali nization of l ocal anestheti cs appears to be debatabl e as a cl inicall y useful
tool to improve anesthesia.
Systemi c toxici ty from the cli nical use of l ocal anestheti cs for regi onal
anesthesia appears to be an uncommon occurrence. Surveys from France and
the Uni ted States approximate the seizure rate to be 1/10,000 for epi dural
injecti on and 7/10,000 for peripheral nerve bl ock.
Nonethel ess, systemi c toxi ci ty from l ocal anestheti cs shoul d be promptl y
INTRODUCTION
Local anesthetics block the generati on, propagation, and osci ll ati ons of electri cal i mpulses i n
el ectricall y excitabl e ti ssue. Use of l ocal anestheti cs i n cl i ni cal anesthesi a i s vari ed and
incl udes direct i njecti on i nto ti ssues, topical appl icati on, and intravenous admini stration to
produce cl i ni cal effects at varied locations i ncl udi ng the central neuraxi s, peri pheral nerves,
mucosa, ski n, heart, and ai rway. Detai led knowl edge of perti nent anatomy and pharmacol ogy wil l
ai d i n optimal therapeuti c use of l ocal anesthetics. Care shoul d be taken to avoi d potenti al central
nervous system (CNS) and cardi ovascul ar toxici ty from l ocal anestheti cs.
MECHANISMS OF ACTION OF LOCAL ANESTHETICS
Anat omy of Ner ves
Local anesthetics are often used to bl ock nerves ei ther peri pheral l y or central l y. Peripheral nerves
are mi xed nerves contai ni ng afferent and efferent fi bers that may be myelinated or unmyel inated.
Each axon wi thin the nerve fi ber i s surrounded by endoneuri um composed of nonneural gli al cel l s.
Indi vi dual nerve fi bers are gathered i nto fasci cl es and surrounded by peri neuri um composed of
connecti ve tissue. Fi nall y, the enti re

peri pheral nerve i s encased by epineurium composed of dense connecti ve ti ssue (Fi g. 17-1). Thus,
several l ayers of protecti ve ti ssue surround individual axons, and these l ayers act as barri ers to
the penetrati on of l ocal anestheti cs.
1
In additi on to the envel opi ng connecti ve tissue, al l
mammal ian nerves wi th a diameter greater than 1 m are myeli nated. Myel inated nerve fibers are
segmental ly encl osed by Schwann cel l s formi ng a bi l ayer l i pi d membrane that i s wrapped several
hundred ti mes around each axon.
2
Thus, myel i n accounts for over hal f the thi ckness of nerve
fi bers >1 m (Fi g. 17-2). Separating the myel inated regions are the nodes of Ranvier where
structural elements for neuronal excitati on are concentrated (Fi g. 17-3).
3
The nodes are covered
by i nterdi gi tati ons from nonmyeli nati ng Schwann cel ls
4
and by negati vel y charged gl ycoprotei ns.
Although axonal membranes are not freely in contact with their envi ronment at the nodes, these
areas do al l ow passage of drugs and i ons.
5
Furthermore, the negati vel y charged protei ns may bi nd
basic l ocal anestheti cs and thus act as a depot. Unmyel i nated nerve fi bers (di ameter <1 m) are
encased by a Schwann cell that si mul taneousl y i nsul ates several (5 to 10) axons (Fi g. 17-2).
These fi bers are conti nuously encased by Schwann cel l s and do not possess i nterruptions (nodes of
Ranvier). The exi stence of multi ple protecti ve l ayers around both myelinated and unmyeli nated
nerve fi bers presents a substantial barrier to the entry of cl i ni cal l y used l ocal anestheti cs. For
example, animal model s suggest that onl y 1.6% of an injected dose of l ocal anestheti c penetrates
into the nerve fol l owing performance of peri pheral nerve blocks.
6

treated. Pati ents wi th cardi ovascul ar col l apse from bupi vacai ne, ropivacai ne,
and levo-bupi vacaine may be especi al l y di ffi cul t to resuscitate.
P.454
FIGURE 17-1. Schemati c cross section of typical peri pheral nerve. The epineurium,
consi sti ng of col lagen fibers, i s oriented al ong the l ong axi s of the nerve. The peri neuri m is a
di screte cel l l ayer, whereas the endoneuri um i s a matrix of connecti ve ti ssue. Both afferent
and efferent axons are shown. Sympathetic axons (not shown) are al so present i n mi xed
peri pheral nerves. (Adapted wi th permission from Strichartz GR: Neural physi ol ogy and l ocal
anesthetic acti on. In Cousins MJ, Bridenbaugh PO [eds]: Neural Bl ockade in Clinical
Anesthesi a and Management of Pai n, p 35. Phi ladel phi a, Lippi ncottRaven, 1998.)
FIGURE 17-2. Schwann cell s form myel i n around one myel inated axon or encompass several
Nerve fi bers are commonly classi fi ed by si ze, conducti on vel oci ty, and functi on (Tabl e 17-1). In
general , i ncreasi ng myel i nati on and nerve di ameter l ead to increased conduction vel oci ty. The
presence of myel i n accel erates conducti on vel oci ty because of i ncreased electri cal i nsul ati on of
nerve fi bers and saltatory conducti on. Increased nerve diameter accel erates conducti on vel oci ty
both by i ncreased myel i nati on and by improved el ectrical cabl e conducti on properti es of the nerve.
Myeli nated and unmyel i nated nerves carry out both afferent and efferent functi ons.
unmyel i nated axons. (Adapted with permission from Carpenter RL, Mackey DC: Local
anesthetics. In Barash PG, Cul l en BF, Stoel ti ng RF [eds]: Cl i ni cal Anesthesi a, p 413.
Phi ladelphi a, Lippi ncottRaven, 1996.)
FIGURE 17-3. Di agram of node of Ranvi er di splayi ng mi tochondria (M), ti ght junctions i n
paranodal area (P), and Schwann cel l (S) surroundi ng node. (Adapted wi th permission from
Strichartz GR: Mechani sms of acti on of l ocal anestheti c agents. In Rogers MC, Ti nker JH,
Covino BG, et al [eds]: Pri nci pl es and Practi ce of Anesthesi ology, p 1197. St. Louis, Mosby
Year Book, 1993.)
TABLE 17-1 Classification of Nerve Fibers
CLASSIFICATION DIAMETER
()
MYELIN CONDUCTION
(m/sec)
LOCATION FUNCTION
A-al pha
A-beta
622 + 30120 Afferents/efferents
for muscl es and
joi nts
Motor and
propri ocepti
A-gamma 36 + 1535 Efferent to muscl e
spi ndl e
Muscl e tone
A-del ta 14 + 525 Afferent sensory Pai n
El ect r ophysi ol ogy of Neur al Conduct i on
Ioni c di sequi l i bri a across semipermeable membranes form the basi s for neuronal resti ng potenti als
and for the potential energy needed to i ni tiate and mai ntai n electri cal i mpulses. The resti ng
potential of neural membranes averages -60 to -70 mV, with the cel l i nteri or bei ng negati ve to the
cel l exteri or. This resti ng potenti al is predominantl y maintai ned by a potassi um gradi ent wi th a 10
ti mes greater concentrati on of potassium within the cell . Thi s gradi ent is mai ntai ned by an acti ve
protei n pump that transports potassi um into the cel l and sodi um out of the cel l through voltage-
gated potassi um channel s that are open at resti ng potenti al s.
7
Potassi um equi li brium i s not the
only factor i n resti ng potenti al , as a resti ng potenti al of approxi matel y -90 mV i s predi cted by the
Nernst equati on i f onl y potassi um is considered. In addi ti on to

potassium channel s, voltage-independent channel s that al low leak currents of sodi um, chl oride,
and other i ons affect the resti ng potenti al .
In contrast to the dependence of resting membrane potential on potassi um disequi l ibri a,
generati on of acti on potentials i s primari ly a resul t of activati on of vol tage-gated sodi um
channel s.
7
These channel s are protei n structures spanning the bil ayer l i pi d membrane composed of
structural elements, an aqueous pore, and voltage-sensi ng el ements that control passage of i ons
through the pore (Fi g. 17-4).
8
Sodi um channels exi st i n several conformati ons dependi ng on
membrane potential and time. At resting membrane potenti al, sodi um channel s predomi nantl y
exist i n a resti ng (cl osed) conformati on.
7, 9
Duri ng membrane depol ari zati on, channels open wi thin
a few hundred mi croseconds and al l ow passage of 10
7
ions/sec
-1
. Sodi um channels are rel ati vel y
sel ecti ve, but other monovalent ions can also gain passage through the channel . For example,
li thi um traverses about as wel l as sodi um, whereas potassi um only about one-tenth as wel l .
Foll owi ng acti vation (openi ng) of the sodi um channel and depol ari zation, the channel wi ll
spontaneousl y cl ose i nto an inactivated state i n a time-dependent fashi on to al low repol ari zati on
and then revert to a resti ng conformati on.
10
Thus, a three-state ki neti c scheme (Fi g. 17-5)
conceptual i zes the changes in sodi um channel conformati on that account for changes in sodi um
conductance duri ng depol ari zation and repol ari zati on.
nerve Touch
Temperature
B <3 + 315 Pregangl ioni c
sympatheti c
Autonomi c
function
C 0.31.3 - 0.71.3 Postgangl i onic
sympatheti c
Afferent sensory
nerve
Autonomi c
function
Pai n
Temperature
P.455
FIGURE 17-4. Di agram of bi l ayer l i pi d membrane of conducti ve tissue with sodi um channel
(cross-hatchi ng) spanning the membrane. Tertiary ami ne local anestheti cs exi st as neutral
base (N) and protonated, charged form (NH
+
) i n equi li brium. The neutral base (N) i s more
li pi d sol ubl e, preferenti al l y parti ti ons i nto the l i pophi l i c membrane i nteri or, and easi l y passes
through the membrane. The charged form (NH
+
) is more water sol ubl e and bi nds to the
sodium channel at the negati vel y charged membrane surface. Both forms can affect functi on
of the sodi um channel . The N form can cause membrane expansion and closure of the sodi um
channel . The NH
+
form wi l l di rectl y i nhibi t the sodi um channel by bi ndi ng wi th a l ocal
anesthetic receptor. The natural local anestheti c tetrodotoxin (TTX) bi nds at the external
surface of the sodi um channel and has no interacti on wi th cli nicall y used local anestheti cs.
(Adapted wi th permi ssi on from Stri chartz GR: Neural physi ol ogy and local anestheti c acti on.
In Cousins MJ, Bridenbaugh PO [eds]: Neural Blockade i n Cl ini cal Anesthesi a and
Management of Pai n, p 35. Phil adel phia, Lippi ncottRaven, 1998.)
FIGURE 17-5. Il l ustrati on of dominant form of sodi um channel duri ng generati on of an
acti on potential. R = resti ng form, O = open form, I = inactive form. Figure A demonstrates
An acti on potenti al wi l l be generated by depol ari zati on when the impul se-firi ng threshold of the
axon i s reached. That i s the poi nt at whi ch no further depol ari zati on i s required for local processes
to generate a complete action potential . This threshol d i s not an absol ute voltage, but rather
depends on the dynami cs of the sodi um and potassi um channel s. For exampl e, a brief maxi mall y
depol arizing sti mul us wi l l not generate an

acti on potential because there is insuffici ent ti me for sodium channel s to open. Nor wi l l a
depol arizing sti mul us that i ncreases too sl owl y create an acti on potenti al . As the stimul us sl owly
increases, i ni ti all y activated sodi um channel s wi l l spontaneously inactivate, so there wil l never be
enough open channel s at one ti me to generate an acti on potenti al . Furthermore, vol tage-sensi ti ve
potassium channel s woul d begin to increase potassium conductance that would further i nhi bit
generati on of an action potential . Thus, successful generati on of an action potential requires a
depol arizing sti mul us of correct i ntensity and durati on.
Once an action potential i s generated, propagati on of the potenti al al ong the nerve fi ber i s
requi red for i nformati on to be transmi tted. Both i mpul se generati on and propagati on are al l or
nothing phenomena. In the case of i mpul se propagation, either the l ocal ly generated acti on
potential reaches the threshol d potenti al of adjacent segments and causes propagati on along the
nerve, or the l ocal depol ari zati on ends. Nonmyel inated fibers requi re achi evement of threshol d
potential at the immedi ately adjacent membrane, whereas myel i nated fibers require generati on of
threshol d potenti al at a subsequent node of Ranvi er.
Repolarizati on after acti on potenti al generati on and propagati on rapi dly foll ows owing to
increasi ng equil i bri a of i nternal and external sodi um ions, a ti me-control led decrease in sodi um
conductance, and a vol tage-control led increase i n potassi um conductance.
11
In addi tion, active
internal concentration of potassi um occurs vi a the membrane-bound enzyme Na
+
/K
+
/ATPase that
extrudes three sodi um ions for every two potassium ions absorbed. Although many mammalian
nonmyeli nated nerve fi bers devel op a peri od of hyperpol ari zati on after the action potential ,
myel inated nerve fi bers return directl y to resti ng membrane potenti al .
11

Mol ecul ar Mechani sms of Act i on of Local Anest het i cs
The sodi um channel is the key target of local anestheti c acti vi ty. The wi de variety of
compounds that exhibi t l ocal anesthetic activity combi ned with the di fferent effects of neutral
and charged l ocal anestheti cs suggest that l ocal anestheti cs may act on the sodium channel ei ther
by modi fi cati on of the l i pi d membrane surroundi ng it or by di rect interaction wi th i ts protei n
structure.
Previ ous studies have demonstrated that anestheti cs can reduce sodi um conductance through
sodium channel s by i nteracti ng with the surroundi ng l i pi d membrane.
12
Al terations i n neuronal
membranes by l ocal anestheti cs can occur by al teri ng the fl ui dity of the membrane that causes
membrane expansi on and subsequent cl osure of the sodium channel . Furthermore, al terati ons i n
membrane composi ti on may lower the probabi l ity of occurrence of the open sodi um channel state.
Such observations can account for local anestheti c acti ons of neutral and l i pophil i c local
anesthetics, but do not expl ain the di fferent acti vi ty of cli ni cal l y used, terti ary ami ne l ocal
anesthetics (e.g., l i docai ne).
Instead, the mechani sms of acti on of these l ocal anesthetics are best expl ai ned by di rect
the concurrent generation of an action potential , as the membrane depolarizes from resti ng
potential . Figure B demonstrates concurrent changes i n i on fl ux, as i nward sodi um current
(I
Na
+
) and outward potassi um current (I
K
+
) together yiel d the net i oni c current across the
membrane (I
i
). (Adapted wi th permi ssion from Stri chartz GR: Neural physi ology and l ocal
anesthetic acti on. In Cousins MJ, Bridenbaugh PO [eds]: Neural Bl ockade i n Cl i ni cal
Anesthesi a and Management of Pai n, p 35. Phil adelphia, Li ppi ncottRaven, 1998.)
P.456
interaction wi th the sodi um channel (modulated receptor theory).
13
The commonl y used tertiary
amine local anestheti cs exi st i n free equil i bri um as both a l i pid-solubl e neutral form and a
hydrophi l i c, charged form dependi ng on pK
a
and environmental pH. Al though the neutral form may
exert anestheti c actions as described earl i er, the cati onic speci es i s cl earl y the more potent form
(see Fi g. 17-4).
13
These tertiary ami ne l ocal anestheti cs al so demonstrate greater sodi um channel
bl ockade when the neural membrane i s repeti ti vel y depol ari zed (1 to 100 Hz),
14, 15
whereas neutral
local anestheti cs exhi bit l i ttl e change i n acti vi ty with increased frequency of sti mul ati on (use-
dependent bl ock). Increasing frequency of sti mulation increases the probabil i ty that sodi um
channel s wi ll exi st in the open and i nacti ve forms as compared to the unsti mul ated state. Thus,
differences in activity of tertiary ami ne l ocal anestheti cs between use-dependent (repeti tive
stimul ati on) and toni c (unsti mul ated) block are wel l expl ained by the exi stence of a si ngl e l ocal
anesthetic receptor withi n the sodi um channel that possesses di fferent affi ni ties duri ng di fferent
channel conformations (resti ng, open, inacti ve). Speci fi cal l y, higher affiniti es occur during the
open and i nacti ve phases. In support of thi s theory, when the affinity of inactive channel s for local
anesthetics i s decreased through geneti c mani pul ati on, use-dependent bl ock i s reduced.
16, 17

Mol ecular mani pul ati on of the sodium channel has reveal ed speci fi cs of the l ocal anesthetic
receptor.
8
Bi ndi ng si tes to l ocal anesthetics are l ocated on the i ntracell ul ar si de of the sodi um
channel , may have di fferent bi ndi ng areas duri ng the open and i nacti vated conformati ons of the
sodium channel , and possess stereosel ecti vi ty wi th preference for the R isomers.
9, 17, 18

Mechani sm of Bl ockade of P er i pher al Ner ves
Local anesthetics may bl ock functi on of peripheral nerves through several mechani sms. As
di scussed earl i er, sodi um channel bl ockade leads to attenuati on of neural acti on potenti al
formation and propagation. Al though i t remai ns unknown in humans by what percent the neural
acti on potenti al must be decreased before functi onal bl ock occurs, animal studi es suggest that the
acti on potential must be decreased by at l east 50% before measurabl e loss of functi on i s
observed.
6
Previ ous studies have exami ned the di fferences i n suscepti bi li ty of nerve fiber to l ocal
anestheti c bl ockade based on si ze, myel i nati on, and l ength of fiber exposed to local anestheti c.
Cli nicall y, one can often discern a differenti al pattern of sensory bl ock after appl i cation of local
anesthetic to a peri pheral nerve.
19
Cl assicall y, the sensation of temperature i s l ost, foll owed by
sharp pain, then li ght touch. Thus, an ini ti al assumpti on was that smal l , unmyel i nated (C) fibers
conducti ng temperature sensation were i nherentl y more suscepti bl e to l ocal anestheti c blockade
than large, myelinated (A) fibers conducti ng touch. However, experi mental studi es reveal a more
compl ex pi cture. In vi vo studies of sciatic nerve bl ock i n rats wi th l idocai ne indicate that l arger A
fibers are more susceptibl e to toni c and phasi c bl ock than smal l er C fi bers.
15
Di fferenti al bl ock of
large and smal l nerve fibers is al so affected by choice of local anestheti c. Those wi th an amide
group, hi gh pK
a
, and l ower l i pi d sol ubi l i ty are more potent bl ockers of C fi bers. Thus, experi mental
studi es indi cate that l ocal anestheti c bl ock of nerve fibers wi ll i ntri nsi cal l y depend on type (size)
of fi ber, frequency of membrane stimul ati on, and choi ce of local anestheti c.
14, 20

During cli ni cal appl icati ons, the exposure length of the nerve fiber may expl ai n differenti al
bl ock,
21, 22
as smal l nerve fibers require a shorter l ength of fi ber exposed to l ocal anestheti c for
bl ock to occur than do large fi bers. It is theori zed that thi s observati on is because of decremental
conducti on bl ock of a criti cal l ength of nerve.
22
Decremental conducti on descri bes the decreased
abi li ty of successi ve nodes of Ranvi er to propagate an i mpul se in the presence of l ocal anesthetic
(Fi g. 17-6). As i nternodal di stances become greater wi th i ncreasing nerve fi ber si ze,
23
larger
nerve fi bers wi l l demonstrate i ncreasing resi stance to l ocal anestheti c bl ock. Evidence for thi s
mechani sm i s confli cti ng. Sciatic nerve bl ocks in rats demonstrate greater length of spread al ong
the nerve and greater intraneural content of radi ol abeled l i docaine wi th injections of high volume
and low concentrations of l i docaine. However, the use of small vol umes and greater concentrati ons
of li docaine produced more effective sensory and motor bl ock despi te l esser spread and
intraneural penetrati on of li docai ne.
24
Further cl inical studi es on decremental conducti on and rol e
of criti cal

length wil l be needed, especial ly as nerve blocks i n humans typi cal l y i nvol ve much greater
P.457
lengths of affected nerve than ani mal model s. For exampl e, sciatic nerve bl ocks in humans
probabl y resul t in 5 to 10 cm of affected nerve l ength.
6

A fi nal mechani sm whereby l ocal anesthetics may bl ock peri pheral nerve functi on i s vi a
degradation of transmi tted el ectri cal patterns. It is theori zed that a l arge part of the sensory
information transmi tted vi a peri pheral nerves i s carri ed vi a codi ng of el ectri cal si gnal s in after-
potential s and after-osci l lations.
25
Evi dence for thi s theory i s found in studi es demonstrating l oss
of sensory nerve functi on after i ncompl ete l ocal anestheti c blockade. For exampl e, sensati on of
temperature of the ski n can be l ost despi te uni mpeded conducti on of smal l fi bers.
26
Furthermore,
a surgi cal depth of epi dural and peripheral nerve bl ock anesthesia can be obtai ned with onl y mi nor
changes i n somatosensory evoked potenti al s from the anestheti zed area.
27, 28
Previ ous studies
have demonstrated that appli cati on of sub-bl ocking concentrati ons of local anestheti c wi l l
suppress normal l y occurring after-potential s and after-osci l lations without si gni fi cantl y affecting
acti on potenti al conduction.
29
Thus, di srupti on of codi ng of el ectrical information by l ocal
anesthetics may be another mechanism for bl ock of peri pheral nerves.
Mechani sm of Bl ockade of Cent r al Neur axi s
Central neuraxi al bl ock vi a spi nal or epi dural admi nistrati on of local anestheti cs involves the same
mechani sms at the l evel of spi nal nerve roots, ei ther i ntra- or extradural , as di scussed earl ier. In
addi ti on, central neuraxi al admi ni strati on of l ocal anestheti cs all ows multi ple potential acti ons of
local anestheti cs within the spinal cord at di fferent si tes. For exampl e, wi thin the dorsal horn,
local anestheti cs can exert fami l iar ion channel bl ock of sodi um and potassi um channels i n dorsal
horn neurons and i nhi bit generati on and propagati on of nociceptive electri cal activity.
30
Other
spi nal cord neuronal ion channel s, such as cal ci um channels, are al so important for afferent and
FIGURE 17-6. Di agram i ll ustrating the pri nci pl e of decremental conducti on bl ock by l ocal
anesthetic at a myel i nated axon. The first node of Ranvier at left contai ns no local anestheti c
and gives ri se to a normal acti on potenti al (soli d curve). If the nodes succeedi ng the first are
occupi ed by a concentrati on of l ocal anestheti c hi gh enough to block 74 to 84% of the sodi um
conductance, then the action potential ampl itudes decrease at successi ve nodes (ampl itudes
are i ndi cated by i nterrupted bars representi ng three i ncreasing concentrati on of l ocal
anesthetic). Eventual l y, the impul se decays to bel ow threshol d ampl i tude i f the seri es of l ocal
anesthetic contai ni ng nodes is l ong enough. Propagati on of the impul se has then been
bl ocked by decremental conduction, even though none of the nodes are completel y bl ocked.
Concentrati ons of l ocal anesthetic that bl ock more than 84% of the sodi um conductance at
three successi ve nodes prevent any i mpulse propagati on at al l. (Adapted wi th permi ssi on
from Fi nk BR: Mechani sms of di fferenti al axial blockade in epi dural and spi nal anesthesi a.
efferent el ectri cal activity. Admi ni strati on of cal cium channel bl ockers to spinal cord N (neuronal )
calci um channel s results i n hyperpol arizati on of cell membranes, resistance to electri cal
stimul ati on from noci cepti ve afferents, and intense anal gesia.
31
Local anesthetics appear to have
si mi l ar acti ons on cal cium channel s, whi ch may contri bute to anal gesi c actions of central
neuraxial ly admi ni stered local anestheti cs.
32

In addi tion to i on channels, mul tipl e neurotransmi tters are involved i n noci ceptive transmi ssi on i n
the dorsal horn of the spi nal cord.
33
For exampl e, tachyki ni ns (substance P) are important
neurotransmitters modul ati ng noci cepti on from C fi bers.
34
Admi ni strati on of l ocal anestheti cs i n
concentrations that occur after spinal and epidural anesthesi a inhi bi ts postsynapti c depol ari zati ons
dri ven by substance P and may decrease nocicepti on vi a this i nhi bitory mechani sm.
35
Other
neurotransmitters that are i mportant for noci ceptive processi ng i n the spinal cord, such as
acetylchol ine, -aminobutyri c aci d (GABA), and N-methyl -D-aspartate (NMDA), can al l be affected
by l ocal anestheti cs ei ther pre- or postsynapti cal l y.
8, 35
These studies suggest that anti noci cepti ve
effects of central neuraxi al l ocal anestheti c block may be medi ated vi a complex interactions at
neural synapses i n addi ti on to i on channel bl ockade.
PHARMACOLOGY AND PHARMACODYNAMICS
Chemi cal P r oper t i es and Rel at i onshi p t o Act i vi t y and P ot ency
The cli nicall y used local anestheti cs consi st of a l i pid-solubl e, substi tuted benzene ri ng li nked to
an ami ne group (terti ary or quaternary dependi ng on pK
a
and pH) vi a an al kyl chai n contai ni ng
ei ther an amide or ester l inkage (Fi g. 17-7). The type of l i nkage separates the local anestheti cs
into ei ther aminoami des, metabol ized in the l i ver, or aminoesters, metabol i zed by pl asma
chol i nesterases. Several chemi cal properti es of local anestheti cs wi l l affect thei r effi cacy and
potency.
All cl inicall y used l ocal anesthetics are weak bases that can exi st as ei ther the l ipi d-solubl e,
neutral form or as the charged, hydrophi li c form. The combi nati on of pH of the environment and
pK
a
, or di ssoci ati on constant, of a local anestheti c determi nes how much of the compound exi sts i n
each form (Tabl e 17-2). As previ ously discussed, the pri mary site of acti on of l ocal anestheti cs
appears to exist on the intracel l ul ar si de of the sodi um channel , and the charged form appears to
be the predomi nantl y acti ve form.
13
Penetrati on of the li pi d-solubl e form through the l i pid neural
membrane appears to be the pri mary form of access of l ocal anestheti c molecul es, although some
FIGURE 17-7. General struture of cl i ni cal l y used l ocal anestheti cs. (Adapted with permission
from Carpenter RL, Mackey DC: Local anestheti cs. In Barash PG, Cul l en BF, Stoel ti ng RF
[eds]: Cl i ni cal Anesthesi a, p 413. Phi l adel phi a, Li ppincottRaven, 1996.)
access by the charged form can be gai ned vi a the aqueous sodi um channel pore (see Fi g. 17-4).
39

Thus, decreasing pK
a
for a given environmental pH will increase the percentage of l i pi d-sol ubl e
forms i n existence, hastening penetration of neural membranes and onset of acti on.

Lipi d sol ubi l i ty is another important determinant of activity. Although i ncreasing l ipi d
solubi li ty may hasten penetrati on of neural membranes, i ncreasi ng sol ubi li ty may also resul t
in i ncreased sequestration of local anestheti c i n myel in and other li pi d-solubl e compartments.
Thus, i ncreasi ng l i pid solubi li ty usual l y sl ows the rate of onset of action.
40
Similarly, duration of
TABLE 17-2 Physicochemical Properties of Clinically Used Local Anesthetics
LOCAL
ANESTHETIC
pKa % IONIZED
(at pH 7.4)
PARTITION
COEFFICIENT (LIPID
SOLUBILITY)
% PROTEIN
BINDING
AMIDES
Bupi vacai ne
a
8.1 83 3,420 95
Etidocai ne 7.7 66 7,317 94
Li docai ne 7.9 76 366 64
Mepi vacai ne 7.6 61 130 77
Pri locai ne 7.9 76 129 55
Ropi vacaine 8.1 83 775 94
ESTERS
Chl oroprocai ne 8.7 95 810 N/A
Procai ne 8.9 97 100 6
Tetracai ne 8.5 93 5,822 94
N/A, not avail able.
a
Levo-bupi vacaine has same physi cochemical properties as racemate.
Data from Liu SS. Local anesthetics and anal gesia. In Ashburn MA, Rice LJ (eds): The
Management of Pai n, pp 141170. New York, Churchi ll Li vi ngstone Inc., 1997.
P.458
acti on i s increased as absorpti on of l ocal anesthetic mol ecul es i nto myeli n and surroundi ng neural
compartments creates a depot for slow rel ease of l ocal anestheti cs.
40
Fi nal l y, i ncreased l ipi d
solubi li ty i ncreases potency of the l ocal anestheti c.
12, 13
Thi s observati on may be expl ai ned by a
correlation between l ipi d sol ubi l i ty and both sodi um channel receptor affi ni ty and abi li ty to al ter
sodium channel conformati on by di rect effects on l i pid cel l membranes.
Degree of protei n bi ndi ng al so affects activi ty of l ocal anestheti cs, as onl y the unbound form i s
free for pharmacol ogi c activi ty. In general , the more l i pi d sol uble and longer acti ng agents have
i ncreased protei n bi ndi ng.
41
Al though the sodi um channel i s a protei n structure, it does not appear
that degree of local anestheti c protei n bi ndi ng correl ates wi th bi nding to the local anestheti c
receptor. Studies suggest that di ssoci ati on of l ocal anesthetic mol ecul es from the sodi um channel
occurs i n a matter of seconds regardl ess of degree of protei n bi ndi ng of the local anestheti c.
42

Thus, prol ongati on i n durati on of acti on associated wi th an increased degree of protei n bi ndi ng
must involve other extracell ular or membranous protei ns.
A fi nal physi cal property of i nterest i s stereoi someric mixture of the commerci al l y avail able
local anestheti cs. All currentl y avail able l ocal anestheti cs are racemi c mi xtures with the
excepti on of l i docai ne (achiral ), ropi vacai ne (S), and levo-bupi vacaine (l = S).
43, 44
Stereoi somers
of local anestheti cs appear to have potenti al l y di fferent effects on anestheti c potency,
pharmacokineti cs, and systemi c toxi city.
19, 43, 44
For exampl e, R i somers appear to have greater in
vi tro potency for bl ock of both neural and cardiac sodi um channel s and may thus have greater
therapeutic efficacy and potenti al systemi c toxi ci ty.
18, 43, 44, 45

Rel ati ve i n vi tro potencies of the cl i ni cal ly used l ocal anestheti cs have been i denti fied and vary
dependi ng on i ndi vi dual nerve fibers and frequency of sti mulation, and overal l i ncreasi ng l i pid
solubi li ty of l ocal anestheti c correlates with i ncreasi ng anestheti c potency (see Tabl e 17-2).
46

However, cl i ni cal use of local anestheti cs i s complex and i n vi vo potenci es often do not correl ate
with in vi tro determi nants.
47
Local factors affecti ng diffusi on and spread of anestheti c wi l l have
great i mpact on cl i ni cal effects and wi l l vary wi th di fferent appl i cations (e.g., peripheral nerve
bl ock vs. spi nal injecti on). Furthermore, cl i ni cal use may not require absolute suppressi on of the
compound action potenti al , but rather a disruption of informati on codi ng i n the pattern of
di scharges. Few rigorous studi es have been performed to evaluate relative cl i ni cal potenci es of
local anestheti cs, and commonl y accepted values are li sted in Tabl e 17-3.
TABLE 17-3 Relative Potency of Local Anesthetics for Different Clinical Applications
BUPIVACAINE CHLORO-
PROCAINE
LIDOCAINE MEPIVACAINE PRILOCAINE ROP
Peri pheral
nerve
3.6 N/A 1 2.6 0.8
Spinal 9.6 1 1 1 1
Epidural 4 0.5 1 1 1
N/A, not avail able.
Data from Camorci a M. Mi nimum l ocal anal gesic doses of ropi vacai ne, l evobupi vacai ne, and bupi vacai n
intrathecal labor anal gesi a. Anesthesi ology 2005:102:646. Faccenda KA. A comparison of l evobupi vaca
and racemi c bupi vacai ne 0.5% for extradural anesthesi a for caesarean secti on. Reg Anesth Pai n Med
Tachyphyl axi s t o Local Anest het i cs
Tachyphyl axis to l ocal anesthetics i s a cl ini cal phenomenon whereby repeated i njecti on of the
same dose of local anestheti c l eads to decreasi ng effi cacy. Tachyphyl axis has been described after
central neuraxi al blocks, peripheral nerve bl ocks, and for different local anestheti cs.
48, 49
An
interesti ng cl inical feature of tachyphylaxi s to l ocal anestheti cs i s dependence on dosi ng interval.
If dosi ng i nterval s are short enough such that pai n does not occur, tachyphyl axi s does not
develop. Conversely, l onger periods of pati ent di scomfort before redosi ng hasten devel opment of
tachyphylaxis.
48
Both pharmacoki netic and dynami c mechani sms may be involved. A study
exami ni ng repeated sci ati c nerve bl ocks and i nfi l tration anal gesia i n rats noted tachyphyl axi s
accompani ed by i ncreased cl earance of radi ol abel ed l idocai ne out of nerves and skin.
50
Not all
studi es support a pharmacoki neti c mechani sm for tachyphyl axi s. For exampl e, wi th the
development of cl i ni cal tachyphyl axis, there i s no di fference in l ocal anesthetic spread withi n or
cl earance from the epi dural space.
51

The observati on that pai n is i mportant for the devel opment of tachyphyl axis has l ed to specul ati on
that there is a pharmacodynamic mechani sm for tachyphylaxi s vi a spi nal cord sensi ti zati on.
52
Rats
recei vi ng repeated sci atic nerve blocks fail ed to devel op tachyphyl axi s i n the absence of noxi ous
stimul ati on. Exposure of the rats to i ncreasingl y noxi ous degrees of thermal sti mulati on
increasi ngl y hastened development of tachyphyl axis, whereas pretreatment wi th an NMDA
antagonist (MK-801) that prevents spi nal cord sensi tizati on al so prevented development of
tachyphyl axi s. Second-messenger effects of ni tri c oxide for NMDA pathways may be especi al l y
important, as admi ni strati on of ni tri c oxide synthetase i nhibi tors prevented devel opment of
tachyphyl axi s i n a

dose-dependent manner in the same model.
53
The cl inical rel evance of these fi ndi ngs needs to be
explored, but the devel opment of a mechanism for tachyphyl axis may l ead to cl i ni cal means for i ts
preventi on.
Addi t i ves t o I ncr ease Local Anest het i c Act i vi t y
Epinephrine
Epi nephri ne has been added to local anestheti cs si nce the early 1890s. Reported benefi ts of
epi nephri ne incl ude prolongation of local anestheti c bl ock, increased i ntensi ty of bl ock, and
decreased systemi c absorption of local anestheti c.
54
Epi nephri ne' s vasoconstri cti ve effects
augment l ocal anestheti cs by antagoni zi ng i nherent vasodi lating effects of l ocal anestheti cs,
decreasing systemic absorpti on and intraneural cl earance, and perhaps by redi stri buting
intraneural l ocal anestheti c.
54, 55

Direct anal gesi c effects from epi nephri ne may also occur vi a interacti on wi th -2 adrenergic
2003;28:394. McDonal d SB. Hyperbari c spi nal ropi vacai ne: a comparison to bupi vacai ne i n vol unteers.
Anesthesi ol ogy 1999:90:971. Marsan A. Pril ocai ne or mepi vacaine for combi ned sci ati c-femoral nerve
patients recei vi ng electi ve knee arthroscopy. Mi nerva Anestesi ol 2004;70:763. Casati A. Li docai ne ver
ropivacai ne for conti nuous interscalene brachi al pl exus blockafter open shoul der surgery. Acta Anaesth
Scand 2003;47:35. Casati A. A double-bl i nd study of axi ll ary brachi al pl exus bl ock by 0.75% ropi vacai
mepivacaine. Eur J Anaesthesi ol 1998;15:549. Fanel l i G. A doubl e-bl i nd compari son of ropi vacai ne, bu
and mepi vacai ne duri ng sci ati c and femoral nerve bl ockade. Anesth Anal g, 1998;87:597. Yoos JR. Spi n
chloroprocai ne: a compari son wi th small -dose bupi vacai ne i n volunteers. Anesth Analg 2005 Feb;100:5
ME. Spi nal 2-chloroprocai ne: a compari son with li docai ne i n vol unteers. Anesth Analg 2004 Jan:98:75.
P.459
receptors i n the brain and spi nal cord,
56
especi al l y because l ocal anestheti cs i ncrease the vascul ar
uptake of epinephrine.
57
Cl ini cal use of epinephrine i s li sted i n Tabl e 17-4. The smal lest dose is
suggested, as epi nephri ne combi ned with l ocal anesthetics may have toxi c effects on ti ssue,
58
the
cardi ovascul ar system,
59
peri pheral nerves, and the spi nal cord.
33, 54

TABLE 17-4 Effects of Addition of Epinephrine to Local Anesthetics
INCREASE
DURATION
DECREASE
BLOOD LEVELS
(%)
DOSE/CONCENTRATION OF
EPINEPHRINE
NERVE BLOCK
Bupi vacai ne +- 1020 1:200,000
Li docai ne ++ 2030 1:200,000
Mepi vacai ne ++ 2030 1:200,000
Ropi vacaine -- 0 1:200,000
EPIDURAL
Bupi vacai ne +- 1020 1:300,0001:200,000
L-bupi vacai ne +- 10 1:200,000400,000
Chl oroprocai ne ++ 1:200,000
Li docai ne ++ 2030 1,600,0001:200,000
Mepi vacai ne ++ 2030 1:200,000
Ropi vacaine -- 0 1:200,000
SPINAL
Bupi vacai ne +- 0.2 mg
Li docai ne ++ 0.2 mg
Tetracai ne ++ 0.2 mg
Alkalinization of Local Anesthetic Solution
Since the late 1800s, l ocal anestheti c sol utions have been al kal inized i n order to hasten onset of
neural bl ock.
60
The pH of commerci al preparati ons of local anestheti cs ranges from 3.9 to 6.47 and
is especi all y acidi c i f prepackaged wi th epinephrine.
61

As the pK
a
of commonl y used l ocal anestheti cs ranges from 7.6 to 8.9 (see Tabl e 17-2), l ess than
3% of the commerci al l y prepared l ocal anesthetic exi sts as the li pi d-solubl e neutral form. As
previ ously discussed, the neutral form is beli eved to be the most important for penetration into
the neural cytoplasm, whereas the charged form pri maril y interacts wi th the l ocal anestheti c
receptor wi thin the sodium channel . Therefore, the rati onale for alkal i ni zati on was to increase the
percentage of l ocal anestheti c exi sting as the l ipi d-solubl e neutral form. However, cl ini cal ly used
local anestheti cs cannot be al kal i ni zed beyond a pH of 6.05 to 8 before precipi tati on occurs,
61
and
such pHs wi l l only i ncrease the neutral form to about 10%.
Cli nical studi es that have shown an associ ati on between al kal inizati on of l ocal anesthetics and
hasteni ng of block onset have shown a decrease of l ess than 5 mi nutes when compared to
commercial preparations.
60, 62
In addi tion, a recent ani mal study suggests that al kal inizati on of
li docaine decreases the durati on of peri pheral nerve bl ocks i f the sol ution does not al so contain
epi nephri ne.
63
Overall , the value of al kal inizati on of l ocal anesthetics appears debatabl e as a
cl i ni cal ly useful tool to i mprove anesthesia.
Opioids
Additi on of opi oids to local anestheti cs has gai ned populari ty. Opi oids have multi ple central
neuraxial and peripheral mechani sms of analgesic action. Supraspi nal admini stration of opi oi ds
resul ts i n anal gesia vi a opiate receptors i n multi ple si tes,
64
vi a activation of descendi ng spi nal
pathways
65
and vi a activati on of nonopi oi d anal gesi c pathways.
66
Spinal administrati on of opi oi ds
provi des anal gesi a pri maril y by attenuati ng C fi ber noci cepti on
67
and i s i ndependent of supraspi nal
mechanisms.
68
Coadministration of opi oids wi th central neuraxi al local anestheti cs resul ts i n
synergi sti c anal gesia.
69
An excepti on to thi s analgesi c synergy i s 2-chloroprocai ne, whi ch appears
to decrease the effecti veness of epidural opi oids when used for epi dural anesthesia.
70
The
mechani sm for this acti on i s uncl ear but does not appear to i nvol ve di rect antagoni sm of opioi d
receptors.
71
Overall , cl ini cal studies support the practice of central neuraxial coadmi ni strati on of
local anestheti cs and opi oids i n humans for prol ongati on and intensi fi cati on of analgesi a and
anesthesia.
69

The di scovery of peri pheral opi oi d receptors offers yet another ci rcumstance i n whi ch the
coadmini stration of local anestheti cs and opioids may be useful.
72
The most promi si ng cl i ni cal
resul ts have been from i ntra-arti cul ar admi ni strati on of l ocal anestheti c and opi oid for
postoperative anal gesia,
73
whereas combi ning l ocal anesthetics and opioi ds for nerve bl ocks
++, overal l supported; --, overal l not supported; +-, inconsi stent.
Data from Liu SS. Local Anestheti cs and Anal gesi a. In, Ashburn MA, Ri ce LJ (eds): The
Management of Pai n. New York: Churchi ll Li vi ngstone Inc., 1997:141170 and Kopacz
DJ. A comparison of epi dural l evobupi vacai ne 0.5% with or wi thout epinephrine for
lumbar spi ne surgery. Anesth Analg 2001;93:755.
P.460
appears to be i neffecti ve.
74
There are several reasons for a predicted lack of effect of
coadmini stration of local anestheti c and opi oi d for peri pheral nerve blocks. Anatomical l y,
peri pheral opioid receptors are found pri maril y at the end termi nal s of afferent fibers.
75
However,
peri pheral nerves are commonl y bl ocked by deposi ti on of anestheti c proxi mal to the end terminals
of nerve fi bers. In addi ti on, common sites for peri pheral nerve bl ocks are encased i n mul tipl e
layers of connecti ve tissue that the anestheti cs must traverse before gai ni ng access to peri pheral
opi oi d receptors. Final l y, previ ous studi es have demonstrated the i mportance of concomitant l ocal
ti ssue infl ammation for anal gesic effecti veness of peri pheral opioi d receptors.
72
The mechanism for
the underl yi ng dependence on local i nflammati on i s specul ati ve and may i nvol ve upregulation or
acti vation of peri pheral opioi d receptors or looseni ng of intercel l ul ar junctions to al l ow passage
of opi oi ds to receptors. Lack of i nfl ammati on at the si te of a peri pheral nerve block may al so
reduce the effects of coadmi ni strati on of l ocal anestheti c and opi oid. All of these factors combi ne
to decrease the theoreti cal effecti veness of combi nati ons of l ocal anesthetics and opioi ds for
peri pheral nerve bl ocks. In summary, coadministration of opi oi ds and l ocal anestheti c in the
central neuraxi s appears to be an effecti ve, nontoxi c
33
means to improve acti vi ty of l ocal
anesthetic, whereas there i s li ttl e theoretical reason to expect the mi xture to enhance peri pheral
nerve block.
-2 Adrenergic Agonists
-2 adrenergic agonists can be a useful adjuvant to l ocal anestheti cs. -2 agoni sts, such as
cl oni dine, produce anal gesi a vi a supraspi nal and spinal adrenergi c receptors.
76
Clonidine also has
di rect i nhibi tory effects on peripheral nerve conducti on (A and C nerve fi bers).
77
Thus, addi tion of
cl oni dine may have multi ple routes of acti on dependi ng on type of appl icati on. Preli mi nary
evidence suggests that coadmini stration of an -2 agoni st and local anestheti c results i n central
neuraxial and peripheral nerve analgesi c synergy,
78
whereas systemi c (supraspi nal) effects are
addi ti ve.
79
Overall , cl ini cal tri al s i ndi cate that cl onidi ne enhances i ntrathecal and epi dural
anesthesia, peripheral nerve blocks,
80
and i ntravenous regi onal anesthesi a
81
wi thout evi dence for
neurotoxi ci ty.
33

PHARMACOKINETICS OF LOCAL ANESTHETICS
Clearance of l ocal anestheti c from neural ti ssue and from the body governs both durati on of effect
and potenti al toxici ty. Cl i ni cal effects of neural block from l ocal anesthetics are pri mari l y
dependent on l ocal factors as discussed in the Pharmacol ogy section. However, systemi c toxici ty is
pri mari l y dependent on bl ood l evel s of l ocal anesthetics. Resultant bl ood l evels after
administrati on of l ocal anestheti cs for neural bl ockade depend on absorpti on, di stri buti on, and
el i mi nation of local anestheti cs.
Syst emi c Absor pt i on
In general , l ocal anestheti cs wi th decreased systemi c absorpti on wi ll have a greater margin of
safety i n cl i ni cal use. The rate and extent of absorpti on wi l l depend on numerous factors, of whi ch
the most i mportant are the si te of i njecti on, the dose of l ocal anestheti c, the physi cochemical
properties of the l ocal anesthetic, and the additi on of epinephrine.
The rel ati ve amounts of fat and vascul ature surroundi ng the si te of local anestheti c i njection wil l
interact wi th the physicochemi cal properti es of the l ocal anesthetic to affect rate of systemi c
uptake. In general , areas wi th greater vascularity wil l have more rapi d and compl ete uptake as
compared to those wi th more fat, regardless of type of l ocal anesthetic. Thus, rates of absorption
from injecti on of l ocal anesthetic i nto vari ous sites general l y decrease i n the foll owing order:
intercostal > caudal > epi dural > brachi al pl exus > sci ati c/femoral (Tabl e 17-5).
82, 83

TABLE 17-5 Typical C
max
after Regional Anesthetics with Commonly Used Local
Anesthetics
LOCAL
ANESTHETIC
TECHNIQUE DOSE
(mg)
C
max
(mcg/mL)
T
max

(min)
TOXIC PLASMA
CONCENTRATION
(mcg/mL)
Bupi vacai ne Brachi al
pl exus
150 1.0 20 3
Celiac plexus 100 1.50 17
Epidural 150 1.26 20
Intercostal 140 0.90 30
Lumbar
sympatheti c
52.5 0.49 24
Sci ati c
femoral
400 1.89 15
L-
bupi vacaine
Epidural 75 0.36 50 4
Brachi al
pl exus
250 1.2 55
Li docai ne Brachi al
pl exus
400 4.00 25 5
Mepi vacai ne Brachi al
pl exus
500 3.68 24 5
Sci ati c
femoral
500 3.59 31
Ropi vacaine Brachi al 190 1.3 53 4
The greater the total dose of l ocal anestheti c injected, the greater the systemi c absorpti on and
peak bl ood l evel s (C
max
). Thi s rel ati onshi p i s nearl y l i near (Fi g. 17-8) and is rel ati vel y unaffected
by anestheti c concentrati on
84
and speed of i njecti on.
82, 83

Physi cochemi cal properti es of l ocal anesthetics wi ll affect systemi c absorpti on. In general, the
more potent agents wi th greater l i pi d sol ubi l i ty and protei n bi ndi ng wi l l resul t i n l ower systemi c
absorpti on and C
max
(Fi g. 17-9).
83
Increased bi ndi ng to neural and nonneural ti ssue probabl y
explai ns thi s observati on.
pl exus
C
max
, peak pl asma l evel s; T
max
, ti me unti l C
max
.
Data from Liu SS. Local Anestheti cs and Anal gesi a. In Ashburn MA, Ri ce LJ (eds): The
Management of Pai n. New York: Churchil l Li vi ngstone Inc., 1997:141170, Berri sford RG.
Pl asma concentrati ons of bupi vacai ne and i ts enantiomers during conti nuous extrapleural
intercostal nerve bl ock. Briti sh Journal of Anaesthesi a 70:201, 1993. Kopacz DJ. A
compari son of epi dural levobupivacai ne 0.5% wi th or without epi nephri ne forl umbar
spi ne surgery. Anesth Anal g 2001 Sep:93:755, and Crews JC. Levobupi vacai ne for
axi l lary brachi al plexus bl ock: a pharmacoki netic and cl i ni cal comparison i n patients with
normal renal functi on or renal disease. Anesth Anal g 2002;95:219.
FIGURE 17-8. Increasi ng doses of ropi vacaine used for wound i nfi l trati on result i n l i nearl y
increasing maximal plasma concentrations (C
max
). (Data from from Mul roy MF, Burgess FW,
Emanuelsson B-M: Ropivacaine 0.25% and 0.5%, but not 0.125%, provi de effecti ve wound
infi ltration anal gesia after outpati ent herni a repai r, but wi th sustai ned pl asma drug l evel s.
Reg Anesth Pai n Med 24:136, 1999.)
The effects of epi nephri ne have been previ ously di scussed. In bri ef, epi nephri ne can counteract
the inherent vasodi lating characteristics of most l ocal anestheti cs. The reducti on i n C
max
with
epi nephri ne is most effecti ve for the l ess l ipi d-solubl e,

less potent, shorter acting agents (see Tabl e 17-4), as i ncreased ti ssue bi ndi ng rather than local
bl ood fl ow may be a greater determi nant of absorption for the long-acti ng agents.
Di st r i but i on
After systemic absorpti on, l ocal anestheti cs are rapi dl y di stri buted to the body. Regi onal
di stri bution of local anestheti c wi l l depend on organ bl ood fl ow, the parti ti on coeffi ci ent of l ocal
anesthetic between compartments, and pl asma protei n bi ndi ng. The end organs of mai n concern
for toxi city are wi thin the cardi ovascul ar and the central nervous systems. Both are consi dered
members of the vessel -ri ch group and wi ll have l ocal anesthetic rapi dly di stri buted to them.
Despi te the hi gh bl ood perfusi on, regi onal bl ood and tissue l evel s of local anestheti cs wi thin these
organs wi ll not i ni tial ly correl ate wi th systemi c bl ood level s because of hysteresi s.
85
As regional,
rather than systemi c, pharmacoki netics govern subsequent pharmacodynamic effects, systemic
bl ood level s may not correlate wi th effects of local anestheti cs on end organs.
86
Regi onal
pharmacokineti cs of local anestheti cs for the heart and brain have not been full y del i neated; thus
the vol ume of di stri buti on at steady state (VDss) is often used to describe l ocal anestheti c
di stri bution (Tabl e 17-6). However, VDss descri bes the extent of total body di stri buti on and may
be inaccurate for speci fi c organ systems.
FIGURE 17-9. Fracti on of dose absorbed i nto the systemic ci rcul ati on over ti me from
epi dural injecti on of l idocai ne or bupi vacai ne. Bupi vacai ne i s a more l i pid sol ubl e, more
potent agent wi th l ess systemic absorpti on over ti me. (Adapted wi th permission from Tucker
GT, Mather LE: Properti es, absorpti on, and disposi tion of local anestheti c agents. In Cousi ns
MJ, Bri denbaugh PO [eds]: Neural Bl ockade i n Cli ni cal Anesthesi a and Management of Pain, p
55. Phi l adel phi a, Li ppi ncottRaven, 1998.)
P.461
TABLE 17-6 Pharmacokinetic Parameters of Clinically Used Local Anesthetics
LOCAL ANESTHETIC VDss (L/kg) CL (L/kg/hr) T1/2 (hr)

El i mi nat i on
Clearance (CL) of ami noester l ocal anesthetics i s pri mari l y dependent on pl asma cl earance by
chol i nesterases,
87
whereas ami noami de l ocal anesthetic cl earance i s dependent on cl earance by
the li ver.
88
Thus, hepati c extracti on, hepatic perfusi on, hepatic metabol i sm, and protei n bi ndi ng
(Tabl e 17-2) wil l primaril y determi ne the rate of cl earance of ami noami de local anestheti cs. In
general , l ocal anesthetics wi th hi gher rates of cl earance wi l l have a greater margin of safety.
83

Cl i ni cal P har macoki net i cs
The primary benefi t of knowl edge of the systemic pharmacoki neti cs of l ocal anesthetics i s the
abi li ty to predi ct C
max
after the agents are admi ni stered, thereby avoi di ng the admi nistrati on of
toxi c doses (Tabl es 17-5, 17-7, and 17-8). However, pharmacokineti cs are di ffi cul t to predi ct in
any given ci rcumstance as both physi cal and pathophysiol ogi c characteri sti cs wi ll affect the
i ndi vi dual pharmacoki netics. There i s some evi dence for i ncreased systemi c l evels of l ocal
anesthetics i n the very young and i n the el derl y owi ng to decreased cl earance and i ncreased
absorpti on,
83
whereas correlati on of resul tant systemi c bl ood level s between dose of local
anesthetic and pati ent wei ght i s often inconsi stent (Fi gure 17-10).
89
Effects of gender on cli nical
pharmacokineti cs of local anestheti cs have not been wel l defi ned,
90
al though pregnancy may
decrease cl earance.
83
Pathophysi ologi c states such as cardiac and hepatic di sease wi l l al ter
expected pharmacoki netic parameters (Tabl e 17-9), and lower doses of l ocal anesthetics shoul d be
Bupi vacai ne 1.02 0.41 3.5
Levo-bupi vacaine 0.78 0.32 2.6
Chl oroprocai ne 0.50 2.96 0.11
Etidocai ne 1.9 1.05 2.6
Li docai ne 1.3 0.85 1.6
Mepi vacai ne 1.2 0.67 1.9
Pri locai ne 2.73 2.03 1.6
Procai ne 0.93 5.62 0.14
Ropi vacaine 0.84 0.63 1.9
Data from Denson DD: Physi ol ogy and pharmacology of l ocal anestheti cs. In Si natra RS,
Hord AH, Ginsberg B, et al (eds): Acute Pai n. Mechanisms and Management, p 124. St.
Louis, Mosby Year Book, 1992 and Burm AG, van der Meer AD, van Kl eef JW, et al :
Pharmacokineti cs of the enanti omers of bupi vacai ne foll owing i ntravenous administration
of the racemate. Br J Cli n Pharmacol 38:125129, 1994.
P.462
used for these pati ents. As expected, renal di sease has little effect on pharmacoki netic parameters
of local anestheti cs (Tabl e 17-9). Fi nal ly, the ski l l of the anesthesi ol ogist shoul d be consi dered, as
a l arge dose of local anestheti c pl aced i n the correct location may have much less potenti al for
systemi c toxi city than a smal l dose i ncorrectl y i njected intravascul arl y. All of these factors shoul d
be consi dered when util i zi ng l ocal anestheti cs and mi ni mi zi ng systemi c toxi city, the commonl y
accepted maxi mal dosages (Tabl e 17-8) notwi thstandi ng.
TABLE 17-7 Relative Potency for Systemic Central Nervous System Toxicity by Local
Anesthetics and Ratio of Dosage Needed for Cardiovascular System: Central Nervous
System (CVS:CNS) Toxicity
AGENT RELATIVE POTENCY FOR CNS
TOXICITY
CVS:CNS
Bupi vacai ne 4.0 2.0
Levo-bupi vacaine 2.9 2.0
Chl oroprocai ne 0.3 3.7
Etidocai ne 2.0 4.4
Li docai ne 1.0 7.1
Mepi vacai ne 1.4 7.1
Pri locai ne 1.2 3.1
Procai ne 0.3 3.7
Ropi vacaine 2.9 2.0
Tetracai ne 2.0
Data from Liu SS. Local Anestheti cs and Anal gesi a. In Ashburn MA, Ri ce LJ, (eds): The
Management of Pai n. New York: Churchi ll Li vi ngstone Inc., 1997:141170. Groban L.
Central nervous system and cardi ac effects from long-acti ng ami de local anestheti c
toxi ci ty i n the i ntact ani mal model . Reg Anesth Pai n Med 2003 JanFeb; 28(1):311.
TABLE 17-8 Clinical Profile of Local Anesthetics
LOCAL
ANESTHETIC
CONCENTRATION
(%)
CLINICAL
USE
ONSET DURATION
(h)
RECOMMENDED
MAXIMUM
ESTERS
Benzocai ne Up to 20 Topi cal Fast 0.51 200
Chl oroprocai ne 1 Infi ltration Fast 0.51 800/1,000 +
epi nephri ne
2 Peri pheral
nerve block
Fast 0.51 800/1,000 +
epi nephri ne
23 Epidural
anesthesia
Fast 0.51 800/1,000 +
epi nephri ne
Cocaine 410 Topi cal Fast 0.51 150
Procai ne 10 Spi nal
anesthesia
Fast 0.51 1,000
Tetracai ne 2 Topi cal Fast 0.51 20
0.5 Spi nal
anesthesia
Fast 26 20
Adapted wi th permi ssi on from Covi no BG, Wil dsmi th JAW: Cl inical pharmacol ogy of l ocal anestheti c
agents.
In Cousins MJ, Bridenbaugh PO (eds): Neural bl ockade i n cl i ni cal anesthesia and management of
pai n, pp 97128. Phi l adephi a, Li ppincottRaven, 1998.
TABLE 17-9 Effects of Cardiac, Hepatic, and Renal Disease on Lidocaine
Pharmacokinetics
VD ss (L/Kg) CL (mL/kg/min) T1/2(hr)
Normal 1.32 10.0 1.8
Cardi ac fai l ure 0.88 6.3 1.9
Hepati c di sease 2.31 6.0 4.9
CLINICAL USE OF LOCAL ANESTHETICS
Local anesthetics are used i n a vari ety of ways i n cl ini cal anesthesi a practi ce. Probabl y the most
common cli ni cal use of local anestheti cs for anesthesiol ogi sts i s for regional anesthesi a and
anal gesi a. Central neuraxi al anesthesi a and anal gesi a can be accompli shed by epi dural or spi nal
injecti ons of local anestheti cs. Placement of epi dural and spi nal catheters can al l ow conti nuous
infusi on of l ocal anesthetics and other anal gesics for extended durati ons. Intravenous regional
anesthesi a and peri pheral nerve bl ocks al l ow for anesthesi a of the head and neck i ncluding the
ai rway, upper extremiti es, trunk, and l ower extremi ti es. Newly devel oped catheters for conti nuous
peri pheral nerve blocks can al so be placed to al low continuous i nfusions of l ocal anestheti cs and
other anal gesics for prolonged anal gesi a i n a fashi on si mi lar to continuous epidural analgesia.
Topi cal appl i cation of l ocal anesthetics to the ai rway, eye, and ski n provides suffi ci ent anesthesi a
for painl ess performance of minor anestheti c and surgical procedures such as tracheal i ntubation,
intravenous catheter pl acement, or dural puncture.
91
Typi cal appl i cations for each l ocal anesthetic
are li sted in Tabl e 17-8.
92

Other common cl inical uses for l ocal anestheti cs i ncl ude admini stration of li docai ne to blunt
Renal di sease 1.2 13.7 1.3
VDss, vol ume of di stributi on at steady state; CL, total body cl earance; T1/2, termi nal
el i mi nation hal f-li fe.
Data from Thomson PD. Lidocai ne pharmacoki netics i n advanced heart fai l ure, li ver
di sease, and renal fail ure i n humans. Ann Intern Med 1973;78:499.
FIGURE 17-10. Lack of correl ati on between pati ent wei ght and peak plasma concentrati on
after epidural admini stration of 150 mg of bupi vacai ne. (Data from Sharrock NE, Mather LE,
Go G, et al: Arteri al and pul monary concentrati ons of the enati omers of bupi vacai ne after
epi dural injecti on i n el derl y pati ents. Anesth Anal g 86:812, 1998.)
responses to tracheal i nstrumentati on and to suppress cardi ac dysrhythmi as. Intravenous or
topical administrations of li docai ne have been used with vari abl e success to blunt hemodynami c
response to tracheal i ntubation and extubati on.
93, 94
In addi tion to hemodynami c responses,
instrumentation of the ai rway can result i n coughi ng, bronchoconstri cti on, and other ai rway
responses. Intravenous li docai ne can be effecti ve for decreasi ng ai rway sensiti vi ty to
instrumentation by depressi ng ai rway reflexes and decreasi ng calci um fl ux in airway smooth
muscle.
95, 96
Doses of i ntravenous l i docaine from 2 to 2.5 mg/kg are needed to consi stentl y bl unt
hemodynamic and ai rway responses to tracheal instrumentation.
95, 96, 97
Intravenous l i docai ne is
al so effecti ve for attenuating i ncreases i n intra-ocul ar pressure, i ntracrani al pressure, and i ntra-
abdominal pressure during

ai rway instrumentati on.
98
Attenuati on of all these responses may be benefi cial in selected cl i ni cal
si tuati ons (e.g., corneal lacerati on or increased i ntracranial pressure). Intravenous l idocai ne has
well -recognized cardiac anti dysrhythmi c effects.
99

Fi nal ly, i ntravenous l i docaine (1 to 5 mg/kg) is an effecti ve anal gesic and has been used to treat
postoperative
100
and chronic neuropathi c pai n.
101
Peri pheral and central i nhi biti on of generati on
and propagation of spontaneous electri cal acti vi ty i n i njured C nerve fi bers and A nerve fi bers are
thought to be pri mary mechani sms as opposed to typi cal conducti on bl ock.
102, 103, 104
Posi tron
emissi on tomography i n patients with neuropathi c pai n suggests that al tered acti vi ty i n cerebral
bl ood flow to the thal amus
105
may al so contri bute to systemi c anal gesi c effects of l ocal
anesthetics. The abi l ity of local anestheti cs to provi de systemic anal gesic effects at central and
peri pheral sites may i n part expl ai n the abi l ity of a si ngl e neural bl ock to provi de l ong-lasti ng
anal gesi a from neuropathi c pain. In addi ti on, oral ly admi ni stered mexi l eti ne (a Cl ass I
anti dysrhythmic agent simi lar to l idocai ne) has been successful ly used to treat chroni c pain
condi ti ons.
101

TOXICITY OF LOCAL ANESTHETICS
Syst emi c Toxi ci t y of Local Anest het i cs
Central Nervous System Toxicity
Local anesthetics readi ly cross the bl ood-brain barrier, and general ized CNS toxici ty may occur
from systemi c absorption or

di rect vascul ar i njecti on. Signs of general ized CNS toxici ty because of l ocal anestheti cs are dose
dependent (Tabl e 17-10). Low doses produce CNS depressi on, and hi gher doses resul t i n CNS
exci tati on and seizures.
106
The rate of intravenous admi ni strati on of l ocal anestheti c wil l also
affect signs of CNS toxici ty, as hi gher rates of i nfusi on of the same dose wil l l essen the
appearance of CNS depressi on whil e l eaving exci tati on i ntact.
107
Thi s dichotomous reacti on to l ocal
anesthetics may be a resul t of a greater sensi tivity of corti cal i nhibi tory neurons to the impul se
bl ocking effects of local anestheti cs.
106, 108, 109

P.463
P.464
TABLE 17-10 Dose-Dependent Systemic Effects of Lidocaine
PLASMA CONCENTRATION (mcg/mL) EFFECT
15 Anal gesi a
510 Li ghtheadedness
Ti nni tus
Numbness of tongue
Local anesthetic potency for general ized CNS toxi ci ty approxi matel y paral l el s acti on potenti al
bl ocking potency (Tabl es 17-3 and 17-7).
106
In general , decreased l ocal anesthetic protei n bi nding
and cl earance wi l l increase potenti al CNS toxici ty. External factors can increase potency for CNS
toxi ci ty, such as aci dosi s and i ncreased PCO
2
, perhaps via i ncreased cerebral perfusi on or
decreased protei n bi ndi ng of l ocal anestheti c.
106
There are also external factors that can decrease
local anestheti c potency for general i zed CNS toxi ci ty. For example, sei zure threshol ds of local
anesthetics are i ncreased by admi nistration of barbiturates and benzodi azepi nes.
110

Additi on of vasoconstrictors such as epi nephri ne may reduce or promote the potenti al for
general ized local anestheti c CNS toxici ty. Addi ti on of epinephrine to l ocal anestheti cs wil l decrease
systemi c absorption and peak blood l evel s and i ncrease the safety margi n. On the other hand, the
convul si ve threshol d for i ntravenous admi ni strati on of l idocai ne i n the rat i s decreased by about
42% when epinephrine (1:100,000), norepi nephrine, or phenylephri ne i s added to the pl ai n
solution.
111
The mechanisms of i ncreased toxi ci ty wi th addi ti on of epi nephri ne are uncl ear but
appear to depend on the devel opment of hypertensi on from vasoconstri cti on. A hyperdynami c
ci rculatory system may enhance the toxi c effects of l ocal anesthetics by causi ng increased
cerebral bl ood fl ow and del i very of li docaine to the brain
112, 113
or through di srupti on of the blood-
brain barrier.
114
In additi on to enhanci ng di stri bution of local anestheti c to the brai n,
hyperdynami c circul atory changes can al so decrease cl earance of l ocal anesthetic from the body
because of changes i n di stri bution of blood flow away from the l i ver. Changes i n total body
cl earance from hyperdynamic ci rcul atory changes i nduced by local anestheti c seizures have been
studi ed i n dogs.
115
Seizures si gni fi cantl y increased heart rate, blood pressure, and cardi ac output
whi l e si gnifi cantly decreasi ng total body clearance (29 to 68%) of l idocai ne, mepivacaine,
bupi vacai ne, and eti docai ne.
Cli nical reports suggest toxici ty from l ocal anestheti cs used for regional anesthesi a is
uncommon. Surveys from France and the United States of over 280,000 cases of regi onal
anesthesia report an incidence of sei zures wi th epi dural i njection approximati ng 1/10,000 and an
inci dence of 7/10,000 with peri pheral nerve blocks.
108, 109
There appears to be a hi gher i nci dence
of local anestheti c toxici ty duri ng peri pheral nerve bl ocks, perhaps because of differences i n
practi ce or less cl i ni cal awareness. Nonetheless, epi dural anesthesi a (pri mari l y obstetri cal )
consti tuted all the cases of death or brai n damage resul ti ng from uni ntentional intravenous
injecti on of l ocal anesthetic i n an analysi s of closed malpracti ce cl aims in the Uni ted States from
1980 to 1999.
116

Cardiovascular Toxicity of Local Anesthetics
In general , much greater doses of l ocal anesthetics are requi red to produce cardi ovascul ar (CV)
toxi ci ty than CNS toxi city. Simi lar to CNS toxi ci ty, potency for CV toxi city refl ects the anestheti c
potency of the agent (Tabl es 17-3 and 17-7). Attention has focused on the apparently excepti onal
cardi otoxi ci ty of the more potent, more li pi d-solubl e agents (bupi vacai ne, l evo-bupi vacaine,
1015 Sei zures
Unconsci ousness
1525 Coma
Respi ratory arrest
>25 Cardi ovascul ar depressi on
ropivacai ne). These agents appear to have a di fferent sequence of CV toxici ty than l ess potent
agents, wi th bupi vacai ne bei ng the most cardi otoxi c. For exampl e, increasi ngl y toxi c doses of
li docaine l ead to hypotension, bradycardi a, and hypoxi a, whereas toxi c doses of bupi vacai ne, l evo-
bupi vacaine, and ropivacai ne often resul t i n sudden cardiovascular col lapse as a result of
ventri cul ar dysrhythmi as that are resi stant to resusci tation (Fi g. 17-11).
106, 110, 117

Use of the singleoptical isomer (S/L) preparations of ropi vacai ne and levo-bupi vacaine may
i mprove the safety profi l e for l ong-l asti ng regi onal anesthesi a. Both ropi vacai ne and

levo-bupi vacaine appear to be approxi matel y equi potent to racemi c bupi vacaine for epi dural and
pl exus anesthesi a (see Tabl e 17-3).
118, 119
Both ropi vacai ne and levo-bupi vacaine have
approxi mately 30 to 40% l ess systemi c toxi city than bupi vacai ne on a mg:mg basi s i n ani mal
studi es
46, 106
(Fi g. 17-12), al though human studi es are less dramatic (Fi g. 17-13).
120, 121
Reduced
potential for cardi otoxi ci ty i s l ikel y because of reduced affi ni ty for brai n and myocardial tissue
from their single isomer preparati on.
18, 45, 106
In addi tion to stereoselectivity, the larger butyl si de
chai n i n bupi vacai ne may also have more of a cardi odepressant effect as opposed to the propyl -
si de chain of ropi vacaine.
122

FIGURE 17-11. Success of resuscitati on of dogs after cardiovascular col lapse from
intravenous infusi ons of l idocai ne, bupi vacai ne, l evo-bupi vacaine, and ropivacai ne. Success
rates were greater for l idocai ne (100%), than ropi vacai ne (90%), than l evo-bupi vacaine
(70%), and than bupi vacai ne (50%). Required doses to induce cardi ovascul ar col l apse were
greater for l i docaine (127 mg/kg), than ropi vacai ne (42 mg/kg), than levo-bupi vacaine (27
mg/kg), and than bupi vacai ne (22 mg/kg). (Data from Groban L, Deal DD, Vernon JC, et al :
Cardi ac resusci tation after incremental overdosage wi th l i docaine, bupi vacai ne,
levobupi vacai ne, and ropi vacai ne i n anesthetized dogs. Anesth Anal g 92:37, 2001.)
P.465
FIGURE 17-12. Serum concentrati ons in sheep at each toxi c mani festation for bupivacai ne,
levo-bupi vacaine, and ropi vacai ne i n sheep. Both l evo-bupi vacaine and ropi vacai ne requi red
si gni fi cantl y greater serum concentrati ons than bupivacai ne. (Data from Santos AC, DeArmas
PI: Systemi c toxi ci ty of l evobupi vacai ne, bupi vacai ne, and ropi vacai ne duri ng conti nuous
intravenous i nfusi on to nonpregnant and pregnant ewes. Anesthesi ology 95:1256, 2001.)
FIGURE 17-13. Mil d prol ongati on i n QRS i nterval and reducti on i n cardi ac output are
observed after intravenous i nfusions of bupi vacaine (103 mg), l evobupivacaine (37 mg), and
ropivacai ne (115 mg) in heal thy vol unteers. Data from: Knudsen K, Beckman Suurkul a M, et
al . Central nervous and cardiovascular effects of i.v. i nfusions of ropi vacai ne, bupi vacai ne
and placebo i n volunteers. Br Anaesth 1997:78:507. Stewart J, Kell ett N, Castro D. The
central nervous system and cardiovascular effects of l evobupi vacai ne and ropi vacai ne i n
heal thy volunteers. Anesth Analg 2003:97:412.
Cardiovascular Toxicity Mediated at the CNS. It has been demonstrated that the central and
peri pheral nervous systems may be i nvol ved i n the increased cardi otoxi ci ty wi th bupivacaine. The
nucl eus tractus soli tari i in the medul la i s an i mportant regi on for autonomi c control of the
cardi ovascul ar system. Neural acti vi ty i n the nucl eus tractus sol itari i of rats is markedl y
di minished by i ntravenous doses of bupivacaine immedi atel y pri or to devel opment of hypotensi on.
Furthermore, di rect intracerebral injecti on of bupivacaine can el i ci t sudden dysrhythmias and
cardi ovascul ar coll apse.
123

Peri pheral effects of bupi vacai ne on the autonomi c and vasomotor systems may al so augment i ts
CV toxici ty. Bupivacaine possesses a potent peri pheral i nhi bi tory effect on sympatheti c refl exes
123

that has been observed even at blood concentrati ons si mi l ar to those measured after
uncompl icated regi onal anesthesi a.
124
Fi nal l y, bupi vacai ne al so has potent di rect vasodi l ati ng
properties, whi ch may exacerbate cardiovascular col lapse.
125

Cardiovascular Toxicity Mediated at the Heart. The more potent l ocal anestheti cs appear to
possess greater potenti al for direct cardi ac el ectrophysiol ogi c toxi city.
45, 106
Al though al l local
anesthetics bl ock the cardi ac conducti on system vi a a dose-dependent bl ock of sodium channel s,
two features of bupi vacaine' s sodium channel bl ocki ng abi l iti es may enhance its cardi otoxici ty.
Fi rst, bupi vacai ne exhi bi ts a much stronger bi ndi ng affinity to resti ng and i nacti vated sodi um
channel s than l idocai ne.
126
Second, local anestheti cs bi nd to sodi um channels duri ng systol e and
di ssociate during diastol e (Fi g. 17-14). Bupi vacai ne di ssociates from sodium channel s duri ng
cardi ac diastole much more sl owly than l i docai ne. Indeed, bupi vacai ne di ssociates so sl owl y that
the durati on of di astol e at physi ol ogi c heart rates (60 to 180 bpm) does not al low enough ti me for
compl ete recovery of sodi um channel s and bupivacaine conducti on bl ock accumul ates. In contrast,
li docaine full y dissoci ates from sodi um channel s during di astol e and l i ttl e accumul ati on of
conducti on bl ock occurs (Fi g. 17-15).
126, 127
Thus, enhanced el ectrophysiologi c effects of more
potent l ocal anesthetics on the cardiac conducti on system may expl ai n their i ncreased potenti al to
produce sudden cardi ovascul ar coll apse via cardi ac dysrhythmi as.
FIGURE 17-14. Di agram i ll ustrating rel ati onshi p between cardi ac acti on potenti al (top),
sodium channel state (middle), and bl ock of sodi um channel s by bupi vacai ne (bottom). R =
resti ng, O = open, and I = inactive forms of the sodi um channel . Sodi um channel s are
predomi nantly i n the resting form duri ng di astole, open transientl y duri ng the acti on
potential upstroke, and are i n the i nacti ve form during the acti on potenti al pl ateau. Block of
sodi um channel s by bupivacai ne accumul ates during the acti on potenti al (systol e) with
recovery occurri ng duri ng diastol e. Recovery of sodi um channels i s from di ssoci ati on of
bupi vacai ne and i s ti me dependent. Recovery duri ng each di astoli c i nterval i s incomplete and

Increased potency for di rect myocardi al depressi on from the more potent l ocal anestheti cs i s
another contributi ng factor to i ncreased cardiotoxi city (Fi g. 17-16).
106, 122
Agai n, multi ple
mechani sms may account for the i ncreased potency for myocardi al depressi on from more potent
local anestheti cs. Bupi vacai ne, the most compl etel y studi ed potent local anestheti c, possesses a
hi gh affi nity for sodi um channels in the cardi ac myocyte.
18, 45, 106
Furthermore, bupivacai ne i nhi bits
myocyte rel ease and uti l izati on of cal ci um
128
and reduces mi tochondri al energy metabol i sm,
especi al l y during hypoxia.
129
Thus, multi ple di rect effects of bupi vacai ne on acti vi ty of the cardi ac
myocyte may expl ai n the cardiotoxi city of bupivacai ne and other potent l ocal anestheti cs.
resul ts i n accumul ati on of sodi um channel bl ock wi th successi ve heartbeats. (Adapted wi th
permi ssi on from Clarkson CW, Hondegham LM: Mechani sms for bupi vacai ne depressi on of
cardi ac conducti on: Fast block of sodi um channels duri ng the acti on potenti al wi th sl ow
recovery from bl ock duri ng di astol e. Anesthesi ol ogy 62:396, 1985.)
FIGURE 17-15. Heart rate dependent effects of l i docaine and bupi vacai ne on velocity of the
cardi ac acti on potenti al (V
max
). Bupi vacai ne progressi vel y decreases V
max
at heart rates above
10 bpm because of accumul ati on of sodi um channel bl ock, whereas l i docaine does not
decrease V
max
unti l heart rate exceeds 150 bpm. (Adapted with permission from Clarkson CW,
Hondegham LM: Mechanisms for bupi vacai ne depressi on of cardi ac conducti on: Fast block of
sodium channel s during the acti on potenti al with sl ow recovery from bl ock duri ng di astol e.
P.466
Tr eat ment of Syst emi c Toxi ci t y f r om Local Anest het i cs
The best method for avoiding systemic toxicity from local anestheti cs is through preventi on.
Toxi c systemic l evel s can occur by unintenti onal intravenous or i ntra-arterial i njecti on or by
systemi c absorption of excessi ve doses pl aced i n the correct area. Uni ntenti onal i ntravascul ar and
intra-arterial i njecti ons can be minimi zed by frequent syri nge aspirati on for blood, use of a small
test dose of l ocal anesthetic (~3 mL) to test for subjecti ve systemi c effects from the patient (e.g.,
ti nnitus, ci rcumoral numbness), and ei ther sl ow injecti on or fracti onati on of the rest of the dose of
local anestheti c.
110
Detai led knowl edge of local anestheti c pharmacoki neti cs wi l l al so ai d i n
reduci ng the administration of excessi ve doses of l ocal anestheti cs. Ideal l y, heart rate, blood
pressure, and the el ectrocardi ogram shoul d be monitored duri ng administrati on of l arge doses
local anestheti cs. Pretreatment wi th a benzodi azepine may al so l ower the probabl i li ty of sei zure by
raisi ng the sei zure threshhol d.
Treatment of systemi c toxici ty is pri mari l y supporti ve. Injection of l ocal anesthetic shoul d be
stopped. Oxygenati on and ventil ati on shoul d be maintai ned, as systemic toxici ty of l ocal
anesthetics i s enhanced by hypoxemia, hypercarbia, and aci dosi s.
110
If needed, the pati ent's
trachea shoul d be i ntubated and posi tive pressure venti lation insti tuted. As previ ousl y di scussed,
si gns of CNS toxi ci ty wil l typi call y occur pri or to CV events. Sei zures can i ncrease body
metabol i sm and cause hypoxemi a, hypercarbi a, and aci dosi s. Pharmacol ogic treatment to
termi nate sei zures may be needed i f oxygenati on and venti l ati on cannot be mai ntai ned.
Intravenous admini stration of thiopental (50 to 100 mg), midazolam (2 to 5 mg), and propofol (1
mg/kg) can termi nate sei zures from systemic l ocal anestheti c toxi ci ty. Succinyl chol i ne (50 mg)
can termi nate muscul ar acti vi ty from seizures and faci l itate ventil ati on and oxygenati on. However,
succi nyl choli ne wi ll not termi nate sei zure

acti vi ty i n the CNS, and increased cerebral metabol ic demands wil l conti nue unabated.
Cardi ovascul ar depression from less potent l ocal anesthetics (e.g., li docai ne) i s usuall y mi ld and
caused by mi l d myocardi al depressi on and vasodi l ati on. Hypotensi on and bradycardia can usual l y
be treated wi th ephedri ne (10 to 30 mg) and atropine (0.4 mg). As previ ousl y discussed, potent
local anestheti cs (e.g., bupivacaine) can produce profound CV depressi on and mal i gnant
FIGURE 17-16. Pl asma concentrati ons requi red to i nduce myocardi al depressi on i n dogs
administered bupivacai ne, levo-bupi vacaine, ropi vacai ne, and l i docai ne. dP/dtmax = 35%
reduction of inotropy from basel ine measure. %EF = 35% reducti on i n ejection fraction from
baseli ne measure. CO = 25% reducti on i n cardi ac output from baseli ne measure. (Data from
Groban L, Deal DD, Vernon JC, et al : Does l ocal anestheti c stereosel ecti vi ty or structure
predi ct myocardi al depressi on i n anestheti zed cani nes? Reg Anesth Pai n Med 27:460, 2002.)
P.467
dysrhythmias that should be promptl y treated. Oxygenation and venti l ati on must be immediately
insti tuted, wi th cardiopul monary resusci tation if needed. Ventri cul ar dysrhythmi as may be di ffi cul t
to treat and may need l arge and multi ple doses of el ectri cal cardioversi on, epi nephri ne,
vasopressi n, and ami odarone. The use of calci um channel bl ockers in thi s setting i s not
recommended, as i ts cardi odepressant effect i s exaggerated.
110
A novel and promi si ng treatment
for cardi ac toxi city i s the admi ni strati on of i ntravenous li pi d to theoreti cal ly remove bupi vacai ne
from si tes of acti on. Admi ni stration of a 20% li pi d sol uti on at a dose of 4 mL/kg foll owed by a 0.5
mL/kg/mi n i nfusi on for 10 mi nutes al l owed for the resusci tati on of 100% of dogs wi th i nduced
bupi vacaine cardi otoxici ty at a dose of 10mg/kg.
130
None of the dogs gi ven an equi val ent vol ume
of crystal loi d were rescusci tated i n thi s study. These fi ndi ngs rai se the question of whether
propofol i n a 10% l i pi d soluti on would be a preferred treatment for cardiac toxi city. Propofol has
been reported to termi nate bupi vacai ne-i nduced sei zures and cardi ac depressi on i n pati ents.
130

However, the dose of l i pid i n a standard i nducti on dose of propofol (2 mg/kg) woul d be onl y 3% of
the dose used i n the aforementi oned ani mal experi ment. As effects of l i pi d on cardi ac toxi ci ty are
dose rel ated, further i nformation is needed pri or to reaching concl usi ons on cl i ni cal use of propofol
for l ocal anestheticinduced cardiac toxi city.
Neur al Toxi ci t y of Local Anest het i cs
In addi tion to systemic toxi ci ty, l ocal anestheti cs can cause injury to the central and peripheral
nervous system from di rect exposure. Mechanisms for l ocal anesthetic neurotoxici ty remai n
specul ati ve, but previ ous studi es have demonstrated l ocal anestheticinduced i njury to Schwann
cel ls, inhi bi ti on of fast axonal transport, di srupti on of the bl ood-nerve barri er, decreased neural
bl ood flow wi th associ ated i schemi a, and di sruption of cel l membrane i ntegri ty via a detergent
property of l ocal anestheti cs.
131, 132
Al though al l cl i ni cal ly used l ocal anestheti cs can cause
concentration-dependent nerve fi ber damage i n peri pheral nerves when used in high enough
concentrations, previ ous studi es have demonstrated that l ocal anesthetics i n cl inicall y used
concentrations are general ly safe for peri pheral nerves.
133
The spi nal cord and the nerve roots, on
the other hand, are more prone to injury.
Spinal cord toxici ty of l ocal anesthetics has been assessed by admini stration of local anestheti cs
to rabbi ts via i ntrathecal catheters. These studi es suggest that bupivacai ne (2%), l idocai ne (8%),
and tetracai ne (1%) cause hi stopathol ogi c changes and neurol ogi c defi ci ts. On the other hand,
cl i ni cal ly rel evant concentrati ons of these agents, chl oroprocai ne and ropivacaine (2%), did not
di srupt spi nal cord histol ogy or cause nerurol ogi cal defi cits.
134
Desheathed peri pheral nerve
model s, desi gned to mi mi c unprotected nerve roots i n the cauda equina, have been used to further
assess el ectrophysi ol ogic neurotoxici ty of l ocal anesthetics.
135, 136, 137
Li docai ne 5% and tetracai ne
0.5% caused i rreversi ble conducti on bl ock i n these models, whereas l idocai ne 1.5%, bupi vacaine
0.75%, and tetracai ne 0.06% did not. El ectrophysiologi c toxi ci ty of l i docaine i n i sol ated nerve
preparati ons represented by i ncomplete recovery of neuromuscular functi on occurs at 40 mM
(~1%) (Fi g. 17-17), with irreversibl e abl ation of the compound acti on potenti al seen at 80 mM
(~2%). Al though such studi es do not refl ect i n vivo condi tions, they suggest that l i docai ne and
tetracai ne may be especi al l y neurotoxi c in a concentrati on-dependent fashi on and that
neurotoxi ci ty could theoreti cal l y occur with cl i ni cal l y used soluti ons. Local anestheti c effects on
spi nal cord bl ood fl ow, another possi bl e eti ology of neurotoxici ty from di rect drug exposure,
appear beni gn. Spi nal admi ni stration of bupi vacai ne, l i docaine, mepi vacai ne, and tetracai ne cause
vasodil ati on and i ncrease spinal cord bl ood fl ow, whereas ropivacai ne causes vasoconstriction and
reduction in spinal cord bl ood fl ow i n a concentrati on-dependent fashi on.
138

Neurohi stopathol ogi c data i n humans after intrathecal exposure to local anestheti cs is not
avai labl e. El ectrophysiol ogi c parameters such as somatosensory evoked potenti al s, monosynapti c
H-refl ex,
139
and cutaneous current perception thresholds
140
have been used to eval uate recovery
after spi nal anesthesi a. These measurements have shown compl ete return to basel ine acti vi ty
after 5% li docai ne spi nal anesthesi a i n very small study populations. Prospective surveys of over
80,000 spi nal anestheti cs report an i ncidence of 0 to 0.02% l ong-term neurol ogi c i njury in
patients undergoi ng spi nal anesthesi a.
109
Thus, spi nal ly admi ni stered local anestheti cs have not
notably mani fested cl i ni cal neurotoxi ci ty.
Tr ansi ent Neur ol ogi c Sympt oms af t er Spi nal Anest hesi a
Prospecti ve, randomi zed studi es reveal a 4 to 40% i nci dence of transient neurol ogic symptoms
(TNS), i ncluding pain or sensory abnormal iti es in the l ower back, buttocks, or lower extremiti es,
after li docai ne spinal anesthesi a.
139
These symptoms have been reported wi th other local
anesthetics as well (Tabl e 17-11). Increased risk of TNS is associ ated with li docai ne, the li thotomy
positi on, and ambul atory anesthesia, but not wi th bari ci ty of soluti on or dose of l ocal
anesthetic.
139
The potenti al neurologi cal eti ology of thi s syndrome coupl ed wi th known
concentration-dependent toxi city of li docai ne l ed to concerns over a neurotoxi c eti ology for TNS
from spi nal l idocai ne.
FIGURE 17-17. The nonreversibl e effect of 40 mM l i docaine on the compound action
potential (CAP) of frog sci ati c nerve. Li docaine was appl i ed to a stabl e nerve preparati on for
15 mi nutes and then washed with frog Ri nger' s sol uti on for 2 hours. Tracings represent CAPs
in response to stimul us (1-Hz stimul us = heavy li ne; 40-Hz sti mulus = thi n li ne). 40 mM
li docaine completely ablated the CAP when appl i ed to the nerve. The 1-Hz CAP response
began to return after 10 to 15 mi nutes of washi ng and reached a new l evel in 45 minutes,
where it was stable for the subsequent 2 hours of observati on. The recovered 1-Hz CAP is
only 65% of the ori ginal. (Adapted wi th permission from Bainton C: Concentrati on
dependence of l idocai ne-induced i rreversi ble conduction loss frog nerve. Anesthesi ology
81:657, 1994.)
TABLE 17-11 Incidences of Transient Neurological Symptoms (TNS) Vary with Type of
Spinal Local Anesthetic and Surgery
LOCAL
ANESTHETIC
CONCENTRATION
(%)
TYPE OF
SURGERY
APPROXIMATE
INCIDENCE OF TNS
As previ ously discussed, l aboratory work i n both i ntrathecal and desheathed peri pheral nerve
model s has proved that

the concentration of l idocai ne i s a cri ti cal factor i n neurotoxi ci ty. As concentrati ons of l i docai ne
bel ow 40 mM (~1.0%) are not neurotoxi c to desheathed peri pheral nerve, such di l ute
concentrations of spi nal li docai ne shoul d not cause TNS if the syndrome i s a resul t of subcl i ni cal
concentration-dependent neurotoxi city. The dil uti on of l i docai ne to as low as 0.5%, however, does
not decrease the incidence of TNS.
141
The hi gh i nci dence of TNS observed wi th l idocai ne
concentrations <1% despi te further dil uti on i n cerebrospi nal fl ui d l essens the pl ausi bi li ty of a
concentration-dependent neurotoxi c eti ology. Furthermore, a vol unteer study compari ng
individual s wi th and wi thout TNS symptoms after l idocai ne spi nal anesthesi a showed no di fference
detected by electromyography, nerve conducti on studies, or somatosensory evoked potenti al s.
(%)
Li docai ne 25 Lithotomy
positi on
3036
25 Knee
arthroscopy
1822
0.5 Knee
arthroscopy
17
25 Mi xed supi ne
positi on
48
Mepi vacai ne 1.54 Mi xed 23
Procai ne 10 Knee
arthroscopy
6
Bupi vacai ne 0.50.75 Mi xed 1
Levo-
bupi vacaine
0.5 Mi xed 1
Pri locai ne 25 Mi xed 1
Ropi vacaine 0.50.75 Mi xed 1
Data from: Pol lock JE. Transient neurologic symptoms: eti ol ogy, ri sk factors, and
management. Reg Anesth Pai n Med 2002;27:581 and Breebaart MB. Uri nary bl adder
scanni ng after day-case arthroscopy under spinal anaesthesi a: compari son between
li docaine, ripovacai ne, and levobupivacai ne. Br J Anaesth 2003;90:309.
P.468
Overal l , there is l i ttl e evi dence to support a neurotoxic eti ol ogy for TNS.
139
Other potenti al
eti ol ogi es for TNS include pati ent posi ti oni ng, sci ati c nerve stretch, muscl e spasm, and myofasci al
strai n.
139

Interest i n findi ng a short-acti ng spi nal anestheti c wi th a l esser incidence of TNS has served as an
impetus for i nvestigations i nto the use of 2-chloroprocai ne as a spinal anesthetic. Preli mi nary
studi es show that preservative-free 2-chloroprocai ne provi des an anestheti c profi le si mi l ar to
li docaine wi thout report of TNS, whi ch would make 2-chloroprocai ne potential ly useful for
outpati ent procedures (Tabl e 17-12). Enthusiasm for spi nal 2-chloroprocai ne should be tempered
by the potenti al for neurotoxi ci ty. In a laboratory study, 2-chloroprocai ne (14 mg/kg)
administered to rats vi a intrathecal catheter was noted to be hi stologi call y neurotoxi c to the spinal
cord to the same degree as 2.5% l idocai ne. Thi s fi ndi ng call s i nto questi on the long held beli ef
that the anti oxidant sodi um bi sul fi te i s to bl ame for 2-chloroprocai ne' s cli nical neurotoxi ci ty.
142

The cli nical appl icabil i ty of thi s fi ndi ng i s uncertai n, as the dose of chloroprocaine is far greater
than the dose used for spinal s in humans (0.6 mg/kg).
Myotoxicity of Local Anesthetics
Toxi city to skel etal muscl e is an uncommon side effect of l ocal anestheti c injecti on. Experi mental
TABLE 17-12 Dose Range of Spinal 2-Chloroprocaine and Comparison to Lidocaine
2-CHLOROPROCAINE 30 MG 45 MG 60 MG LIDOCAINE 40
MG
Sensory Block Height
Peak T7 T5 T2 T8
Ti me to L1 regressi on
(mins)
5330 7514 9213 8435
Thi gh tourni quet
tolerance (mins)
3711 4211 6210 3824
Complete regression
(mins)
9820 11615 13223 12616
Time to ambulation
(mins)
10020 11915 13320 13414
Time to bladder void
(mins)
10021 13219 14121 13414
Data from Kouri ME, Kopacz DJ: Spi nal 2-chloroprocai ne: A compari son wi th l i docaine in
vol unteers. Anesth Anal g 98(1):7580, Jan 2004, and Smi th KN, Kopacz DJ, McDonal d
SB: Spi nal 2-chl oroprocai ne: A dose-rangi ng study and the effect of added epi nephri ne.
Anesth Anal g 98(1): 8188, Jan 2004.
data suggests, however, that local anestheti cs have the potenti al for myotoxici ty i n cl ini cal ly
appl icable concentrati ons (Fi g. 17-18). Histopathologic evidence shows that the i njecti on of these
agents causes di ffuse myonecrosis, whi ch i s both reversi bl e and cl inicall y impercepti bl e. The
reversi bl e nature of this injury is possi bly because of the rel ati ve resi l ience of myobl asts, whi ch
regenerate damaged ti ssue. Theoreti cal mechani sms of i njury are numerous but dysregulati on of
intracel lular cal cium concentrati ons i s the most l i kel y cul pri t. One study shows that ropivacaine i s
l ess myotoxi c than bupivacaine pri maril y because of the l atter causing

apoptosis (programmed cell death).
143
Further i nvesti gation is needed to determi ne the cl i ni cal
rel evance of local or systemi c myotoxici ty foll owing si ngl e injecti on or conti nuous i nfusi on of local
anesthetics.
Al l er gi c React i ons t o Local Anest het i cs (see also Chapter 49)
True al l ergi c reacti ons to l ocal anesthetics are rare and usuall y involve Type I (IgE) or Type IV
(cell ular immuni ty) reacti ons.
144, 145
Type I reacti ons are worri some, as anaphylaxi s may occur,
and are more common wi th ester than ami de l ocal anestheti cs. True Type I al l ergy to ami noamide
agents i s extremel y rare.
145
Increased al l ergeni c potenti al with esters may be a resul t of
hydrol yti c metabol i sm to para-aminobenzoi c aci d, whi ch i s a documented al l ergen. Added
preservatives such as methyl paraben and metabisulfite can also provoke an al lergi c response. Ski n
testi ng wi th i ntradermal i njections of preservative-free l ocal anestheti cs has been advocated as a
means to determine tol erance to l ocal anestheti c. These tests should be undertaken wi th caution,
as potenti al l y severe and even fatal reacti ons can occur i n trul y all ergic pati ents.
145

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FIGURE 17-18. Skel etal muscl e cross section wi th characteri sti c histol ogi c changes after
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myofi bri l s to enti rel y di sintegrated and necroti c cel l s. The majority of the myocytes are
morphol ogi cal l y affected. Additi onal l y, a marked intersti tial and myoseptal edema appears
within the secti ons. However, scattered fibers remai n intact. (Reprinted with permission from
Zink W, Graf B: Local anestheti c myotoxi ci ty. Reg Anesth Pai n Med 29(4):33340, Jul Aug
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122. Groban L, Deal DD, Vernon JC, et al : Does l ocal anestheti c stereosel ecti vi ty or structure
predi ct myocardi al depressi on i n anestheti zed cani nes? Reg Anesth Pai n Med 27:460, 2002
123. Pi ckering AE, Waki H, Headley PM, et al : Investigation of systemi c bupi vacai ne toxi ci ty
using the i n si tu perfused worki ng heart-brainstem preparati on of the rat. Anesthesi ology
97:1550, 2002
124. Chang KSK, Yang M, Andresen MC: Cli nicall y rel evant concentrati ons of bupi vacai ne
inhi bit rat aortic baroreceptors. Anesth Anal g 78:501, 1994
125. Hogan QH, Stadnicka A, Bosnjak ZJ, et al: Effects of l i docai ne and bupi vacai ne on
isol ated rabbit mesenteric capacitance vei ns. Reg Anesth Pain Med 23:409, 1998
126. Guo XT, Castl e NA, Chernoff DM, et al : Comparati ve inhi bi ti on of vol tage-gated cation
channel s by l ocal anestheti cs. Ann N Y Acad Sci 625:181, 1991
127. Clarkson CW, Hondegham LM: Mechanisms for bupi vacai ne depressi on of cardi ac
conducti on: Fast bl ock of sodi um channel s duri ng the action potential wi th sl ow recovery from
bl ock duri ng di astol e. Anesthesi ol ogy 62:396, 1985
128. Mi o Y, Fukuda N, Kusakari Y, et al : Bupi vacai ne attenuates contracti l ity by decreasi ng
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129. Nouette-Gaul ain K, Foresti er F, Mal gat M, et al: Effects of bupi vacai ne on mi tochondrial
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134. Yamashi ta A, Matsumoto M, Matsumoto S, et al : A comparison of the neurotoxi c effects
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intrathecall y in rabbi ts. Anesth Anal g 97:512, 2003
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conducti on l oss in frog nerve. Anesthesiol ogy 81:657, 1994
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mani festati ons of l idocai ne neurotoxi ci ty i n vi tro. Anesth Anal g 86:569, 1998
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hi gh concentrati ons of l ocal anesthetics. Anesthesi ology 80:1082, 1994
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Anesth Pai n Med 27:581, 2002
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transi ent neurol ogi c symptoms. Anesthesi ology 90:445, 1999
142. Taniguchi M, Bol len AW, Drasner K: Sodium bi sulfite: Scapegoat for chloroprocai ne
neurotoxi ci ty? Anesthesi ol ogy 100:85, 2004
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144. Chen AH: Toxici ty and al lergy to local anesthesi a. J Cali fornia Dent Assoc 26:683, 1998
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46:747, 2002
> Tabl e of Contents > Secti on IV - Prepari ng for Anesthesi a > Chapter 18 - Preoperati ve Eval uati on and
Management
Chapter 18
Preoperative Evaluation and Management
Hata Tara M.
Moyers John R.
KEY POINTS
The goal s of preoperative eval uation are to reduce pati ent ri sk and the morbi di ty of surgery,
as wel l as to promote effi ci ency and reduce costs. The Joint Commi ssion for the Accredi tation
The Joi nt Commi ssi on for the Accreditati on of Heal thcare Organi zations (JCAHO)
requi res that all pati ents recei ve a preoperati ve anesthetic eval uati on and the
Ameri can Soci ety of Anesthesi ol ogi sts (ASA) has approved Basic Standards for
Preoperati ve Care.
When eval uating the pati ent with hypertensi on, i t i s important to determi ne the
presence of end-organ damage (heart, lung, and cerebrovascular systems).
Exerci se tol erance i s a major determi nant of cardi ac ri sk and need for further
testi ng.
The al gori thm for preoperati ve eval uati on of cardi ac pati ents undergoi ng
noncardiac surgery is very useful i n gui di ng further testi ng and eval uati on.
Preoperati ve l aboratory tests shoul d be ordered onl y based on defi ned
indicati ons such as posi ti ve findi ngs on history and physi cal exam.
No best drug or combi nati on of drugs exi sts for preoperati ve medi cati on.
Psychol ogi cal preparati on i s as i mportant as pharmacologi c preparati on for
anesthesia and surgery.
Ti ming of del ivery is as important as drug sel ecti on wi th preoperati ve
medi cati on.
Age of the chi l d i s a major determi nant of the approach to preoperati ve
medi cati on.
of Heal thcare Organi zati ons (JCAHO) requi res that al l pati ents receive a preoperati ve anestheti c
eval uati on. The Ameri can Soci ety of Anesthesi ol ogi sts (ASA) has approved Basi c Standards for
Preanestheti c Care, whi ch outli nes the mi ni mum requirements for a preoperati ve eval uati on.
Conducting a preoperati ve eval uation i s based on the premi se that i t wi ll modi fy pati ent care and
improve outcome. There is evidence, al though not enti rel y convinci ng i n al l i nstances, that the
preoperati ve eval uati on wil l i ncrease pati ent safety. That i s, armed wi th knowl edge preoperati vel y
the anesthesi ol ogi st can formul ate and conduct an anestheti c plan that avoids dangers inherent in
patient disease states. Furthermore, preoperative eval uations may very wel l reduce costs and
cancell ati on rates, i ncreasing resource uti l i zati on i n the operati ng room. Thi s assumes that
eval uations are done by anesthesi ologi sts and others fami l i ar wi th anestheti cs, surgery, and
peri operative events.

The preoperative evaluati on has several components and goals. One shoul d obtain a hi story and
perform a physi cal exam pertinent to the pati ent and surgery contempl ated. Based on the history
and physi cal , the appropri ate l aboratory tests and preoperative consultati ons shoul d be obtained.
Through these one needs to determine whether the pati ent' s preoperative condi tion may be
improved prior to surgery. Gui ded by the above, the anesthesiol ogi st should choose the
appropriate anestheti c and care pl an. Final l y, the process shoul d be used to educate the pati ent
about anesthesi a and the perioperative peri od, answer al l questi ons, and obtai n informed consent.
The fi rst part of thi s chapter outli nes cl inical ri sk factors pertinent to pati ents schedul ed for
anesthesia and surgery and the use of tests to confi rm di agnoses. The second part di scusses
preoperati ve medicati on. The chapter provi des only an overview of the preoperati ve management
process; for more detail s, the reader i s referred to chapters focusi ng on speci fic organ systems.
CHANGING CONCEPTS IN PREOPERATIVE EVALUATION
In the past, patients were admi tted to the hospi tal at least a day pri or to surgery. Currentl y, more
and more patients are admitted to the hospi tal on the day of surgery. Older pati ents are schedul ed
for more compl ex procedures, and there is more pressure on the anesthesiol ogi st to reduce the
ti me between cases. The fi rst ti me the anesthesiologi st performi ng the anestheti c sees the pati ent
may be just pri or to anesthesi a and surgery. The pati ent has been seen previ ousl y by others in a
preoperati ve eval uati on cl ini c. Only a short ti me exi sts to engender trust and answer last-mi nute
questi ons. It i s often impossibl e to al ter medical therapy at this juncture i mmedi atel y
preoperati vel y. However, preoperati ve screening cli ni cs are becoming more effecti ve and cl i ni cal
practi ce gui del i nes becoming more preval ent. Informati on technology has helped the
anesthesiol ogi st i n previewi ng the upcomi ng patients that wi ll be anestheti zed. Preoperative
questi onnai res and computer-dri ven programs have become al ternati ves to tradi tional i nformati on
gathering. Finall y, when anesthesi ol ogi sts are responsi bl e for orderi ng preoperati ve l aboratory
tests, cost savi ng occurs and cancel lations of pl anned surgi cal procedures become l ess li kel y. In
this setti ng i t i s important that communi cation between the preoperati ve eval uation cl i ni c and the
anesthesiol ogi st performing the anestheti c occur through the pati ent record and i n person.
APPROACH TO THE HEALTHY PATIENT
The preoperati ve eval uati on form is the basis for formulating the best anestheti c pl an tai l ored to
the pati ent. It should ai d the anesthesiologi st in i dentifyi ng potential compl i cations, as wel l as
serve as a medi col egal document. The importance of the desi gn has increased because of the fact
that i t i s more common today for the eval uation to be compl eted i n a preop cl i ni c by another
physi ci an or health professi onal who wi l l not personal l y be performi ng the anestheti c, but al so
because regulatory agenci es such as JCAHO demand better documentati on. Therefore, the
information obtai ned needs to be compl ete, conci se, and l egi bl e. In those hospitals that have
computerized pati ent forms, legi bi li ty i s no l onger an i ssue. A group from Uni versi ty of Cal i forni a,
San Di ego (UCSD) studi ed the qual i ty of preoperati ve eval uati on forms across the United States
and rated them i n three categories: i nformational content, ease of use, and ease of reading.
1

Their results reveal ed that a surpri singl y high percentage of forms are mi ssi ng i mportant
information. Fi gure 18-1 is an exampl e of the preoperative evaluati on form i n use at the
P.476
Uni versi ty of Iowa Hospi tal s, whi ch attempts to document all perti nent informati on.
The approach to the patient should al ways begi n wi th a thorough hi story and physi cal exam. Thi s
al one may be suffi cient (wi thout additi onal routi ne l aboratory tests) pri or to noni nvasi ve
procedures.
The i ndi cation for the surgi cal procedure i s part of the preoperati ve hi story, because i t wi ll help
determi ne the urgency of the surgery. True emergent procedures, whi ch are associated wi th an
accepted higher anestheti c morbi dity and mortali ty, requi re a more abbrevi ated eval uati on. A l ess-
defi ned area i s the approach to urgent procedures. For example, ischemi c li mbs requi re surgery
soon after presentati on, but can usual ly be del ayed for 24 hours for further eval uati on. The
indicati on for the surgical procedure may also have i mpl i cations on other aspects of perioperative
management. For exampl e, the presence of a small bowel obstructi on has i mpl icati ons regarding
the ri sk of aspi rati on and the need for a rapi d sequence i nducti on. The extent of a lung resecti on
wil l di ctate the need for further pul monary testi ng and peri operative moni toring. Pati ents
undergoi ng caroti d endarterectomy may requi re a more extensive neurologic examinati on, as well
as testi ng to rule out coronary artery disease (CAD). Frequentl y, further i nformati on wil l be
requi red that necessi tates contacting the surgeon. Peri operati ve care of the pati ent, as well as
effi ci ency i n the operati ng room, i s al ways enhanced by cl ose communi cation wi th the surgeons.
The abil i ty to revi ew previ ous anesthetic records i s hel pful in detecti ng the presence of a di ffi cul t
ai rway, a hi story of mal ignant hyperthermi a, and the i ndi vi dual' s response to surgi cal stress and
specific anestheti cs. The pati ent shoul d be questi oned regardi ng any previ ous di fficulty with
anesthesi a or other fami l y members having di ffi cul ty wi th anesthesi a. A patient hi story rel ati ng an
al lergy to anesthesi a shoul d make one suspi cious for mal i gnant hyperthermi a.
The hi story shoul d i ncl ude a complete l ist of medi cati ons, including over-the-counter and herbal
products, to defi ne a preoperati ve medi cati on regi men, anti ci pate potenti al drug i nteractions, and
provi de cl ues to underl yi ng di sease. A compl ete l i st of drug al l ergi es, incl uding previous reacti ons,
should al so be obtai ned.
The anesthesi ologist shoul d determi ne when the pati ent l ast ate, as wel l as note the sites of
FIGURE 18-1. Exampl e of pre-anesthetic eval uati on form.
preexi sti ng i ntravenous cannulae and i nvasi ve moni tors. Once the general i ssues are compl eted,
the preoperati ve hi story and physi cal exam can focus on speci fi c systems.
Syst ems Appr oach
Airway
A basi c concern of the anesthesiol ogi st i s always the pati ent's ai rway. The abi l ity to review
previ ous anestheti c records is especi all y useful in uncoveri ng unsuspected di fficul t airways or to
confi rm previ ous uneventful intubati ons, assuming the pati ent' s body habi tus has not changed i n
the interi m. Eval uati on of the ai rway i nvol ves determi nati on of the thyromental di stance, the
abi li ty to fl ex the base of the neck and extend the head, and exami nation of the oral cavi ty
incl udi ng dentiti on. The Mal l ampati cl assi fi cation has become the standard for assessi ng the
rel ati onship of the tongue size rel ati ve to the oral cavi ty (Tabl e 18-1),
2
al though by itself the
Mal lampati cl assi fi cation has a low positi ve predictive value i n i denti fyi ng patients who are di ffi cul t
to intubate.
3, 4
In trauma pati ents, as wel l as those wi th severe rheumatoi d arthri ti s or Down

syndrome, assessment of the cervi cal spine is criti cal . In appropri ate patients, the presence of
pai n or symptoms of cervi cal cord compressi on on movement should be assessed. In other
instances, radi ographic exami nati on may be requi red.
Pulmonary
A screeni ng eval uati on should i ncl ude questi ons regardi ng the hi story of tobacco use, shortness of
breath, cough, wheezi ng, stridor, and snori ng or sl eep apnea. The patient should al so be
questi oned regardi ng the presence or recent history of an upper respi ratory tract infecti on.
Physi cal exam shoul d assess the respi ratory rate as well as the chest excursi on, use of accessory
muscles, nai l col or, and the pati ent' s abi li ty to carry on a conversati on or to walk wi thout
dyspnea. Auscul tation should be used to detect decreased breath sounds, wheezi ng, stri dor, or
rales. For the patient wi th posi ti ve findings, see preoperati ve eval uati on of the pul monary pati ent.
Cardiovascular System
When screeni ng a pati ent for cardi ovascul ar di sease pri or to surgery, the anesthesi ol ogi st is most
P.477
TABLE 18-1 Airway Classification System
CLASS DIRECT VISUALIZATION, PATIENT
SEATED
LARYNGOSCOPIC VIEW
I Soft pal ate, fauces, uvul a, pil l ars Enti re gl ottic
II Soft pal ate, fauces, uvul a Posterior commi ssure
III Soft pal ate, uvul ar base Ti p of epi gl ottis
IV Hard palate only No gl ottal structures
Modi fi ed wi th permi ssion from Mal l ampati RS, Gatt SP, Gugino LD et al : A cl i ni cal sign to
predi ct diffi cult tracheal intubati on: A prospecti ve study. Can Anaesth Soc J 32:429,
1985.
interested i n recogni zi ng signs and symptoms of uncontrol led hypertensi on and unstabl e cardi ac
di sease such as myocardi al i schemi a, congesti ve heart fail ure, val vular heart di sease, and
si gni fi cant cardi ac dysrhythmi as. Symptoms of cardi ovascular di sease should be careful l y
determi ned, especi all y the characteri sti cs of chest pai n, i f present. Certain popul ati ons of
patients, such as the elderly, women, or di abeti cs, may present with more atypical features. The
presence of unstable angi na has been associ ated wi th a high peri operati ve ri sk of myocardi al
infarction (MI).
5
The perioperative peri od is associ ated with a hypercoagul abl e state and surges in
endogenous catechol ami nes, both of which may exacerbate the underlyi ng process i n unstabl e
angina, increasi ng the ri sk of acute i nfarcti on.
6
The preoperati ve evaluation can affect both a
patient' s short- and long-term heal th by insti tuting treatment of unstable angi na. Symptoms of
cl i ni cal ly i mportant valvul ar di sease shoul d be sought, such as angi na,

syncope, or congestive heart fai lure from aorti c stenosis that woul d requi re further eval uati on. A
hi story of other valvul ar di sease such as mi tral valve prol apse may si mpl y di ctate the need for
SBE prophylaxis.
The exam of the cardiovascular system should incl ude bl ood pressure, measuri ng both arms when
appropriate. The anesthesiol ogi st should take into account the effects of preoperative anxiety and
may want a record of resti ng bl ood pressure measurements. However, Bedford and Fei nstei n
reported that the admission blood pressure was the best predi ctor of response to laryngoscopy.
7

Auscultati on of the heart i s performed, speci fi cal l y l i steni ng for a murmur radi ati ng to the caroti ds
suggestive of aorti c stenosis or abnormal rhythms, or a gall op suggesti ve of heart fai lure. The
presence of bruits over the caroti d arteri es woul d warrant further work-up to determi ne the ri sk of
stroke. The extremiti es should al so be exami ned for the presence of peripheral pul ses to exclude
peri pheral vascular disease or congenital cardi ovascul ar di sease.
Neurologic System
A screeni ng of the neurol ogical system i n the apparentl y heal thy pati ent can mostl y be
accompl i shed through si mpl e observati on. The pati ent's abi l ity to answer health hi story questi ons
practi cal ly ensures a normal mental status. Questions can be directed to exclude the presence of
increased intracrani al pressure, cerebrovascul ar di sease, sei zure hi story, preexi sti ng
neuromuscul ar di sease, or nerve injuries. The neurologi c exami nati on may be cursory in heal thy
patients, or extensive in pati ents wi th coexisting di sease. Testi ng of strength, reflexes, and
sensati on may be i mportant i n pati ents i f the anestheti c plan or surgical procedure may resul t i n a
change in the condi tion.
Endocrine System
Each pati ent shoul d be screened for endocri ne di seases that may affect the peri operati ve course:
di abetes, thyroid disease, parathyroi d di sease, endocri ne-secreting tumors, and adrenal corti cal
suppressi on.
Eval uat i on of t he P at i ent wi t h Known Syst emi c Di sease
Cardiac Disease
The preoperative evaluati on of the pati ent with suspected cardiovascular disease has been
approached i n two ways: cli ni cal ri sk indi ces and preoperati ve cardi ac testi ng. The goal s are to
define ri sk, determine which pati ents wi ll benefit from further testi ng, form an appropri ate
anesthetic pl an, and i dentify pati ents who wi l l benefit from perioperati ve beta-bl ockade,
interventi on therapy, or even surgery. Cli ni cal ri sk i ndi ces range from the physi cal status i ndex of
the Ameri can Soci ety of Anesthesi ol ogists (Tabl e 18-2) to the Gol dman Cardi ac Ri sk Index, which
has recentl y been updated.
P.478
TABLE 18-2 American Society of Anesthesiologists Physical Status Classification
In an update of the Goldman Cardi ac Risk Index, the i nvesti gators studi ed 4,315 pati ents aged 50
years and older who were undergoi ng el ecti ve, major noncardiac procedures.
8
Si x i ndependent
predi ctors of compli cati ons were i denti fi ed and i ncl uded i n a revi sed ri sk index: hi gh-ri sk type of
surgery, history of i schemi c heart di sease, history of congestive heart fai lure, hi story of
cerebrovascul ar di sease, preoperative treatment wi th i nsul i n, and preoperati ve serum creati ni ne
>2.0 mg/dL. Cardiac compl i cations rose with an i ncrease in the number of risk factors present.
Rates of major cardi ac compl icati ons wi th 0, 1, 2, or 3 of these factors were 0.5, 1.3, 4, and 9%,
respectively, i n the deri vati on cohort and 0.4, 0.9, 7, and 11%, respecti vel y, among 1,422
patients i n the val idati on cohort (Fi g. 18-2).
STATUS DISEASE STATE
ASA Cl ass 1 No organi c, physi ol ogi c, bi ochemi cal , or psychiatri c disturbance
ASA Cl ass 2 Mi l d to moderate systemi c di sturbance that may not be rel ated to
the reason for surgery
ASA Cl ass 3 Severe systemi c di sturbance that may or may not be rel ated to
the reason for surgery
ASA Cl ass 4 Severe systemi c di sturbance that i s l i fe threateni ng wi th or
without surgery
ASA Cl ass 5 Moribund patient who has l ittle chance of survi val but i s submi tted
to surgery as a l ast resort (resusci tati ve effort)
Emergency
operation (E)
Any patient in whom an emergency operati on i s requi red
From i nformati on i n Ameri can Soci ety of Anesthesi ologi sts: New cl assi fi cation of physi cal
status. Anesthesi ology 24:111, 1963.
Whil e al l of these i ndices provi de i nformati on to assess the probabi l ity of compl i cations and
provi de an esti mate of ri sk, they do not prescri be peri operati ve management. In contrast,

the anesthesi ol ogi st is most concerned wi th forming an anestheti c pl an after defi ni ng the
cardi ovascul ar ri sk factors.
In pati ents wi th symptomati c coronary di sease, the preoperati ve evaluati on may l ead to the
recogniti on of a change i n the frequency or pattern of anginal symptoms. Certain popul ati ons of
patientsfor exampl e, the el derl y, women, or diabeticsmay present with more atypical features.
The presence of unstable angi na has been associ ated wi th a high peri operati ve ri sk of MI.
5

In vi rtual ly all studi es, the presence of acti ve congesti ve heart fail ure preoperatively has been
associated wi th an i ncreased i ncidence of peri operati ve cardi ac morbidi ty.
9, 10
Stabi li zation of
ventri cul ar function and treatment for pul monary congestion are important pri or to el ecti ve
surgery. Because the type of perioperative moni toring and treatments woul d be di fferent,
cl ari fyi ng the cause of heart fail ure i s important. Congesti ve symptoms may be a result of
noni schemic cardiomyopathy or cardi ac valvul ar i nsuffi ci ency and/or stenosi s.
Adul ts with a pri or MI al most al ways have coronary artery di sease. Tradi ti onal l y, ri sk assessment
for noncardi ac surgery was based on the ti me i nterval between the MI and surgery. Mul tipl e
studi es have demonstrated an increased i nci dence of reinfarcti on i f the MI was withi n 6 months of
surgery.
11, 12, 13
With improvements i n perioperati ve care, thi s di fference has decreased. Therefore,
the importance of the intervening time interval may no longer be vali d i n the current era of
interventi onal therapy and risk stratificati on after an acute MI. Although many pati ents wi th an MI
may conti nue to have myocardi um at risk for subsequent ischemi a and i nfarcti on, other patients
may have their critical coronary stenoses ei ther total l y occl uded or wi del y patent. For exampl e,
the use of percutaneous transl uminal coronary angiopl asty, thrombol ysis, and early coronary
artery bypass grafting (CABG) has changed the natural hi story of the di sease.
14, 15
Therefore,
pati ents shoul d be eval uated from the perspecti ve of thei r ri sk for ongoi ng i schemi a. The Ameri can
Heart Associ ati on/Ameri can Col lege of Cardi ol ogy Task Force on Peri operative Eval uation of the
Cardi ac Pati ent Undergoi ng Noncardi ac Surgery has defined three ri sk groupsmajor,
intermedi ate, and mi nor (Tabl e 18-3). They i ndi cate that recent MI (MI <30 days) pl aces pati ents
in the group at hi ghest ri sk; after that period, a prior MI places the pati ent at i ntermediate ri sk.
16

FIGURE 18-2. CRI cardiac ri sk index. Bars represent rate of major cardi ac compli cati ons in
enti re pati ent popul ation (both derivati on and val idation cohorts combined) for pati ents in
revi sed CRI cl asses accordi ng to type of procedure performed. AAA, abdomi nal aorti c
aneurysm. Note that, by defini ti on, pati ents undergoi ng AAA, thoraci c, and abdomi nal
procedures were excluded from Cl ass I. In al l subsets except patients undergoi ng AAA, there
was a stati sti cal l y si gni fi cant trend toward greater risk wi th hi gher-ri sk cl ass. See text for
detail s. (Reproduced wi th permission from Lee TH, Marcantoni o ER, Mangi one CM et al :
Deri vati on and prospecti ve val idation of a si mpl e i ndex for prediction of cardi ac ri sk of major
noncardiac surgery. Ci rcul ati on 100:1043, 1999.)
P.479
TABLE 18-3 Clinical Predictors of Increased Perioperative Cardiovascular Risk
(Myocardial Infarction, Congestive Heart Failure, Death)
Major
Unstabl e coronary syndromes
Recent myocardi al i nfarcti on
a
wi th evi dence of i mportant i schemic ri sk by cl inical
Patients with Coronary Artery Disease
For those pati ents wi thout overt symptoms or history, the probabi l ity of CAD vari es with the type
and number of atheroscl eroti c ri sk factors present. Peri pheral arteri al di sease has been shown to
be associ ated wi th CAD in mul ti pl e studies.
17
Di abetes mel li tus i s a common di sease in the el derl y
and represents a process that affects mul ti pl e organ systems. Compl icati ons of di abetes mell i tus
are frequentl y the cause of urgent or emergent surgery, especi al l y i n the el derl y. Di abetes
accel erates the progression of atherosclerosi s, so i t is not surpri sing that di abeti cs have a hi gher
i nci dence of CAD than nondi abetics do. There i s a hi gh i nci dence of both si lent myocardial
infarcti on and myocardial ischemia.
18
Eagle et al demonstrated that diabetes i s an i ndependent
ri sk factor for perioperati ve cardi ac morbi dity.
19
In attempti ng to determi ne the degree of thi s
symptoms or noni nvasi ve study
Unstabl e or severe
b
angina (Canadi an Class III or IV)
c

Decompensated congesti ve heart fail ure
Significant arrhythmi as
Hi gh-grade atri oventricul ar bl ock
Symptomati c ventricul ar arrhythmi as in the presence of underl yi ng heart disease
Supraventri cular arrhythmias wi th uncontroll ed ventri cular rate
Severe val vular disease
Intermediate
Mi l d angina pectori s (Canadi an Class I or II)
Pri or myocardi al infarction by history or pathologi cal Q waves Compensated or pri or
congesti ve heart fail ure
Diabetes mel li tus
Minor
Advanced age
Abnormal ECG (l eft ventricul ar hypertrophy, l eft bundl e-branch bl ock, ST-T
abnormali ties)
Rhythm other than si nus (e.g., atrial fi bri l lation)
Low functi onal capaci ty (e.g., inabil i ty to cl imb one fl i ght of stai rs wi th a bag of
groceries)
History of stroke
Uncontroll ed systemic hypertensi on
a
The Ameri can Col l ege of Cardi ology National Database Li brary defi nes recent MI as
greater than 7 days but l ess than or equal to 1 month (30 days).
b
May incl ude stabl e angina in pati ents who are unusual l y sedentary.
c
Campeau L: Gradi ng of angi na pectoris. Ci rcul ati on 54:522, 1976.
Reproduced wi th permission from Eagle K, Brundage B, Chaitman B et al : Guidel i nes for
peri operative cardiovascular evaluati on of the noncardi ac surgery. A report of the
Ameri can Heart Associ ati on/American Col lege of Cardi ol ogy Task Force on Assessment of
Diagnosti c and Therapeuti c Cardi ovascul ar Procedures. Ci rculation 93:1278, 1996.
increased probabil i ty, the l ength of the di sease and other associ ated end-organ dysfuncti on shoul d
be taken into account. Autonomi c neuropathy has been found to be the best predi ctor of si lent
coronary artery disease.
20
Because these patients are at very high risk for a si l ent MI, an
el ectrocardi ogram (ECG) shoul d be obtai ned to exami ne for the presence of Q waves.
Hypertensi on has also been associ ated with an i ncreased incidence of sil ent myocardi al i schemi a
and infarction.
18
Hypertensi ve pati ents who have l eft ventricular hypertrophy and are undergoi ng
noncardiac surgery are at a higher peri operative ri sk than nonhypertensi ve pati ents.
21

Investi gators have suggested that the presence of a strain pattern on ECG suggests a chronic
ischemi c state.
22
Therefore, these pati ents should al so be consi dered to have an increased
probabi l ity of CAD and for peri operati ve morbi di ty.
There i s controversy regardi ng a tri gger to del ay or cancel a surgi cal procedure in a pati ent
with untreated or i nadequately treated hypertensi on. Hypertension has been di vi ded i nto
three stages, wi th Stage 3 denoti ng that which mi ght be used as a cutoff (Tabl e 18-4).
23

Aggressi ve treatment of bl ood pressure is associ ated with increased reduction in l ong-term risk,
al though the effect dimini shes i n al l but di abeti c pati ents as di astol i c bl ood pressure i s reduced
bel ow 90 mmHg. Although there has been a suggesti on i n the l iterature that a case shoul d be
del ayed i f the di astoli c pressure i s greater than 110 mm Hg, the study often quoted as the basis
for thi s determi nation demonstrated no major morbi di ty i n that smal l group of patients.
24
Other
authors state that there is l i ttl e associ ati on between bl ood pressures of less than 180 mmHg
systol i c or 110 mm Hg diastol ic and postoperative outcomes. However, such patients are prone to
peri operative myocardi al i schemi a, ventri cul ar dysrhythmi as, and l abi l i ty i n bl ood pressure. It i s
less cl ear i n pati ents with blood pressures above

180/100 mmHg, although no absol ute evi dence exi sts that postponi ng surgery wil l reduce ri sk.
25

In the absence of end-organ changes, such as renal insuffici ency or l eft ventri cular hypertrophy
with strai n, it would seem appropri ate to proceed with surgery. In contrast, a pati ent wi th a
markedl y elevated bl ood pressure and new onset of a headache shoul d have surgery del ayed for
further treatment.
P.480
TABLE 18-4 Blood Pressure (mmHg)
CATEGORY SYSTOLIC DIASTOLIC
Optimal <120 and <80
Normal <130 and <85
Hi gh-normal 130139 or 8589
Hypertension
Stage 1 140159 or 9099
Stage 2 160179 or 100109
Stage 3 180 or 110
Several other risk factors have been used to suggest an i ncreased probabi l ity of CAD. These
incl ude the atheroscleroti c processes associated wi th tobacco use and hyperchol esterol emi a.
Although these ri sk factors i ncrease the probabi l ity of developi ng coronary artery disease, they
have not been shown to increase perioperative ri sk. When attempti ng to determi ne the overall
probabi l ity of di sease, the number of ri sk factors and severity of each are important.
I mpor t ance of Sur gi cal P r ocedur e
The surgical procedure i nfluences the scope of preoperative evaluati on requi red by determi ni ng
the potenti al range of physi ologic flux during the perioperative peri od. Few hard data exi st
defining the surgery-specific i nci dence of compli cati ons. It i s known that peri pheral procedures,
such as those i ncluded i n a study of ambul atory surgery compl eted at the Mayo Cl inic, are
associated wi th an extremel y l ow i ncidence of morbi dity and mortality,
26
whi l e major vascul ar
procedures are associ ated with the hi ghest i ncidence of compl i cati ons. Eagl e et al publ i shed data
on the i ncidence of peri operati ve myocardi al i nfarcti on and mortal i ty by procedure for pati ents
enrolled in the Coronary Artery Surgery Study (CASS).
27
They determi ned the overal l ri sk of
peri operative morbi di ty i n patients wi th known coronary artery di sease treated medi cal l y
compared to those patients who had pri or coronary artery bypass grafti ng. Hi gh-ri sk procedures
incl ude major vascul ar, abdominal , thoraci c, and orthopaedi c surgery. The Ameri can Heart
Associ ati on/Ameri can Coll ege of Cardi ology Guidel i nes described a ri sk strati fi cati on for noncardi ac
surgery that is shown i n Tabl e 18-5.
16

Reproduced with permission from Sixth report of the Joint National Committee on
Preventi on, Detecti on, Eval uati on, and Treatment of Hi gh Bl ood Pressure. Arch Intern
Med 157:2413, 1997.
TABLE 18-5 Cardiac Risk
a
Stratification for Noncardiac Surgical Procedures

HIGH (Reported cardi ac ri sk often >5%)
Emergent major operations, parti cul arly i n the elderly
Aorti c and other major vascular
Peri pheral vascular
Anti ci pated prol onged surgi cal procedures associ ated
wi th l arge fl ui d shi fts and/or blood loss
INTERMEDIATE (Reported cardi ac ri sk generall y <5%)
Caroti d endarterectomy
Head and neck
I mpor t ance of Exer ci se Tol er ance
Exerci se tol erance i s one of the most i mportant determi nants of peri operati ve ri sk and the
need for further testing and invasive moni toring. An excell ent exerci se tol erance, even i n
patients with stable angina, suggests that the myocardi um can be stressed wi thout fai li ng. If a
patient can walk a mi le wi thout becomi ng short of breath, the probabi li ty of extensive coronary
artery di sease i s smal l . Al ternati vel y, if pati ents experi ence dyspnea associ ated with chest pai n
duri ng mi ni mal exerti on, the probabi l ity of extensive coronary artery di sease is high, which has
been associ ated wi th greater peri operati ve risk. Addi ti onal l y, these pati ents are at ri sk for
developing hypotensi on wi th i schemi a, and therefore may benefi t from more extensi ve monitori ng,
coronary i nterventi on therapy, or revasculari zation. Exercise tol erance can be assessed wi th
formal treadmi ll testi ng or wi th a questi onnai re that assesses acti vi ti es of dai l y l i vi ng (Tabl e 18-
6).
16

Intraperitoneal and i ntrathoraci c
Orthopaedic
Prostate
LOW
b
(Reported cardi ac ri sk generall y <1%)
Endoscopi c procedures
Superfici al procedures
Cataract
Breast
a
Combined i ncidence of cardiac death and nonfatal myocardial i nfarction.
b
Do not generall y requi re further preoperati ve cardi ac testi ng. Reproduced wi th
permission from Eagle K, Brundage B, Chaitman B et al : Guidel i nes for peri operative
cardi ovascul ar eval uation of the noncardi ac surgery. A report of the American Heart
Associ ati on/Ameri can Col lege of Cardiol ogy Task Force on Assessment of Di agnosti c and
Therapeuti c Cardi ovascul ar Procedures. Circul ation 93:1278, 1996.
TABLE 18-6 Estimated Energy Requirement for Various Activities
a

1 MET Can you take care of
yoursel f?
Eat, dress, or use the
toil et?
Wal k i ndoors around
the house?
Wal k a bl ock or two on
level ground at 23
mph or 3.24.8 km/hr?
Do l i ght work around
the house l ike dusting
or washi ng di shes?
4METs Wal k on l evel ground at 4 mph or 6.4
km/hr?
Run a short di stance
Do heavy work around the house l i ke
scrubbing fl oors or li fti ng or movi ng
heavy furni ture?
Parti cipate in moderate recreati onal
acti vi ties l i ke golf, bowl i ng, danci ng,
doubl es tenni s, or throwi ng a basebal l
or footbal l ?
Rei l ly et al have eval uated the predictive value of sel f-reported exerci se tolerance for seri ous
peri operative compli cati ons and demonstrated that a poor exercise tol erance (could not walk four
bl ocks and cl i mb two fl i ghts of stai rs) i ndependentl y predi cted a compl i cati on wi th an odds rati o of
1.94.
28
The l i kel ihood of a seri ous adverse event was i nversel y rel ated to the number of bl ocks
that could be walked. Therefore, there is good evi dence to suggest that mini mal addi ti onal testi ng
is necessary i f the pati ent i s abl e to descri be a good exerci se tol erance.
INDICATIONS FOR FURTHER CARDIAC TESTING
Mul ti pl e al gori thms have been proposed to determi ne whi ch patients require further testing. As
descri bed previousl y, the ri sk associ ated with the proposed surgi cal procedure i nfl uences the
deci si on to perform further diagnosti c testing and i nterventi ons. Gui del i nes must be tempered by
recent studi es i n whi ch perioperati ve cardi ac morbi dity was greatl y reduced by peri operati ve -
adrenergi c bl ockade admi ni strati on.
29
With the reducti on i n perioperative morbi di ty, i t has been
suggested that extensi ve cardi ovascul ar testi ng i s not necessary. However,

unti l these findings can be confi rmed, further testing may be warranted.
The algori thm to determine the need for testi ng proposed by the Ameri can Col l ege of
Cardi ol ogy/Ameri can Heart Association Task Force and an update in 2002,
30
i s based on the
avai labl e evi dence and expert opi ni on that integrates cli ni cal hi story, surgery-specific risk, and
exercise tol erance (Fi g. 18-3).
16
In step one, the cli ni ci an evaluates the urgency of the surgery
and the appropri ateness of a formal preoperati ve assessment. Next, determine i f the patient has
undergone a recent revascul arizati on procedure or coronary eval uation. Those patients with
unstabl e coronary syndromes shoul d be i dentified, and appropri ate treatment i nstituted. Fi nal l y,
the deci sion to undergo further testi ng depends on the i nteracti on of the cli ni cal ri sk factors,
surgery-specific risk, and functional capaci ty. For pati ents at i ntermediate cl i ni cal risk, both
exercise tol erance and the extent of the surgery are taken i nto account to determine the need for
further testi ng. Importantl y, no preoperati ve cardi ovascul ar testi ng should be performed i f the
resul ts wil l not change peri operati ve management.
4
METs
Climb a flight of stairs
or walk up a hi ll ?
>10
METs
Parti cipate in strenuous sports l ike
swi mmi ng, si ngles tenni s, football ,
basketbal l , or ski i ng?
MET = metaboli c equi val ent.
a
Adapted from the Duke Acti vi ty Status Index and AHA Exerci se Standards.
Reproduced wi th permission from Eagle K, Brundage B, Chitman B et al : Guidel i nes for
peri operative cardiovascular eval uation of the noncardi ac surgery. A report of the
Ameri can Heart Associ ati on/Ameri can Col l ege of Cardi ol ogy Task Force on Assessment of
Diagnosti c and Therapeuti c Cardi ovascul ar Procedures. Circul ation 93:1278, 1996.
P.481
Car di ovascul ar Test s
FIGURE 18-3. The Ameri can Heart Associ ati on/American Col lege of Cardi ol ogy Task Force on
Peri operative Eval uati on of Cardi ac Pati ents Undergoing Noncardiac Surgery has proposed an
al gori thm for deci si ons regardi ng the need for further eval uati on. Thi s represents one of
mul tipl e algorithms proposed i n the li terature. It i s based on expert opi nion and incorporates
si x steps. Fi rst, the cl ini ci an must evaluate the urgency of the surgery and the
appropriateness of a formal preoperative assessment. Next, he or she must determine
whether the pati ent has had a previous revascul ari zation procedure or coronary evaluati on.
Those patients wi th unstabl e coronary syndromes shoul d be identi fi ed, and appropriate
treatment should be insti tuted. The decisi on to have further testi ng depends on the
interaction of the cli ni cal risk factors, surgery-specific risk, and functional capaci ty. (Adapted
with permission from Eagle K, Brundage B, Chai tman B et al : Guidel i nes for peri operative
cardi ovascul ar eval uation of noncardi ac surgery. A report of the Ameri can Heart
Associ ati on/Ameri can Coll ege of Cardi ology Task Force on Assessment of Diagnosti c and
Therapeuti c Cardi ovascul ar Procedures. Circul ati on 93:1278, 1996.)
Electrocardiogram
Preoperati ve 12-lead electrocardiogram can provi de i mportant informati on on the state of the
patient' s myocardi um and coronary ci rcul ation. Abnormal Q waves i n hi gh-ri sk pati ents are hi ghly
suggesti ve of a past myocardi al i nfarcti on. Confi rmati on of acti ve i schemi a usual ly requires
changes in at least two l eads. It has been esti mated that approximately 30% of myocardi al
infarcti ons occur wi thout symptoms (si l ent infarctions) and can only be detected on routi ne
el ectrocardi ograms, wi th the hi ghest inci dence occurri ng i n pati ents wi th ei ther di abetes or
hypertensi on. The Frami ngham study showed that l ong-term prognosi s is not i mproved by l ack of
symptoms.
18
The absence of Q waves on the el ectrocardiogram does not excl ude the occurrence of
a Q-wave myocardi al i nfarcti on i n the past. It has been shown that 5 to 27% of Q waves di sappear
over the 10-year peri od fol l owi ng an i nfarcti on.
32
Those patients i n whom the el ectrocardiogram
reverts to normal have improved survi val compared wi th those with consi stent abnormali ties, wi th
or wi thout Q waves. The presence of Q waves on a preoperati ve el ectrocardi ogram i n a hi gh-ri sk
patient, regardl ess of symptoms, should al ert the anesthesiol ogi st to the i ncreased peri operati ve
ri sk and the possi bi li ty of acti ve i schemi a.
It has not been establ i shed that i nformation obtai ned from the preoperati ve el ectrocardi ogram
affects cl i ni cal care. A revi ew of cl ini cal studi es on the matter i s i nconclusi ve. In a retrospective
revi ew of adul t pati ents undergoi ng ambul atory surgery, the preoperati ve el ectrocardi ogram was
not predictive of peri operati ve ri sk.
33
Al though controversy exi sts, current recommendati ons
incl ude the need for a preoperati ve el ectrocardi ogram i n the presence of systemic vascul ar di sease
(for exampl e, those patients wi th hypertensi on or peri pheral vascular disease), for males over 40
years of age and for females over 50.
Noninvasive Cardiovascular Testing
The exerci se electrocardi ogram has been the tradi ti onal method in the past for evaluati ng patients
with suspected coronary artery di sease. It represents the most cost-effecti ve and least i nvasi ve
method for detecti ng ischemia, wi th a sensi ti vi ty of 70 to 80% and a speci fi ci ty of 60 to 75% for
identi fyi ng coronary artery di sease. A posi tive exerci se stress test al erts the anesthesi ol ogi st that
the pati ent i s at risk for i schemi a over a wi de range of heart rates, wi th the greatest ri sk i n those
who devel op ischemi a onl y after mi l d exerci se. However, as di scussed previ ousl y, the abi l ity to
exercise suggests that no further testing i s necessary, and therefore stress electrocardi ography is
infrequently i ndi cated.
A number of hi gh-ri sk pati ents are ei ther unabl e to exerci se or have contraindi cati ons to exercise,
for exampl e, those wi th claudicati on. Therefore, pharmacol ogi c stress testi ng and ambul atory
el ectrocardi ography have come into vogue, parti cul arl y as preoperati ve cardi ovascul ar tests i n
patients schedul ed for vascul ar surgery. Pharmacologi c stress thall i um imagi ng is useful in those
patients who are unable to exerci se. Di pyri damole or adenosi ne i s admini stered as a coronary
vasodil ator to assess flow heterogeneity. The presence of a redi stri buti on defect i s predi cti ve of
postoperative cardi ac events, especial l y i n pati ents undergoi ng peri pheral vascul ar surgery (Fi g.
18-4). Simil arl y, dopami ne can be used to i ncrease myocardi al oxygen demand, by i ncreasi ng
heart rate and bl ood pressure, i n those pati ents who cannot exerci se.

The ambulatory ECG (Hol ter monitori ng) provides a means of conti nuousl y moni tori ng the
el ectrocardi ogram for significant ST segment changes preoperativel y. One study demonstrated
that the presence of si l ent i schemia i s a strong predi ctor of outcome, whi le i ts absence i s
associated wi th a favorable outcome i n 99% of the pati ents studi ed.
34
Other investi gators have
demonstrated the val ue of ambul atory ECG monitori ng, al though the negative predi cti ve val ues
have not been as hi gh as reported by some.
Stress echocardiography i s another preoperative test that may be of value i n eval uati ng pati ents
with suspected coronary artery di sease. The appearance of ei ther new or more severe regi onal
wal l motion abnormali ties with exerci se is considered a positi ve test. Either represents areas at
ri sk for myocardi al i schemi a. The advantage of the stress echocardi ogram i s that it i s a dynamic
assessment of ventri cul ar function. Dobutami ne echocardi ography has al so been studi ed and found
to have among the best predi cti ve values. It i s general l y accepted that the group at ri sk i s
compri sed by those who demonstrate regional wall moti on abnormal iti es at l ow heart rates.
Several groups have publ i shed meta-anal yses of preoperati ve diagnosti c tests. One group of
FIGURE 18-4. A di pyri damol e-thal l i um SPECT i mage demonstrati ng a reversibl e defect. The
top i mage demonstrates defects consistent wi th areas of low perfusi on or ischemia, whi ch
fil l s in on subsequent imagi ng (bottom). (See upper l eft portion of image.)
P.482
i nvesti gators demonstrated good predi cti ve val ues usi ng ambulatory ECG moni tori ng, radi onucl i de
angi ography, di pyri damol e thal l ium imagi ng, or dobutami ne stress echocardi ography.
35
Shaw et al
al so demonstrated good predictive values of dipyri damol e thal l i um i magi ng and dobutami ne stress
echocardi ography.
36
Both of these studies demonstrated the superi or val ue of dobutami ne stress
echocardi ography; however, there was si gni fi cant overlap of the confi dence i nterval s wi th other
tests. The most i mportant determi nant with respect to the choice of preoperati ve testing i s the
expertise of the local i nsti tuti on. The deci si on to perform further i nvasi ve testi ng shoul d be based
on the knowledge that the i nterventi on wil l affect both short- and l ong-term outcomes.
Assessment of Ventricular and Valvular Function
Both echo and radi onucl ide angi ography can assess cardi ac ejecti on fracti on at rest and under
stress, but echo i s less i nvasive and i s al so abl e to assess regional wall moti on abnormal i ti es, wall
thickness, val vular functi on, and val ve area. Pul se-wave Doppl er can be used to determi ne the
velocity ti me integral. Ejecti on fracti on can then be cal culated by determini ng the cross-secti onal
area of the ventri cl e. Confl i cti ng resul ts exi st wi th regard to the predi cti ve val ue of ejecti on
fraction

using ei ther echocardiographi c or radi onucli de measurements. Echocardi ography can provide
important i nformati on regardi ng valvul ar function, whi ch may have i mportant i mpl i cations for
ei ther cardiac or noncardi ac surgery, and is di scussed more full y l ater i n this text. Aortic stenosi s
has been associ ated wi th a poor prognosi s in noncardi ac surgi cal pati ents, and knowl edge of
val vul ar l esi ons may modi fy peri operati ve hemodynami c therapy.
9

Coronary Angiography
Coronary angiography i s currently the best method for defining coronary anatomy. In addi ti on,
information regardi ng ventri cul ar and val vul ar functi on can also be assessed. Hemodynami c
indices can be determi ned such as ventricul ar pressures and pressure gradi ents across valves.
Thi s information is routi nel y avail able in pati ents schedul ed for coronary bypass grafti ng.
Narrowing of the l eft mai n coronary artery and certai n other l esi ons may be associ ated wi th a
greater peri operati ve risk. Di ffuse atheroscl erosis i n smal l vessel s, as seen in di abetics, may lead
to i ncomplete revascul ari zati on and a ri sk of devel oping i schemia despite coronary bypass
grafting. Coronary angiography i s used by cardi ologi sts to determine whether coronary
vascul ari zati on i s an opti on.
Unl i ke the exercise or pharmacol ogi c stress tests di scussed earli er, coronary angi ography provi des
anatomic, not functi onal , i nformati on. Al though a cri tical coronary stenosi s del i neates an area of
ri sk for developi ng myocardi al i schemi a, the functi onal response of that i schemi a cannot be
assessed by angi ography al one. A criti cal stenosi s may or may not be the underlying cause for a
peri operative myocardi al i nfarcti on that occurs. In the ambulatory population, many infarctions
are the result of acute thrombosis of a noncriti cal stenosis. Therefore, the value of routi ne
angi ography pri or to noncardi ac surgery depends on the i denti ficati on of l esi ons that wi ll cause
morbidity and mortality.
The Ameri can Col l ege of Physi cian Gui del i nes attempt to appl y the evi dence-based approach.
37
The
initi al decisi on poi nt i s the assessment of risk using the Detsky modi fi cati on of the CRI.
10
If
patients are Cl ass II or III, they are consi dered high risk. If they are Cl ass I, the presence of
other cl i ni cal factors can be used to further strati fy ri sk. Those who exhi bit mul ti pl e markers for
cardi ovascul ar di sease accordi ng to these ri sk i ndi ces and who are undergoing major vascul ar
surgery are considered appropri ate for further di agnosti c testi ng, ei ther by di pyri damol e i magi ng
or by dobutami ne stress echocardi ography. The Gui del ines suggest that there i s i nsuffici ent
evidence to recommend diagnosti c testi ng for nonvascul ar surgery pati ents.
P er i oper at i ve Cor onar y I nt er vent i ons
The strategi es to reduce the peri operati ve risk of noncardi ac surgery have recentl y been studi ed.
There are several large studi es that suggest that i n pati ents who survi ve CABG, the risk of
P.483
subsequent noncardi ac surgery i s low.
5, 8
Whi le there i s li ttl e data to support the notion of
coronary revascul ari zati on sol el y for the purpose of i mprovi ng perioperative outcome, i t i s true
that for some patients schedul ed for hi gh-ri sk surgery long-term survi val may be enhanced by
revasculari zation. Two studies uti l ized the Coronary Artery Surgery Study database and found that
CABG si gni fi cantl y improved survi val i n those pati ents with both peri pheral vascul ar di sease and
tripl e-vessel coronary di sease, especi al l y the group wi th depressed ventri cul ar functi on.
6
After
revi ewi ng al l avai l abl e data, most cl inici ans beli eve the indicati on for CABG pri or to noncardi ac
surgery remai ns the same as i n other setti ngs and is i ndependent of the proposed noncardi ac
surgery.
The val ue of percutaneous transl umimal coronary angi opl asty (PTCA) is l ess well establ ished. The
current evi dence does not support the use of PTCA beyond establ i shed indicati ons for nonoperati ve
patients.
Coronary stent pl acement may be a uni que i ssue. In a case seri es of 39 pati ents who had
undergone coronary stent pl acement withi n 1 month of noncardiac surgery there was a si gni fi cant
inci dence of perioperati ve death and hemorrhage for pati ents who had surgery wi thi n 14 days of
stent pl acement.
31
The authors of the ACC/AHA Gui del i ne recommended waiti ng a minimum of 2
weeks, and preferabl y 4 weeks.
PULMONARY DISEASE
I nt r oduct i on
Pul monary compl i cations remain a major cause of morbidi ty and mortali ty for pati ents undergoi ng
surgery and anesthesia. They occur more frequentl y than cardi ac compl i cati ons, wi th an incidence
of 5 to 10% i n those havi ng major noncardi ac procedures. Peri operati ve pul monary compl i cations
incl ude atelectasi s, pneumonia, bronchi ti s, bronchospasm, hypoxemi a, and respi ratory fai lure
requi ring mechani cal ventil ati on.
38

The site and type of surgery are the strongest predi ctors of compl i cations. Wi th regard to the
surgi cal si te, thoraci c or

upper abdomi nal surgery i s associ ated with the hi ghest risk for postoperati ve pulmonary problems.
Ri sk i ncreases as the incisi on approaches the di aphragm.
38, 39, 40
Decreases i n postoperati ve vital
capaci ty and functi onal resi dual capaci ty, as wel l as di aphragmatic dysfunction, contribute to
hypoxemi a and atel ectasis.
41
Functional resi dual capaci ty may take up to 2 weeks to return to
baseli ne. Diaphragmati c dysfuncti on occurs despite adequate anal gesia and is theori zed to be
because of phreni c nerve i nhibi tion.
42
The types of surgery carryi ng the hi ghest ri sks were AAA
repai r, thoraci c, and upper abdomi nal surgery, fol l owed by neck, peri pheral vascul ar, and
neurosurgery. Neurosurgery and neck surgery may be associ ated wi th peri operative aspi ration
pneumonia.
The need for emergency surgery and the need for general anesthesi a are also associ ated wi th a
sl i ghtly i ncreased ri sk. Not onl y can the surgery affect pulmonary functi on, but general anesthesi a
al so resul ts i n mechani cal changes such as a decrease i n the FRC and altered di aphragmati c
moti on l eadi ng to

/

mi smatch with shunti ng and dead space venti lation. General anesthesi a al so aggravates these
changes by i ts effects at the mi croscopic l evel : i nhi biti on of mucoci li ary cl earance, i ncreased
al veolar-capil l ary permeabi li ty, i nhibi tion of surfactant rel ease, i ncreased ni tri c oxide synthetase,
and increased sensi ti vi ty of the pul monary vasculature to neurohumoral medi ators. Subanestheti c
level s of i ntravenous or volatil e agents have the abil i ty to bl unt the venti l atory response to
hypoxemi a and hypercarbi a. Duration of anesthesi a is a wel l -establ i shed ri sk factor for
postoperative pul monary compli cati ons, wi th morbi di ty rates increasi ng after 2 to 3 hours.
43

However, al though l aparoscopi c surgery i s often l onger i n durati on, the decreased pul monary
P.484
compl i cati ons postoperati vely compared to an open procedure usuall y outwei gh the risks of
increased anesthesi a time.
44

PATIENT-RELATED FACTORS (TABLE 18-7)
Preoperati ve eval uati on of patients with preexi sti ng pul monary disease should i ncl ude assessment
of the type and severi ty of di sease, as well as i ts reversi bi li ty. Because cl inical observations are
often the best predi ctors for the devel opment of postoperati ve pulmonary compl icati ons, a careful
hi story and physi cal exami nation is i mperati ve. The anesthesi ol ogist shoul d i nqui re about exercise
TABLE 18-7 Potential Patient-Related Risk Factors for Postoperative Pulmonary
Complications
POTENTIAL RISK
FACTOR
TYPE OF
SURGERY
UNADJUSTED RELATIVE RISK WITH
ASSOCIATED FACTOR
Smoki ng Coronary bypass 3.4
Abdomi nal 1.44.3
ASA Class > II Unsel ected 1.7
Thoraci c or
abdomi nal
1.53.2
Age > 70 yr Unsel ected 1.92.4
Thoraci c or
abdomi nal
0.91.9
Obesity Unsel ected 1.3
Thoraci c or
abdomi nal
0.81.7
COPD Unsel ected 2.73.6
Thoraci c or
abdomi nal
4.7
ASA, Ameri can Soci ety of Anesthesi ol ogi sts; COPD, chroni c obstructi ve pul monary
di sease.
Adapted from Smetana GW: Preoperati ve pul monary evaluati on. N Engl J Med 340
(12):942, 1999.
intol erance, chronic cough, or unexpl ai ned dyspnea. On physical exam, fi ndings of wheezi ng,
rhonchi , decreased breath sounds, dul l ness to percussi on, and a prol onged expi ratory phase are
i mportant. Preoperati ve pul monary functi on testi ng i s usual l y reserved for those schedul ed for
lung resection, or for those schedul ed for major surgery who have unexplai ned pul monary si gns
and symptoms after a careful history and physi cal exami nati on. Earl y i ntervention hel ps to ensure
that the patient' s medi cal status is opti mal prior to surgery.
Tobacco
The use of tobacco i s an i mportant risk factor, but one that usual ly cannot be infl uenced. Even
among smokers who have not devel oped chroni c lung disease, smoki ng is known to i ncrease
carboxyhemoglobi n l evel s, decrease ci l iary function and i ncrease sputum producti on, as wel l as
cause sti mul ati on of the cardiovascular system secondary to the nicoti ne. Whi le cessation of
smoki ng for 2 days can decrease carboxyhemogl obi n level s, abol i sh the nicoti ne effects, and
improve mucous cl earance, a prospective study by Warner showed that smoki ng cessati on for at
least 8 weeks was necessary to reduce the rate of postoperative pul monary compli cati ons.
45

Because smokers often show i ncreased ai rway reactivi ty under general anesthesi a, i t i s useful to
administer a bronchodi l ator such as al buterol preoperati vel y.
Asthma
Asthma is one of the most common coexi sti ng di seases that confronts the anesthesi ol ogist. Duri ng
the pati ent i ntervi ew i t i s important to eli cit informati on regardi ng inciti ng factors, severi ty,
reversi bi li ty, and current status. Frequent use of bronchodi lators, hospital i zati ons for asthma, and
the requirement for systemic steroi ds are al l indicators of the severi ty of the disease. After an
epi sode of asthma, ai rway hyperreacti vi ty may persist for several weeks.
46
In additi on to
bronchodil ators, peri operative steroi ds are worth consi deri ng as prophyl axis for the severe
asthmatic; for example, hydrocortisone 100 mg i ntravenousl y every 8 hours on the day of surgery.
The possi bil i ty of adrenal i nsuffici ency i s also a concern i n those pati ents who have recei ved more
than a burst and taper of steroi ds i n the previ ous 6 months. Thi s group of pati ents shoul d be
administered stress doses of steroi ds peri operatively. Kabali n et al found there was a l ow
compl i cati on rate for asthmati cs treated wi th short-term steroids undergoi ng surgery.
47

Significantly, they found no associ ati on wi th i mpai red wound heal i ng or infecti ons. For pati ents
using inhal ed steroi ds, they shoul d be admi nistered regul arly starti ng at l east 48 hours pri or to
surgery for opti mal effecti veness.
Endocr i ne Di sease
Diabetes mell i tus is the most common endocri nopathy and has acute and chronic di sease
mani festati ons. Because of thi s and other factors, diabeti cs are more li kel y to require surgery.
Some recent studies i n the cri ti cal care li terature have sparked a trend toward ti ghter
peri operative gl ucose control , especi al l y i n di abeti cs. Because the majori ty of di abetics devel op
di sease i n one or more systems, end-organ di sease must be i dentified and managed careful l y i n
the peri operati ve period. Whi l e l ong-term, cl ose control of gl ucose may l i mi t some of the
mi crovascul ar effects of diabetes (reti nopathy, neuropathy, and nephropathy), macrovascul ar
events, such as myocardial i nfarcti ons or

stroke, may not be altered in i ncidence. Di abetics have an increased ri sk of coronary artery
di sease, perioperative myocardi al i nfarcti on, hypertensi on, and congesti ve heart fai l ure. In
addi ti on, they are more l i kely than the general popul ati on to have cerebral vascul ar, peri pheral
vascul ar, and renal vascular di sease. Myocardi al i nfarcti on or ischemia may be si l ent if diabeti c
autonomi c neuropathy i s present. A high index of suspi ci on for myocardi al i schemi a or past
infarction should be maintained throughout the preoperati ve period. Admini stration of
peri operative beta-bl ockers shoul d be considered in di abeti c patients with coronary artery disease
to hel p l i mi t peri operati ve myocardi al i schemi a. Some may have concerns regardi ng the use of
beta-bl ockade i n diabetics as a resul t of the fears of worseni ng gl ucose intol erance and maski ng
hypoglycemic symptoms. Despi te the controversy, many cl inici ans beli eve di abeti cs benefi t at
P.485
least as much as the general popul ati on i n recei vi ng peri operati ve beta-bl ockers. Si gni fi cant renal
di sease devel ops commonl y in di abeti cs, many ti mes necessi tati ng chroni c di al ysi s. Peri pheral and
autonomi c neuropathi es are common i n di abetics. These defi ci ts should be documented pri or to
anesthesia and surgery wi th the anestheti c plan adjusted accordi ngl y. Joi nt rigi di ty (stiff joi nt
syndrome) may si gnifi cantly affect the temporomandibular, atl antoocci pital, and cervi cal spi ne
joi nts i n patients wi th l ong-standi ng type 1 di abetes. The joi nt l i mi tation may resul t i n di ffi cul ty
with intubati on and should be identi fi ed prior to anesthesi a and ai rway manipulation.
Thyroi d and parathyroid disease have cl i ni cal manifestati ons that are i mportant to the
preoperati ve eval uati on (Tabl e 18-8). Thyroid di sease i s usual ly adequatel y eval uated by cli ni cal
hi story, al though of course, the thyroid functi on tests are more sensi tive. The preoperati ve
eval uation should focus on evaluati ng the si gns and symptoms of hyperthyroi di sm and
hypothyroi di sm. Hypothyroi di sm can l ead to the devel opment of hypothermi a, hypogl ycemi a,
hypoventi lation and hyponatremia, as wel l as a suscepti bi l i ty to depressant drugs.
Anesthesi ol ogists should be al erted to the possibi l i ty of the hypermetabol ic state of thyroid storm
in pati ents wi th hyperthyroidi sm. A large thyroi d mass may di stort the upper ai rway, produci ng
wheezi ng, especi al l y evi dent i n the supine posi ti on. In these cases, a chest x-ray shoul d be
obtai ned looki ng for evi dence of tracheal devi ati on or narrowing. A computed tomography (CT)
scan of the upper ai rway and trachea wi ll provide better detai l of any ai rway compromi se. Pati ents
with hyperparathyroi di sm often have hypercal cemia, i ndi cati ng preoperati ve determi nati on of a
serum cal ci um l evel . The cl assi c fi ndi ngs for pheochromocytoma i ncl ude i ntermi ttent hypertensi on,
headache, diaphoresi s, and tachychardi a. In pati ents wi th other endocrine tumors, a
pheochromocytoma should be ruled out as the cause of unexpl ai ned hypertension as part of a
mul tipl e endocri ne neopl asi a syndrome. The preoperati ve preparati on of a pati ent wi th a
pheochromocytoma i s ful l y di scussed i n Chapter 41. Over ti me the mortal i ty for surgi cal resecti on
of a pheochromocytoma has decreased because of improvements i n peri operati ve therapy for
patients with the syndrome. The important i ssue i s to i dentify pati ents wi th a pheochromocytoma
preoperati vel y before they are schedul ed for other types of surgery. In pati ents on l ong-term
corti costeroi ds, one shoul d have a hi gh i ndex of suspici on for adrenal -corti cal suppression and
Cushi ng' s syndrome. The hal lmark symptoms found i n Cushi ng's syndrome i ncl ude moon faci es,
stri ati ons of the ski n, trunk obesi ty, hypertensi on, easy bruisabil i ty, and hypovol emi a. The
preoperati ve preparati on i ncludes correcti on of the flui d and el ectrol yte abnormal iti es. There i s
consensus that for patients taking corticosteroids for long peri ods that peri operati ve steroid
supplementation is i ndi cated to cover the stresses of anesthesi a and surgery. However, in patients
who have had onl y a short course of steroi ds wi thi n the 12 months prior to surgery, the use of
steroid supplementati on i s controversi al, al though most cl ini ci ans woul d favor their use
preoperati vel y (Tabl e 18-9).
TABLE 18-8 Clinical Manifestations of Thyroid and Parathyroid Diseases
HYPERTHYROIDISM HYPOTHYROIDISM HYPERPARATHYROIDISM
General Wei ght l oss; heat
intol erance; warm,
moist skin
Col d i ntolerance Wei ght l oss, pol ydi psi a
Cardiovascul ar Tachycardi a, atrial
fibri ll ati on,
congesti ve heart
fai l ure
Bradycardi a,
congesti ve heart
fai l ure,
cardi omegal y,
peri cardi al or
pl eural effusi on
Hypertensi on, heart bl ock
Neurologi c Nervousness,
tremor, hyperacti ve
refl exes
Sl ow mental
functi on, mi nimal
refl exes
Weakness, l ethargy,
headache, i nsomnia,
apathy, depressi on
Musculoskeletal Muscl e weakness,
bone resorpti on
Large tongue,
amyl oi dosi s
Bone pains, arthriti s,
pathologi c fractures
Gastroi ntesti nal Di arrhea Del ayed gastri c
emptying
Anorexi a, nausea,
vomiti ng, constipati on,
epi gastri c pai n
Hematol ogi c Anemi a,
thrombocytopeni a

Renal Impai red free
water cl earance
Pol yuri a, hematuria
Adapted from Roi zen MF: Anesthesi a for the pati ent wi th endocri ne disease, Part 1. Curr Rev
Cli n Anesth 6:43, 1987.
TABLE 18-9 Perioperative Corticosteroid Coverage
For mi nor
surgery
The pati ent shoul d take 1.52 ti mes his or her usual prednisone dosage
on the morni ng of surgery. The fol l owing day the pati ent shoul d take hi s
or her normal predni sone dose (or parenteral equi valent if gut cannot be
used). The surgeon and anesthesi ologi st shoul d be aware that the pati ent
i s gl ucocorti coi d dependent and shoul d be prepared to admi ni ster more
steroids if the surgery becomes prol onged or more extensi ve.
For
moderate
surgery
The pati ent shoul d be gi ven 2 ti mes hi s or her usual glucocorticoi d
dosage oral l y (if possi bl e) on the morni ng of surgery and/or 25 mg
hydrocortisone i v before the operati on, then 75 mg hydrocorti sone iv
duri ng the operati on, and 50 mg hydrocortisone i v after the operati on;
then the dose shoul d be rapi dl y tapered over 48 hr to the usual doseif
the postoperative course i s uncompl i cated.
For major
surgery
The pati ent shoul d be gi ven 2 ti mes hi s or her usual glucocorticoi d
dosage oral l y (if possi bl e) on the morni ng of surgery and/or 50 mg
hydrocortisone i v before the operati on, then 100 mg hydrocorti sone iv
duri ng the operati on. After the operati on, 100 mg iv q 8 hr 24 hr
should be admini stered and then rapi dl y tapered (over 4872 hr) to the
patient' s usual gl ucocorti coi d dosageif the postoperati ve course i s
uncompl icated.
Ot her Or gan Syst ems
Renal di sease has i mportant impli cati ons for fl ui d and el ectrolyte management, as well as
metabol i sm of drugs (see Chapter 35). Liver di sease is associated wi th altered protei n bi ndi ng and
vol ume of di stri buti on of drugs, as well as coagul ati on abnormal i ti es (see Chapter 39).
Coagul ati on di sorders may infl uence the choi ce of regi onal anesthesia. The anesthesi ol ogist shoul d
i nqui re about brui si ng, bl eedi ng, and the use of medicati ons that infl uence pl atel et functi on such
as aspi ri n, other nonsteroidal anti -infl ammatory drugs, and anti coagul ants. The peri operati ve
management of hemogl obinopathi es is revi ewed i n Chapter 19. Muscul oskel etal di sorders have
been associ ated wi th an i ncreased ri sk of mal i gnant hyperthermi a. Osteoarthri ti s may resul t i n
di fficul ty exposing the gl otti c openi ng for tracheal intubati on or di ffi cul ty i n posi ti oni ng for
regi onal anestheti c. Because rheumatoi d arthri ti s i s a multi system di sease, i t is i mportant i n such
patients to perform a thorough revi ew of systems. These patients may have restri cti ve lung
di sease, pl eural effusi ons, peri cardi ti s, anemi a, and atl antoocci pi tal i nstabi li ty. Fi nall y, the
anesthesiol ogi st should inqui re about

infecti ous diseases such as HIV or anti bi oti c-resistant infecti ons.
PREOPERATIVE LABORATORY TESTING
The Val ue of P r eoper at i ve Test i ng: Nor mal Val ues
In attempting to determi ne the opti mal choi ce of preoperati ve tests, i t i s important to
understand the interpretati on of the resul ts. Ideall y, tests woul d either confi rm or excl ude
the presence of a disease; however, the vast majori ty of tests onl y i ncrease or decrease the
probabi l ity of di sease. In determi ni ng reference ranges for diagnosti c tests, values that fall
outsi de of the 95% confi dence intervals for normal i ndi vi dual s are consi dered abnormal.
Therefore, up to 5% of normal individual s can have abnormal test resul ts. To determine i ts
cl i ni cal rel evance, a test must be interpreted wi thi n the context of the cl ini cal situation.
Performing tests in pati ents wi th no risk for having the pathophysiol ogi c process of i nterest can
yi el d a high number of fal se-positi ve results. For exampl e, a l ow potassi um (3.0 mg/dL) in an
otherwi se heal thy individual i s most li kel y a normal resul t. Interpreti ng thi s test as abnormal, and
initi ati ng treatment, coul d l ead to harm wi thout any benefit.
THE VALUE OF PREOPERATIVE TESTING: BAYESIAN ANALYSIS
The use of noni nvasive testi ng i s another area in whi ch the cl i ni cal si tuati on si gnificantly affects
the interpretati on. It is rare for a test resul t to be pathognomoni c for a disease state; that i s, no
test is 100% sensi tive and speci fi c. For exampl e, exerci se or pharmacol ogi c stress testi ng has
sensi ti vi ties rangi ng from 60 to 90% and speci fi citi es rangi ng from 60 to 80% for a si gni fi cant
Adapted from Brussel T, Chernow B: Peri operati ve management of endocri ne probl ems:
Thyroi d, adrenal cortex, pi tui tary. Am Soc Anesthesiol 3:48, 1990.
P.486
coronary artery stenosis. To i nterpret the resul ts of a noni nvasi ve test, i t is i mportant to know the
prevalence of disease i n the population as wel l as the sensi tivity and speci fi ci ty of the test. If a
test i s used i n a popul ati on wi th a very low prevalence of disease, a posi tive resul t i s frequentl y a
fal se-positi ve. Si mi l arl y, a negative resul t i n a popul ati on wi th a very hi gh preval ence of di sease
may be a fal se-negati ve. Bayes' theorem suggests a test is most useful i n a popul ati on wi th a
moderate probabi li ty of disease.
75

RISKS AND COSTS VERSUS BENEFITS
The use of medical testi ng is associated wi th significant cost, both in real doll ars and i n potenti al
harm. Routi ne preoperati ve testi ng has been esti mated to cost $3 bi l li on annuall y. An abnormal
test that i s later determi ned to be a false result can l ead to signi fi cant cost and real harm. For
example, a positi ve exerci se electrocardiographi c stress test i n a heal thy 40-year-ol d femal e may
lead to coronary angi ography. Coronary angi ography i s not a beni gn procedure, and can l ead to
vascul ar i njuries. Based on Bayesi an anal ysi s, a posi ti ve test resul t in thi s pati ent is most l ikel y a
fal se-positi ve, and the test was inappropri ately used. Therefore, the woman and her physi cian
woul d gai n no addi ti onal i nformati on, thousands of doll ars i n medi cal costs would accrue, and she
would sustain morbidi ty.
Several studi es have eval uated the i mpl icati ons of reduced testi ng. Gol ub et al retrospecti vely
revi ewed the records of 325 patients who had undergone pre-admi ssion testi ng pri or to
ambul atory surgery.
48
Of these, 272 (84%) had at least one abnormal screeni ng test resul t, whi l e
only 28 surgeri es were del ayed or cancel ed. The authors esti mated that onl y three pati ents
potential ly benefi ted from pre-admission testi ng, including a new diagnosis of di abetes i n one and
nonspeci fi c ECG changes i n two, one of which had known i schemi c heart disease.
In a study publ i shed i n 1991, Narr and coll eagues at the Mayo Cl ini c demonstrated mi nimal
benefits from routine testing and proposed that routi ne l aboratory screening tests were not
requi red i n heal thy pati ents.
49
In a fol low-up study publ ished i n 1997, a cohort of pati ents who
had no preoperative testing duri ng 1994 was reviewed and found to i ncl ude no deaths or major
peri operative morbi di ty.
50
They concl uded that current anestheti c and medi cal practi ces rapi dl y
identi fy indicati ons for laboratory evaluati on when necessary and therefore routi ne testi ng was not
i ndi cated i n thi s heal thy cohort.
Even i f testi ng better defi nes a di sease state, the ri sks of any interventi on based upon the resul ts
may outwei gh the benefi t. Cardi ovascul ar testi ng i s a cl assic example (Fi g. 18-5). If a noni nvasive
test is posi tive, coronary angi ography may be performed. A posi ti ve angi ogram may then result i n
coronary artery bypass grafti ng pri or to the pl anned noncardi ac surgery. Al though cardi ovascul ar
morbidity and mortality may be reduced i n pati ents wi th significant coronary artery di sease who
have undergone coronary revascul ari zati on, the morbi di ty associ ated wi th both the testi ng and
revasculari zation procedure may be greater than any potenti al benefi t.

Roi zen and Cohn have suggested a protocol for screening tests based on the preoperati ve
eval uation using a benefi tri sk analysi s.
51

Recommended Laboratory Testing
Blood Count
Neonates
Physi ol ogi c age 75 yr
Cl ass C procedure
Mal ignancy
Renal di sease
Tobacco use
Anticoagulant use
Coagulation Studies
Chemotherapy
Hepati c di sease
Bl eedi ng di sorder
Anticoagulants
Electrolytes
Renal di sease
Diabetes
Di ureti c, di goxi n, or steroi d use
CNS disease
BUN/Creatinine
Cl ass C procedure
Cardi ovascul ar di sease
Renal di sease
Diabetes
FIGURE 18-5. A decisi on algori thm evaluati ng the deci si on between vascul ar surgery alone
or coronary artery revascul arizati on before vascul ar surgery. There are currentl y no
randomi zed tri als to address the optimal strategy. By outli ni ng the multi ple deci si on poi nts at
whi ch a pati ent can sustai n mortal i ty by choosing to undergo coronary revascul ari zati on first,
the opti mal strategy for preoperati ve eval uati on can be demonstrated. Specifi cal l y, vari ati on
in mortali ties at each deci si on poi nt can change the optimal strategy. (Reproduced with
permi ssi on from Fl eisher LA, Skol nick ED, Hol royd KJ, Lehmann HP: Coronary artery
revasculari zation before abdominal aortic aneurysm surgery: A deci sion anal yti c approach.
Anesth Anal g 79:661, 1994.)
P.487
Di ureti c or di goxi n use
CNS disease
Blood Glucose
Cl ass C procedure
Diabetes
Steroi d use
CNS disease
Liver Function Tests
Hepati c di sease
Hepati ti s exposure
Mal nutriti on
Chest X-Ray
Pul monary disease
Mal ignancy
Radi ati on Therapy
Tobacco 20 p-y
ECG
Cl ass C procedure
Pul monary disease
Radi ati on therapy
Diabetes
Digoxi n use
CNS disease
Pregnancy Test
Possi bl e pregnancy
Albumin
Cl ass C procedure
Mal nutriti on
T/S
Cl ass C procedure
Compl et e Bl ood Count and Hemogl obi n Concent r at i on
The use of a preoperati ve hemogl obin has been suggested as the onl y test necessary in many
patients pri or to el ecti ve surgery; however, even this minimal standard has been questi oned.
Baron et al revi ewed the records of 1,863 pediatri c pati ents scheduled for el ective outpatient
procedures.
52
In onl y 1.1% of patients was the hematocri t abnormal , and i n none of these pati ents
was the procedure canceled or anestheti c plan

modi fi ed. However, a basel i ne hematocri t is sti ll i ndi cated i n any procedure wi th a risk of blood
loss.
The standard regardi ng the l owest acceptabl e peri operati ve hematocrit and i ndicati on for a
preoperati ve transfusion has changed duri ng the past decade. The current recommendati ons of the
Nati onal Bl ood Resource Educati on Commi ttee i s that a hemogl obi n of 7 g/dL i s acceptabl e i n
patients wi thout systemi c di sease. In pati ents wi th systemic di sease, signs of i nadequate systemi c
oxygen del ivery (tachycardi a, tachypnea) are an indicati on for transfusi on.
El ect r ol yt es
In the past, patients routi nel y received a chemi stry panel pri or to surgery. Because of technol ogy
issues, i t may be cheaper to obtain a standard battery than to determine one parti cular test.
However, testi ng rarel y leads to any change in peri operati ve management.
There are numerous gui del i nes regarding the need for preoperati ve electrolytes. The only
consensus i s the l ack of routi ne testi ng i n asymptomatic adults, although a creati nine and gl ucose
has been recommended i n ol der pati ents. In pati ents wi th systemic di seases or on medicati ons
that affect the ki dneys, a BUN and creatinine are i ndi cated.
Coagul ati on Studi es
Coagul ati on di sorders can have si gni fi cant impact on the surgi cal procedure and peri operati ve
management. However, abnormal l aboratory studi es i n the absence of cl i ni cal abnormal iti es wi ll
rarel y l ead to perioperati ve probl ems. Pati ents wi th known i nheri ted coagul opathi es, such as
hemophi l ia or von Wi l lebrand's di sease, requi re preoperati ve preparati on of the pati ent. It i s
important to identi fy such di sorders from or history of bl eedi ng probl ems. A prothrombi n, parti al
thromboplasti n ti me anal ysi s i s i ndi cated i n the presence of previous bl eeding di sorders such as
fol l owing i njuri es; after tooth extracti on or surgi cal procedures; and i n pati ents with known or
suspected l i ver di sease, mal absorpti on or malnutri tion, and on certain medi cati ons such as
anti bi otics and chemotherapeuti c agents.
Bl eedi ng ti me previ ousl y was advocated as a means of determi ni ng the presence of a qual i tati ve
pl atel et defect. However, recentl y cl i ni cians have questi oned the val ue of this test i n cli ni cal
practi ce. The test i s extremel y operator dependent, and some authors have suggested that the
test shoul d be abandoned in favor of cl i ni cal hi story. In the absence of a cli nical bl eedi ng
di athesi s, compli cati ons are extremel y rare. If such a history exi sts, i t may be prudent to avoi d
regi onal anesthesi a.
P r egnancy Test i ng
Routi ne pregnancy testi ng in women of chi ld-bearing potenti al i s a subject of consi derable debate.
The rati onal e i s that speci fi c agents may be avoi ded, or surgery may be del ayed. Informati on
regardi ng the last menstrual peri od can hel p defi ne the potential , but does not el i mi nate the
possi bi li ty. Roi zen and Cohn suggest that pregnancy testi ng should be li mi ted to femal es who
bel i eve they are pregnant or cannot tel l if they are pregnant.
51
However, a number of studi es have
eval uated the vali di ty of hi story as a means of assessi ng pregnancy status i n adol escents wi th
confl i cti ng resul ts. Current practice varies dramati cal ly among centers and anesthesi ol ogi sts and
P.488
may be a function of the population served wi th regard to the need to routi nel y test those women
with a negati ve pregnancy hi story.
Chest X- Rays
A preoperati ve chest x-ray can i denti fy abnormal i ti es that may l ead to ei ther del ay or cancel lation
of the pl anned surgi cal procedure or modificati on of perioperative care. For exampl e, i dentificati on
of pneumoni a, pul monary edema, pulmonary nodul es, or a medi astinal mass could al l lead to
modi fi cati on of care. However, routi ne testi ng in the popul ati on without risk factors can l ead to
more harm than benefi t. Roi zen and Cohn have demonstrated substanti al harm from addi ti onal
procedures based on shadows performed sol el y as a routine preoperative chest x-ray.
51

The Ameri can Col l ege of Physi cians suggests that a chest x-ray i s indi cated in the presence of
acti ve chest di sease or an i ntrathoracic procedure, but not sol ely on the basis of advanced age
al one.
53
Other gui del i nes suggest that a preoperati ve chest x-ray i s reasonabl e i n patients over
the age of 60 years. In a meta-anal ysi s, Archer et al revi ewed the publi shed reports from 1966 to
1992 i n the Engli sh, French, and Spani sh l i terature.
54
Twenty-one reports were identi fi ed wi th
suffi ci ent data to evaluate the use of testing. On average, abnormal iti es were reported in 10% of
routine preoperative chest x-rays, of which onl y 1.3% were unexpected. These findi ngs resul t i n
modi fi cati on i n management i n onl y 0.1% of pati ents, wi th unknown i nfluence on outcome. The
authors esti mated that each fi ndi ng that i nfl uenced management woul d cost $23,000, concl udi ng
that routi ne chest x-rays wi thout a cl i ni cal indi cati on were not justi fi ed. Therefore, a preoperative
chest x-ray i s indi cated in pati ents wi th a hi story or cl ini cal evi dence of active pul monary disease,
and may be i ndi cated routi nel y onl y i n pati ents wi th advanced age.
P ul monar y Funct i on Test s
Pul monary functi on tests can be general l y di vi ded i nto two categories, spi rometry and an arterial
bl ood gas. Spi rometry can provi de informati on on forced vital capaci ty (FVC), forced expi ratory
vol ume i n 1 sec (FEV
1
), rati o of FEV
1
/FVC, and average forced expiratory fl ow from 25 to 75%.
Although each of these measures has a sound physiol ogi c basi s, their practical assessment can
vary greatl y among heal thy persons. Objective measures defi ning high risk for pulmonary
resection have been proposed. For nonpul monary surgery, they rarel y provi de addi ti onal
information beyond that obtained from history. The one possi bl e i ndi cati on i s the use of pul monary
functi on testing wi th bronchodil ator therapy to assess responsi veness in a pati ent who is
wheezi ng.
Wi th the advent of the pul se oximeter, the use of preoperati ve arteri al bl ood gas sampl i ng has
become l ess i mportant. It may stil l be indi cated, si nce determining the baseli ne CO
2
i s useful i n
managing postoperati ve venti l ation settings and resting hypercapni a i s associ ated with increased
peri operative ri sk. However, the physi cal act of obtai ni ng an arteri al blood gas can l ead to
hyperventi l ati on and change the PaCO
2
. One method of assessi ng the probabi l i ty of CO
2
retention
is eval uati on of the serum bi carbonate. A normal serum bi carbonate wi l l vi rtual ly exclude the
di agnosi s of CO
2
retention. If the serum bi carbonate i s elevated, then an arterial bl ood gas ei ther
preoperati vel y or i mmedi atel y pri or to induction may be i ndi cated.
Another i ndi cati on for an arteri al bl ood gas has been determi nati on of oxygen concentration. With
the advent and avail abil i ty of pul se oximetry i n the preoperative screening cl inic, thi s i s rarel y an
indicati on.

SUMMARY
The preoperative evaluati on of the surgi cal pati ent conti nues to be an i mportant component of the
anesthesiol ogi st' s rol e. A thorough history and physi cal exami nation can be used to i denti fy those
medical condi tions that mi ght affect perioperative management and direct further l aboratory
testi ng. In the current era of capitated care and the desire to reduce i nappropri ate uti l i zati on of
medical technol ogy, the anesthesiol ogi st can have a si gnifi cant impact on health resource
P.489
util i zati on by performi ng appropri ate l aboratory tests. By combi ning data from the history,
physi cal exami nati on, exercise tol erance, and the stress of the surgi cal procedure, i nappropri ate
testi ng can be reduced; but more i mportantl y, appropri ate screeni ng tests wi l l be performed.
PREOPERATIVE MEDICATION
Anestheti c management for pati ents begi ns wi th preoperati ve psychol ogi cal preparati on and,
i f necessary, preoperati ve medication. Speci fi c pharmacologi c acti ons shoul d be kept i n mi nd
when these drugs are admi ni stered before operati on, and they shoul d be tai l ored to the needs of
each patient. The anesthesi ologist shoul d assess the pati ent' s mental and physi cal condi ti on
duri ng the preoperati ve vi si t. Because i t i s part of and the begi nni ng of the anestheti c, choice of
preoperati ve medi cati on i s based on the same consi derations as the choice of anesthesi a,
i ncl udi ng the pati ent' s medi cal probl ems, requi rements of the surgery, and the anesthesi ol ogist's
ski l l s. Sati sfactory preoperative preparation and medi cation faci l itate an uneventful peri operative
course. Poor preparati on may begi n a seri es of probl ems and mi sadventures.
No consensus exi sts on the choi ce of preoperati ve medi cati ons. Thei r use has been domi nated by
tradi tion, whi ch has been modi fied somewhat by the change i n anestheti c agents and techni ques
over the years. Beecher stated that empiri cal procedures firml y establ i shed i n the habits of good
doctors have a li fe, not to say, immortali ty of thei r own.
55
Si mi larl y, the emoti onal attachment
of an anesthesi ol ogi st to his own regi men i s often more obvi ous than his objecti ve assessment of
its effects.
56
Another reason for l ack of consensus may be that several di fferent drugs or
combi nations of drugs can accompli sh the same goals. However, there i s general agreement that
most pati ents shoul d enter the operati ng room after anxi ety has been rel ieved and other specific
goal s have been met through preoperati ve preparati on and medi cation. Thi s shoul d be
accompl i shed wi thout undue sedati on, whi ch can interfere wi th pati ent safety or, gi ven the
dramati c i ncrease in the number of outpatient surgi cal procedures, prolong length of stay i n the
operating room.
PSYCHOLOGICAL PREPARATION
Psychol ogi cal preparati on of the patient i nvol ves the preoperative vi si t and i nterview wi th the
patient and fami l y members. The anesthesi ol ogi st shoul d expl ai n anti ci pated events and the
proposed anestheti c management i n an effort to reduce anxiety and allay apprehensi on. Pati ents
may perceive the day of surgery as the bi ggest, most threateni ng day i n thei r li ves; they do not
wi sh to be treated i mpersonal l y in the operati ng room. The anesthesi ol ogi st' s fi rst di rect
encounter with the pati ent may be in the immediate preoperati ve peri od. A growi ng number of
patients recei ve thei r pre-anesthetic eval uati ons by others in preoperative evaluati on cli ni cs or
just pri or to surgery. Preoperati ve vi si ts must be conducted effici ently, but they must also be
informative and reassuri ng, answeri ng al l questions. Most of the anesthesi ol ogi st' s ti me i s spent
with an unconsci ous or sedated pati ent; therefore, he or she must take ti me before the operati on
to earn the trust and confidence of that pati ent.
Most patients are anxi ous before surgery. Studi es show that, dependi ng on the i ntensi ty of
inqui ry, from 40 to 85% of patients are apprehensi ve before surgery. Preoperati ve anxi ety states
are at a high l evel, and most patients expect apprehensi on to be rel i eved before they arri ve i n the
operating room. The classi c study by Egbert et al showed that an average of 57% of pati ents felt
anxi ous before operati on.
57
An i nformati ve and comforti ng preoperati ve vi si t may repl ace many
mi l l i grams of depressant medi cati on. For example, the study by Egbert and col l eagues showed
that more pati ents were adequatel y prepared for surgery after a preoperati ve intervi ew than after
2 mg/kg of pentobarbi tal gi ven i ntramuscul arly 1 hour before surgery (see Tabl e 18-10).
57

However, psychol ogi cal preparati on cannot accompli sh everythi ng and wi l l not rel ieve al l anxi ety.
Besi des psychol ogi cal preparation, there are other goal s of preoperati ve medicati on. Control of
pai n and sati sfactory l evel s of amnesia or sedati on cannot be achieved wi th consi stent success at
the preoperati ve visi t al one. In addi ti on, emergency si tuati ons may provi de l ittl e or no time for a
preoperati ve i nterview. More seri ousl y i l l or el derl y patients, conversel y, may not tol erate the
physi ol ogi c effects of sedati ve medicati ons. Al ways remember that the substituti on of preoperati ve
depressant drugs for a comforti ng and tactful preoperative vi si t may compromise pati ent safety.
PHARMACOLOGIC PREPARATION
The i deal drug or combi nation of drugs for preoperati ve pharmacol ogi c preparati on i s as el usi ve as
is the i deal anesthetic techni ques and i s not based on a l arge body of data that is ei ther defi ni ti ve
or persuasive. Routi ne administrati on of the same drugs to al l pati ents has fall en into di sfavor as
a sel ective approach has emerged. In sel ecti ng the appropri ate drugs for preoperati ve medi cati on,
the pati ent's psychol ogi cal condi ti on, physi cal status, and age must be consi dered. The surgical
procedure and its durati on are i mportant factors, as wel l. Is thi s an outpati ent procedure? Is it
el ecti ve surgery or emergency surgery? The anesthesi ologist must know the pati ent's weight, pri or
response to depressant drugs, i ncl udi ng unwanted si de effects, and al l ergi es. Fi nal ly, the
anesthesiol ogi st' s experience and fami li ari ty wi th certain preoperative medi cations more than
others are determi nants.
The goal s to be achi eved for each pati ent wi th preoperati ve medicati on are inti mately
invol ved in the selection process (Tabl e 18-11). The desi red goal s may be mul ti pl e and
should

be tai lored to the needs of each pati ent. Some of the goal s, such as reli ef of anxiety and
producti on of sedati on, apply to al most every pati ent, whereas others are i mportant onl y
occasional ly. Prophylaxi s agai nst al l ergi c reacti ons appl i es i n just a few instances. Preventi on of
autonomi c refl exes medi ated through the vagus nerve or an anti emeti c effect may be better
attempted i mmedi atel y before the anti ci pated need rather than achi eved at the time of
preoperati ve medi cati on. Preoperati ve medi cati on regi mens do not produce suffi ci ent obtundation
to be cli nicall y si gnifi cant in reducing anestheti c requirement. Some pati ents should not receive
depressant drugs before surgery. Pati ents wi th l ittle physi ol ogi c reserve, at the extremes of age,
wi th a head i njury, or wi th hypovol emia may be harmed more than helped by many of the
medicati ons normall y used before operati on. In contrast, the conditi ons of others demand that
attempts be made pharmacol ogi cal ly to reduce anxi ety, provi de analgesi a, or dry secreti ons i n the
ai rway to produce a safer peri operati ve course. For el ecti ve surgery, the anesthesi ol ogi st wi ll , i n
most i nstances, want the patient to enter the operati ng room free of anxi ety and sedated, yet
TABLE 18-10 Comparison of Preoperative Visit and Pentobarbital (2 mg/kg im)
(Percentage of Patients)
FELT
DROWSY
FELT
NERVOUS
ADEQUATE
PREPARATION
Control group 18 58 35
Pentobarbi tal group 30 61 48
Preoperati ve visi t 26 40 65
Preoperati ve visi t and
pentobarbi tal
38 38 71
Data from Egbert LD, Battit GE, Turndorf H et al : The val ue of the preoperati ve vi sit by
an anesthestist. JAMA 185:553, 1963.
P.490
easil y arousabl e and cooperati ve. The pati ent shoul d not be overl y obtunded or di splay other
unwanted si de effects of the preoperati ve drugs. The pati ent who asks to be asleep before
leavi ng the hospi tal room should be tol d that apprehensi on and sedati on may be reduced but i t
woul d be unsafe to produce a comatose state. The ti me and route of admi ni strati on of the
preoperati ve medi cati ons are i mportant. As a general rul e, oral medicati ons shoul d be gi ven to the
patient 60 to 90 minutes before arrival i n the operati ng room. It is acceptabl e to admi nister oral
drugs wi th up to 150 mL of water.
58
Intravenous agents produce effects after a few ci rcul ation
ti mes, whi le for full effect, intramuscul ar medicati ons shoul d be gi ven at l east 20 mi nutes and
preferabl y 30 to 60 minutes before the pati ent' s arrival i n the operati ng room. Every attempt
shoul d be made to have the preoperative medi cations achi eve thei r ful l effect before the pati ent' s
arri val in the operating room rather than after inducti on of anesthesi a. The drug(s), doses, route
of administration, and effects shoul d be recorded on the anestheti c record. A l i st of common
preoperati ve medi cati ons i s presented in Tabl e 18-12.
TABLE 18-11 Various Goals for Preoperative Medicine
1. Relief of anxiety
2. Sedation
3. Amnesi a
4. Analgesi a
5. Dryi ng of airway secreti ons
6. Preventi on of autonomi c refl ex responses
7. Reducti on of gastri c fl ui d vol ume and i ncreased pH
8. Antiemeti c effects
9. Reducti on of anestheti c requirements
10. Facil i tati on of smooth i nducti on of anesthesi a
11. Prophyl axi s against al lergic reactions
Modified from Stoelting RK: Psychol ogi cal preparati on and preoperative medi cation. In
Mi l l er RD (ed): Anesthesi a. New York, Churchi ll Li vi ngstone, 1981.
TABLE 18-12 Common Preoperative Medications, Doses, and Administration Routes
MEDICATION ADMINISTRATION ROUTE DOSE (mg)
Diazepam Oral 520
Lorazepam Oral , i m 14
Mi dazolam im 37
iv Ti trati on of 1.02.5-mg doses
Secobarbi tal Oral , i m 50200
Sedat i ve Hypnot i cs and Tr anqui l i zer s
Benzodiazepines
Benzodi azepines are among the most popul ar drugs used for preoperati ve medicati on (Tabl e 18-
13). They are used to produce anxi olysi s, amnesia, and sedation. Because the site of acti on of
benzodiazepi nes i s on speci fi c receptors i n the central nervous system (Fi g. 18-6) there i s
rel ati vely l ittle depressi on of venti l ati on or of the cardi ovascul ar system wi th premedi cant doses.
Benzodi azepines have a wi de therapeuti c index and a l ow i nci dence of toxi city. Other than central
nervous

system depressi on, there are few si de effects of thi s group of drugs. Speci fi cal l y, nausea and
vomiti ng are not usual ly associ ated wi th admi nistrati on of benzodiazepi nes for preoperati ve
medi cati on.
Pentobarbi tal Oral , i m 50200
Morphi ne im 515
Meperi di ne im 50150
Cymeti di ne Oral, im, iv 150300
Rani tidi ne Oral 50200
Metocl oprami de Oral, im, iv 520
Atropine im, i v 0.30.6
Glycopyrrolate im, i v 0.10.3
Scopol ami ne im, i v 0.30.6
im, i ntramuscular; i v, intravenous.
Modi fi ed from Stoel ti ng RK, Mi l ler RD (eds): Basi cs of Anesthesi a.
New York, Churchi ll Li vi ngstone, 1984.
P.491
TABLE 18-13 Comparison of Pharmacologic Variables of Benzodiazepines
DIAZEPAM LORAZEPAM MIDAZOLAM
There are some hazards and unwanted si de effects of the benzodi azepi nes. The central nervous
system depressi on they cause i s sometimes long and excessi ve, especi all y wi th use of l orazepam.
There may be pain at the intramuscul ar or intravenous i njection si te wi th di azepam, as well as the
Dose equi val ent (mg) 10 12 35
Ti me to peak effect after
oral dose (hr)
11.5 24 0.51
El iminati on hal f-ti me (hr) 2040 1020 14
Clearance (mL/kg/mi n) 0.20.5 0.71.0 6.411.1
Volume of di stri buti on
(L/kg)
0.71.7 0.81.3 1.11.7
Adapted from Reves JG, Fragen RJ, Vi ni ck HR et al : Mi dazolam: Pharmacol ogy and uses.
Anesthesi ol ogy 62:310, 1985; and Stoel ti ng RK: Pharmacology and Physi ol ogy i n
Anestheti c Practi ce. Phi l adel phi a, JB Li ppi ncott, 1987.
FIGURE 18-6. Schemati c di agram of possibl e mechanisms for pharmacol ogi c effects of
benzodiazepi nes (BNZs). GABA, -aminobutyri c aci d. (Repri nted from Richter JJ: Current
theories about the mechani sms of benzodi azepi nes and neurol epti c drugs. Anesthesi ology
54:66, 1981.)
possi bi li ty of phl ebi tis. These drugs are not anal gesi c agents. Benzodi azepines may not al ways
produce a cal mi ng effect but may cause agi tati on, as evi denced by restl essness and del i ri um.
Diazepam. Whi le diazepam i s often the standard against whi ch other benzodiazepi nes are
compared, it has l argely been repl aced. Because i t is i nsoluble in water and must be di ssol ved i n
organic sol vents, pain may occur on i ntramuscular or i ntravenous i njecti on. Phl ebi ti s i s often a
sequel a of i ntravenous i njecti on.
Lorazepam. Lorazepam resembl es oxazepam structural ly and i s 5 to 10 ti mes as potent as
di azepam. Lorazepam can produce profound amnesi a, rel ief of anxiety, and sedati on (Fi g. 18-7).
59

When l orazepam i s compared wi th diazepam, their effects are very simi lar. Al though i t i s insol ubl e
in water and requires a solvent such as polyethylene gl ycol or propylene gl ycol , admini stration of
lorazepam, unl i ke di azepam, i s not associated wi th pain on injecti on or phl ebiti s. Prol onged
sedati on i s more li kel y after l orazepam admini stration. Even though the el iminati on hal f-li fe of
di azepam i s l onger than that of l orazepam (20 to 40 hours versus 10 to 20 hours), the effect of
di azepam may be shorter because i t more rapi dly dissoci ates from the benzodi azepi ne receptor.
60

Lorazepam is reli ably absorbed both oral ly and i ntramuscul arly. Maximal effect occurs 30 to 40
mi nutes after i ntravenous injecti on. Bradshaw et al demonstrated cl i ni cal effects 30 to 60 minutes
after oral admi ni strati on of lorazepam.
61
A study by Bl i tt et al demonstrated that l ack of recal l was
not produced unti l 2 hours after intramuscul ar i njecti on.
62
Peak pl asma concentrati ons may not
occur unti l 2 to 4 hours after oral admi ni strati on. Therefore, l orazepam must be ordered wel l
before surgery so that the drug has ti me to be effective before the patient arri ves i n the operati ng
room. Lorazepam al so may be gi ven subl inguall y. As stated previ ously, the el iminati on hal f-li fe is
10 to 20 hours. The usual dose i s about 25 to 50 g/kg. The dose for an adult shoul d usual l y not
exceed 4.0 mg.
59, 60
Wi th recommended doses, anterograde amnesia may be produced for as l ong
as 4 to 6 hours wi thout excessive sedation. Hi gher doses l ead to prol onged and excessi ve sedati on
without more amnesi a. Because of its sl ow onset and l ength of acti on, l orazepam i s not useful i n
instances i n which rapi d awakeni ng i s necessary, such as wi th outpati ent anesthesi a. There are no
acti ve metaboli tes of lorazepam; and because i ts metabol i sm i s not dependent on mi crosomal
enzymes, there is less influence on its effect from age or l i ver disease. As with diazepam, li ttl e
cardi orespiratory depressi on occurs wi th lorazepam. However, there i s the danger of unwanted
FIGURE 18-7. Percentage of patients in each group fail i ng to recall speci fi c events of the
operative day. Medicati ons were administered i ntramuscul arly. (Repri nted wi th permi ssi on
from Fragen RJ, Cal dwel l N: Lorazepam premedicati on: Lack of recall and rel i ef of anxi ety.
Anesth Anal g 55:792, 1976.)
respi ratory depressi on i n those wi th lung di sease.
Midazolam. Mi dazol am has predomi nantl y repl aced the use of diazepam for preoperati ve
medicati on and conscious sedati on. It i s common to admini ster sedati ve doses i ntravenously just
pri or to the tri p to the operating room. The physi cochemical properties of the drug al l ow for i ts
water sol ubi l i ty and rapi d metabol i sm. As wi th other benzodi azepi nes, mi dazol am produces
anxi ol ysis, sedati on, and amnesia. It i s two to three ti mes as potent as di azepam because of its
i ncreased affi ni ty for the benzodi azepine receptor. The usual i ntramuscul ar dose i s 0.05 to 0.1
mg/kg and ti trati on of 1.0 to 2.5 mg at a time i ntravenousl y. There is no i rri tation or phl ebi ti s
with injecti on of mi dazol am. The i ncidence of si de effects after admi ni stration is l ow, al though
depressi on of venti l ati on and sedati on may be greater than expected, especi al l y in el derl y pati ents
or when the drug is combi ned wi th other central nervous system

depressants. There is more rapi d onset of action and predi ctabl e absorption after i ntramuscul ar
injecti on of mi dazolam than after di azepam. The ti me of onset after i ntramuscul ar i njecti on i s 5 to
10 mi nutes, with peak effect occurri ng after 30 to 60 mi nutes. The onset after intravenous
administrati on of 5 mg would be expected to occur after 1 to 2 minutes. In addi ti on to qui cker
onset, more rapi d recovery occurs after mi dazol am admi ni strati on compared wi th di azepam. This
is probably the result of the l ipi d sol ubil i ty of mi dazol am and i ts rapi d di stri buti on i n the
peri pheral ti ssues and metabol i c bi otransformation. For these reasons, midazolam usual ly shoul d
be given wi thi n an hour of i nducti on.
63
Mi dazol am i s metabol i zed by hepati c microsomal enzymes
to essenti al l y i nacti ve hydroxyl ated metabol i tes. H
2
receptor antagoni sts do not interfere wi th i ts
metaboli sm. The el iminati on hal f-li fe of midazol am i s approximately 1 to 4 hours and may be
extended in the el derl y. Tests show that mental functi on usual ly returns to normal withi n 4 hours
of administration.
63
After admi nistrati on of 5 mg, amnesi a l asts from 20 to 30 minutes.
Intramuscul ar admi ni strati on may produce l onger periods of amnesia. The l ack of recal l may be
augmented by concomi tant admi ni strati on of scopol ami ne. The properti es of mi dazol am make it
ideal for shorter procedures.
Other Benzodiazepines. Oxazepam, another benzodi azepi ne that has been used for preoperati ve
medicati on, i s one of the pharmacologi cal ly active metabol ites of diazepam. It i s absorbed sl owl y
after oral admi nistrati on and has an eli minati on hal f-li fe of 5 to 15 hours. Temazepam has been
gi ven i n oral doses of 20 to 30 mg before surgery. It must be gi ven wel l before surgery because
peak plasma levels do not occur until approxi matel y 2 to 2.5 hours after administration. Tri azol am
is a short-acti ng benzodi azepi ne. The adul t oral dose of the drug i s 0.25 to 0.5 mg. Peak pl asma
concentrations occur i n about 1 hour and i ts eli mi nation hal f-li fe i s 1.7 to 5.2 hours. The drug may
become l ong-acti ng in the el derl y. Simi larl y, a study by Pi nnock et al di d not show tri azol am to be
of short durati on when compared wi th di azepam for premedi cati on for mi nor gynecol ogic
surgery.
64
Al prazolam (1 mg) given to adults has been shown to produce a modest reducti on i n
anxiety before surgery.
Barbiturates
Use of barbi turates for preoperati ve medicati on i s a ti me-tested practi ce wi th a l ong record of
safety. These drugs are used pri mari l y for thei r sedati ve effects. Whil e barbi turate admi ni stration
for pharmacol ogi c preparati on before surgery has been replaced in many i nstances by the use of
benzodiazepi nes, they may be useful i n certain setti ngs. There i s li ttl e cardiorespi ratory
depressi on associ ated with the usual preoperative doses. The barbiturates may be gi ven oral l y as
well as parenteral ly, and the drugs are rel ati vel y i nexpensi ve. Barbi turates, however, are unl ikely
to produce sedati on in the presence of pain. In fact, di sori entati on and paradoxical excitati on may
resul t. Low doses of barbi turates have been said to l ower the pai n threshold and be anti anal gesi c.
The agents lack speci fi city of acti on on the central nervous system and have a l ower therapeutic
i ndex than the benzodi azepi nes. Barbi turates shoul d not be used i n patients with certai n kinds of
porphyri a.
Secobarbital. Secobarbi tal usual ly i s admini stered to adul ts i n oral doses of 50 to 200 mg when
used for preoperati ve medi cation. Onset usual l y occurs 60 to 90 mi nutes after admi ni strati on, and
sedati ve effects l ast 4 hours or l onger. Indeed, even though secobarbi tal traditi onal l y has been
P.492
consi dered a short-acti ng barbiturate, i t may impai r performance for as l ong as 10 to 22
hours.
65

Other Sedative Drugs
Hydroxyzine. Hydroxyzi ne is a nonphenothiazi ne tranqui l izer. It i s often given for its proposed
addi ti ve effects to opi oids and does not cause an increase i n si de effects. Hydroxyzi ne has
sedati ve acti on and anxi ol ytic properties. It has l i mi ted anal gesi c properties and does not produce
amnesia. It is an anti hi stamine and an anti emeti c.
Diphenhydramine. Di phenhydramine i s a hi stami ne receptor antagoni st wi th sedati ve and
anti choli nergic acti vi ty. It is al so an antiemeti c. A dose of 50 mg wil l l ast 3 to 6 hours i n an adul t.
Diphenhydrami ne has been used recentl y in combinati on wi th ci metidi ne, steroi ds, and other drugs
for prophyl axis i n patients with chroni c atopy and for prophyl axi s before chemonucl eol ysi s and dye
studi es. Di phenhydramine bl ocks the hi stami ne receptor to prevent effects of hi stami ne
peri pheral ly.
Phenothiazines. Promethazi ne, promazi ne, and perphenazi ne are often used i n combi nati on with
opi oi ds. Phenothi azi nes have sedative, anti choli nergi c, and antiemeti c properti es. These effects,
added to the anal gesi c effects of the opi oi ds, have been used for preoperati ve medi cation.
Opi oi ds
Morphi ne and meperi di ne were hi storicall y the most frequentl y used opi oids for intramuscul ar
preoperati ve medicati on. Recentl y, the use of intravenous fentanyl just before surgery has become
more popul ar. Opi oi ds are used when anal gesi a is needed before operati on. It has been stated i n
the strict sense that unl ess there i s pai n, there is no need for narcoti c in preanesthetic
medi cati on.
66
For the pati ent experienci ng pai n before operati on, the opi oi ds can produce good
anal gesi a and even euphori a. Opi oi ds have been ordered for pati ents before operati on to
amel i orate the discomfort that may occur duri ng regi onal anesthesia or the insertion of invasi ve
moni tori ng catheters or l arge i ntravenous li nes. The dose of opi oi d may need to be reduced i n the
debi l i tated or el derl y pati ent. The elderly pati ent often exhibi ts a reduced sensi ti vi ty to pai n.
Furthermore, el derl y pati ents can have an increased anal gesi c response to opioi ds. Opi oi ds also
have been used before operation i n the opi oid-dependent pati ent.
Preoperati ve admi ni strati on of opioi ds in other setti ngs has been controversial . They have been
gi ven before surgery prior to a ni trous oxideopi oi d anestheti c. This i s done i n an attempt to have
a basal state of anesthesi a on board when the patient arri ves i n the operati ng room and to get a
previ ew of the pati ent' s response to opi oi ds. Opioi ds have been gi ven to pati ents before operati on
to provi de analgesi a on thei r awakeni ng in the recovery room. The other approach is to ti trate the
opi oi d i ntravenousl y during emergence or on the patient' s arrival i n the recovery room.
Preoperati ve admini stration of opi oids can l ower anesthetic requi rements. Thi s may or may not be
cl i ni cal ly significant for a specific pati ent recei vi ng a parti cul ar anestheti c technique. Some
anesthesiol ogi sts use opi oi ds in combi nati on wi th other drugs before operation to faci l i tate
anesthetic i nducti on by mask. It must be remembered that opioi ds decrease venti l ation during
spontaneous breathing and therefore decrease uptake of i nhal ati on drugs. If necessary, the
anesthesiol ogi st may want to use assi sted or control led ventil ati on of the l ungs to overcome the
respiratory depressant effects of the opioi ds. Final ly, opioi ds are not the best drugs to rel i eve
apprehensi on, produce sedati on, or prevent recal l .
Admi ni strati on of opi oids has the potential for causi ng several si de effects. Preoperati vel y, they
usuall y exhi bi t no direct myocardi al effects. However, opi oids do i nterfere wi th the compensatory
constri cti on of smooth muscl es of the peri pheral vascul ature. This may lead to orthostati c
hypotensi on. Hi stami ne release after i njecti on of morphi ne may compound these ci rcul atory
effects. As wi th most preoperati ve medi cati ons, i t i s probabl y safest to have the pati ent remain at
bed rest after opi oi d premedi cati on. The anal gesi c properti es and respiratory

depressant effects of opi oi ds usual l y go hand in hand. The decrease in the carbon di oxi de dri ve at
the medul l ary respi ratory center may be prol onged. Furthermore, there is a decrease i n the
P.493
responsi veness to hypoxi a at the caroti d body after injecti on of onl y l ow doses of opi oids.
67
The
anesthesiol ogi st may wi sh to consi der supplemental oxygen for the pati ent receiving opioi d
premedi cation. In general , the opi oi d agonistantagonists produce l ess respi ratory depressi on, but
they also produce l ess anal gesi a. Rather than euphori a, the opioi ds may produce dysphori a. When
this si de effect does occur, i t is most commonl y seen i n a pati ent who does not have pai n before
operation and has recei ved the opioi d premedi cati on. Nausea and vomi ti ng may result from opi oi d
administrati on. The effect of opi oi ds on the vesti bul ar apparatus leading to moti on si ckness or
stimul ati on of the medul l ary chemoreceptor tri gger zone i s a postulated reason for nausea and
vomiti ng. Chol edochoduodenal sphincter (sphi ncter of Oddi ) spasm has occasi onal l y been noted
subsequent to i njection of opi oids. The opi oid produces smooth muscle constri cti on, which leads to
ri ght upper quadrant pai n. Pai n rel i ef may be achi eved with naloxone or possi bl y gl ucagon.
Occasional ly, the pain from bi li ary tract spasm is diffi cul t to di fferenti ate from the pai n of angi na
pectoris. The admi ni strati on of ni trogl yceri n shoul d reli eve angi na pectori s and pain resul ting from
bi l i ary tract spasm; an opioi d antagoni st shoul d rel i eve onl y pain resulti ng from bi l iary tract
spasm. Some questi on the use of opioi d premedicati on i n patients with bil i ary tract disease. Al l
opi oi ds have the potential to i nduce chol edochoduodenal sphi ncter spasm. Meperi di ne i s less l ikel y
than morphi ne to produce thi s si de effect. Opi oi ds may produce pruri tus. Morphine, possibl y
through hi stami ne rel ease, often produces i tching, especi al l y around the nose. Opioi ds al so may
cause fl ushing, di zzi ness, and mi osi s.
Other drugs are often combined wi th opioi ds for thei r addi tive effects or to overcome the
di sadvantages of opi oi d si de effects. The sedativehypnoti cs and scopol amine are often used with
opi oi ds to produce sedation, anxi ol ysi s, and amnesi a i n addi ti on to anal gesi a. In selected pati ents,
the combi nation of morphine and a benzodi azepi ne or scopol ami ne may be useful for
pharmacol ogic preoperati ve preparati on.
Morphine
Morphi ne i s wel l absorbed after i ntramuscul ar i njecti on. The onset of effect should occur wi thi n 15
to 30 mi nutes. The peak effect occurs in 45 to 90 mi nutes and lasts as long as 4 hours. After
intravenous admi ni strati on, the peak effect usuall y occurs wi thin 20 mi nutes. Morphi ne i s not
rel iabl y absorbed after oral administration. As wi th the other opi oi ds, depressi on of ventil ati on and
orthostatic hypotensi on may occur after i njection of morphine. The effect of morphi ne on the
chemorecepti ve tri gger zone may produce nausea and vomiti ng. Nausea and vomiti ng may al so
occur owi ng to a vestibular component.
Meperidine
Meperi di ne i s about one-tenth as potent as morphi ne. It may be given oral ly or parenteral l y. A
si ngl e dose of meperi di ne usual l y l asts 2 to 4 hours. The onset after i ntramuscular injecti on i s
unpredi ctabl e, and a great deal of variabi li ty i n ti me to peak effect exi sts.
Fentanyl
Fentanyl i s a syntheti c opi oi d agoni st structural l y si mi lar to meperi di ne. It i s 75 to 125 times more
potent than morphi ne in i ts anal gesi c characteri sti cs. The l i pid solubi li ty of fentanyl is greater
than that of morphine, which contributes to its rapi d onset of acti on. Peak pl asma concentrati ons
occur wi thin 6 to 7 mi nutes fol lowi ng intravenous admi ni strati on and i ts el i mi nati on hal f-ti me i s 3
to 6 hours. The drug's short duration of action is attributed to redi stri bution to i nacti ve ti ssues,
such as the lungs, fat, and skeletal muscle. Metabol i sm occurs pri maril y by N-demethyl ati on to
norfentanyl, whi ch i s a l ess potent anal gesic. A decreased clearance rate i n the elderly may
prolong eli mi nation.
In doses of 1 to 2 g/kg intravenously, fentanyl may be used to provi de preoperati ve anal gesi a.
Oral transmucosal fentanyl preparati ons of fentanyl are avai labl e, del iveri ng 5 to 20 g/kg of the
drug. Thi s form has been examined as a premedi cant in both adul ts and chil dren to rel ieve anxi ety
and pai n. Because of a hi gh i nci dence of preoperati ve nausea and vomi ting, oral transmucosal
fentanyl (i n doses greater than 15 g/kg) i s not recommended in chi l dren younger than si x years
of age.
68
Fentanyl causes nei ther myocardi al depression nor hi stami ne release, but may be
associated wi th venti l atory depressi on and profound bradycardia. Synergistic effects with
benzodiazepi nes warrant close observati on when thi s combinati on i s given i n the preoperative
peri od.
Opioid AgonistAntagonists
Opi oi d agoni st-antagonists have been chosen for preoperati ve medi cation in an attempt to reduce
the venti latory si de effects of pure opi oi d agoni sts. However, there i s a cei li ng on the anal gesi a
that can be produced by agoni stantagonist drugs. They are simi lar to the pure opi oi ds wi th
regard to si de effects. In addi ti on, dysphori a may be even more l i kel y to occur after their
administrati on. Another i ssue to remember i s that the agoni stantagonist drug can reduce the
effecti veness of a pure opi oid agoni st needed to control postoperati ve pain. The most commonl y
used opi oid agoni stantagonists are pentazoci ne, butorphanol , and nal buphi ne.
Gast r i c Fl ui d pH and Vol ume
Many pati ents who come to the operati ng room are at ri sk for aspirati on pneumoniti s. The cl assic
example is the patient with acute pai n and a ful l stomach who must have emergency surgery.
The pregnant pati ent, the obese pati ent, the di abeti c, the pati ent wi th hiatal hernia or
gastroesophageal refl ux, al l may be at ri sk for aspi rati on of gastri c contents and subsequent
chemi cal pneumoni ti s. Al though it i s not certai n, i t i s beli eved that in adul ts aspi rati on of more
than 25 mL of gastri c fl ui d wi th a pH l ower than 2.5 wil l cause pulmonary sequel ae. Thi s has not
been, and probabl y never wi l l be, proved in humans. However, using these gui deli nes, some have
estimated that 40 to 80% of pati ents scheduled for el ecti ve surgery may be at ri sk.
69, 70
However,
cl i ni cal ly significant pul monary aspi rati on of gastri c contents i s very rare in heal thy pati ents
havi ng el ecti ve surgical procedures, and few anesthesi ol ogi sts advocate routi ne prophyl axis.
71

The necessi ty of prol onged fasti ng (nothi ng by mouth after mi dni ght) before i nducti on of
anesthesia for elective surgery has been chal l enged.
72
Some i nsti tutions al low i ngestion of clear
li qui ds unti l 3 or even 2 hours before surgery i n sel ected patients. Indeed, gastri c fl ui d vol ume
immedi ately after i nducti on of anesthesi a i s not increased by i ngesti on of 150 mL of water, coffee,
or orange juice 2 to 3 hours earli er. A study by Shevde and Tri vedi descri bed the admi ni strati on of
240 mL of water, coffee, or pulp-free orange jui ce to heal thy vol unteers. Al l had gastri c volumes
of less than 25 mL wi th a sli ght decrease in pH wi thin 2 hours of taking one of the three l iquids.
73

There i s concern about comfort, hypovol emi a, and hypogl ycemi a i n the pedi atri c age group
peri operatively after prol onged fasti ng. An i nvesti gati on by Spl i nter and associ ates concl uded that
dri nki ng cl ear flui d up to 3 hours before schedul ed surgery does not have a measurabl e effect on
gastri c vol ume and pH of heal thy chi ldren aged 2 to 12 years.
74
Other studi es i n infants,

chil dren, and heal thy adults schedul ed for elective surgery have found si mi l ar results. Therefore,
fears that i ngestion of oral fluid on the morni ng of surgery wil l i nvari ably resul t i n a predictabl e
increase i n gastri c fl ui d volume are unfounded. It must be appreci ated, however, that these data
are from healthy pati ents not at risk for aspi ration and appl y onl y to i ngestion of cl ear l i qui ds.
The Ameri can Soci ety of Anesthesi ol ogi sts has defi ned and summari zed preoperati ve fasti ng
practi ces through gui del i nes adapted in 1998 (Tabl e 18-14).
71

P.494
TABLE 18-14 Summary of Fasting Recommendations to Reduce the Risk of Pulmonary
Aspiration
a

INGESTED MATERIAL MINIMUM FASTING PERIOD (APPLIED TO ALL
AGES)
Clear li quids
b
2 hours
Many di fferent ki nds of drugs have been used to al ter gastri c fluid volume and increase the pH of
gastri c fl ui d. Anti chol i nergics, H
2
receptor antagoni sts, antaci ds, and gastroki neti c agents have al l
been used to reduce the possibi l ity of aspirati on pneumoni tis.
Anticholinergics
Nei ther atropi ne nor gl ycopyrrol ate has been shown to be very effecti ve i n i ncreasi ng gastri c fl ui d
pH or reduci ng gastric fluid vol ume.
69, 70
Furthermore, intravenous doses of anti chol i nergics may
cause rel axati on of the gastroesophageal junction (Fi g. 18-8). Therefore, the risk of aspi ration
pneumoniti s may be i ncreased, but thi s speci fi c effect of intramuscul ar admi nistrati on of
anti choli nergics for preoperati ve use has not been proved.
Breast mi lk 4 hours
Infant formula 6 hours
Nonhuman mi l k 6 hours
Light meal (toast and cl ear l i qui ds) 6 hours
a
Appli es only to healthy pati ents who are undergoi ng elective procedures and are not
intended for women i n labor. Foll owing the guidel i nes does not guarantee complete
gastri c emptying.
b
Exampl es of cl ear l i qui ds i nclude water, frui t jui ces wi thout pul p, carbonated beverages,
cl ear tea, and bl ack coffee.
Adapted from Practi ce Gui del i nes for Preoperati ve Fasti ng and the Use of Pharmacol ogi c
Agents to Reduce the Risk of Pul monary Aspi rati on: Appl i cati on to Heal thy Pati ents
Undergoi ng El ecti ve Procedures. A Report by the Ameri can Soci ety of Anesthesi ologi sts
Task Force on Preoperati ve Fasting. Anesthesiol ogy 90:896, 1999.
Histamine Receptor Antagonists
The H
2
receptor antagoni sts cimeti di ne, rani ti di ne, famoti di ne, and ni zati di ne reduce gastri c aci d
secretion. They block the abi li ty of hi stami ne to i nduce secretion of gastri c fl ui d wi th a high
hydrogen i on concentrati on. Therefore, the H
2
receptor antagoni sts i ncrease gastri c fl ui d pH. Thei r
antagonism of the histamine receptor occurs in a sel ecti ve and competiti ve manner. It i s
important to remember that these drugs cannot be expected reliably to affect gastri c fl ui d vol ume
or gastri c emptyi ng ti me. Compared with other premedicants, they have relatively few side
effects. Because there are few side effects, many anesthesiologi sts have advocated the li beral
preoperati ve use of H
2
receptor antagoni sts. Mul ti pl e-dose regi mens may be more effecti ve i n
increasi ng gastri c pH than a si ngl e dose before operati on on the day of surgery. An H
2
antagoni st
also may be used for the al l ergi c pati ent or i n prepari ng a patient for exposure to a tri gger of the
al lergi c response, such as radiol ogi c dye.
Cimetidine. Ci metidi ne usuall y is admini stered i n 150 to 300 mg doses orall y or parenteral ly.
Administrati on of 300 mg of cimetidine orally 1 to 1.5 hours before surgery has been shown to
increase the gastric fluid pH above 2.5 i n 80% of patients.
75, 76
Ci meti di ne can be gi ven
intravenously for those unable to take oral medi cati ons. Ci metidi ne can cross the pl acenta, but
adverse fetal effects are unproved. The gastri c effects of ci metidi ne last as l ong as 3 or 4 hours,
and therefore this drug i s suitable for operati ons of that duration.
Cimeti di ne has few side effects, but there are some of note. It inhi bi ts the hepati c mi xed-functi on
oxi dase enzyme system; therefore, i t can prol ong the hal f-li fe of many drugs, i ncl udi ng diazepam,
chlordi azepoxide, theophyl li ne, propranol ol , and li docaine. The cl i ni cal signi ficance of thi s after
one or two preoperati ve doses of ci meti dine i s uncertain. Li fe-threatening cardiac dysrhythmias,
hypotensi on, cardi ac arrest, and central nervous system depressi on have been reported after
ci metidi ne admini stration. These si de effects may be especi al l y l i kel y to occur in cri ticall y il l
patients after rapid intravenous admi ni strati on. As di scussed previ ousl y, ci meti di ne does not affect
FIGURE 18-8. Barrier pressure (esophageal sphi ncter pressure mi nus gastri c pressure)
before and after intravenous admi ni strati on of gl ycopyrrol ate, 0.3 mg, to adul t patients.
Mean SE. (Repri nted wi th permi ssi on from Brock-Utne JG, Welman RS, Moshal MG et al :
The effect of gl ycopyrrol ate [Robi nul ] on the l ower esophageal sphi ncter. Can Anaesth Soc J
25:144, 1978.)
gastri c fl ui d al ready present.
Ranitidine. Raniti dine i s more potent, speci fi c, and l onger acti ng than cimeti di ne. The usual oral
dose i s 50 to 200 mg. Rani tidi ne, 50 to 100 mg, gi ven parenterall y wil l decrease gastri c flui d pH
within 1 hour. It i s as effective i n reducing the number of patients at ri sk for gastri c aspi ration as
ci meti di ne and produces fewer cardi ovascul ar or central nervous system si de effects. The effects
of rani ti di ne l ast up to 9 hours. Thus, it may be superior to cimeti di ne at the concl usi on of l engthy
procedures i n reduci ng the ri sk of aspi rati on pneumoni ti s duri ng emergence from anesthesia and
extubati on of the trachea.
Other Histamine Receptor Antagonists. Famotidi ne is a thi rd H
2
receptor bl ocker that has been
gi ven preoperati vel y to rai se gastri c fl ui d pH. Its pharmacoki netics are simi lar to those of
ci metidi ne and raniti dine, wi th the excepti on of havi ng a l onger serum eli mi nation hal f-li fe than
the other two drugs. Famotidi ne i n a dose of 40 mg oral l y 1.5 to 3 hours preoperatively

has been shown to be effective i n i ncreasing gastri c pH. Ni zati di ne 150 to 300 mg oral ly 2 hours
before surgery wil l si mil arl y decrease preoperati ve gastri c aci di ty.
77, 78, 79

Antacids
Antaci ds are used to neutral ize the aci d i n gastri c contents. A si ngle dose of antacid given 15 to
30 mi nutes before i nducti on of anesthesi a i s al most 100% effecti ve i n increasi ng gastri c fl ui d pH
above 2.5. The nonparti culate antaci d, 0.3 M sodi um ci trate, is commonl y gi ven before operati on
when an i ncrease in gastric fl ui d pH i s desi red. The nonparticul ate antaci ds do not produce
pul monary damage themsel ves i f aspi rati on of gastri c fl ui d contai ni ng these antaci ds shoul d occur.
Colloid antacid suspension may be more effective than the nonparti cul ate antaci ds in increasi ng
gastri c fl ui d pH. However, aspi rati on of gastric fluid containing particul ate antaci ds may cause
si gni fi cant and persi stent pul monary damage, despi te the i ncrease i n gastri c fl ui d pH. The seri ous
pul monary sequelae have been manifested i n the form of pul monary edema and arteri al
hypoxemi a.
Antaci ds work at the time gi ven. There is no lag time, as wi th the H
2
receptor bl ockers. Antaci ds
are effecti ve on the fl ui d al ready present i n the stomach. Thi s makes them especi al l y attracti ve in
emergency si tuati ons for those pati ents who are abl e to take medicati ons orall y.
However, antaci ds do i ncrease gastri c fl ui d vol ume, unl i ke H
2
receptor bl ockers.
75
The ri sk of
aspi rati on depends on both the pH and the vol ume of gastric content. The increase i n gastri c fl ui d
vol ume from antaci d admi ni strati on may become readi l y apparent after repeated doses, such as
duri ng l abor, during which opi oi d admini stration may al so contri bute to del ayed gastri c emptyi ng.
Wi thhol di ng antaci ds because of concern about increasi ng gastri c volume i s not warranted,
consi deri ng ani mal evi dence documenti ng i ncreased mortal ity after aspi rati on of low vol umes of
aci di c gastri c fl ui d (0.3 mL/kg, pH 1) compared wi th aspi rati on of large volumes of buffered
gastri c fl ui d (1 to 2 mL/kg, pH 1.8).
80
Antaci ds may sl ow gastri c emptyi ng, and compl ete mi xi ng
with al l gastri c contents may be questionabl e in the i mmobi l e patient. The effect of antaci ds on
food parti cl es wi thin the stomach is unknown.
Omeprazole
Omeprazol e suppresses gastri c aci d secreti on i n a dose-dependent manner by bi ndi ng to the
proton pump of the pari etal cel l . For an adul t pati ent intravenous doses of 40 mg 30 mi nutes
before i nduction have been used. Oral doses of 40 to 80 mg must be given 2 to 4 hours before
surgery to be effecti ve. Effect on gastri c pH may l ast as l ong as 24 hours. Much l i ke the other H
2

receptor antagonists, investi gators have found increases i n gastri c pH and inconsi stent effects on
gastri c volume with administration of omeprazole.
81, 82, 83

Gastrokinetic Agents
Gastrokineti c agents are useful because of their effecti veness in reduci ng gastri c fl ui d vol ume.
P.495
Metocl oprami de is an exampl e of a gastroki netic agent that may be admi ni stered before operati on.
Metoclopramide. Metocl oprami de i s a dopamine antagoni st that sti mulates upper gastroi ntesti nal
moti li ty, i ncreases gastroesophageal sphi ncter tone, and rel axes the pyl orus and duodenum. It
al so has anti emeti c properties. Metocl opramide speeds gastri c emptyi ng but has no known effect
on aci d secreti on and gastri c fl ui d pH. It may be admi ni stered oral l y or parenteral l y. A parenteral
dose of 5 to 20 mg i s usual ly gi ven 15 to 30 mi nutes before inducti on. When the drug is
administered i ntravenousl y over 3 to 5 minutes, i t usuall y prevents the abdomi nal crampi ng that
can occur from more rapid admi nistrati on. An oral dose of 10 mg achieves onset wi thi n 30 to 60
mi nutes. The el i mi nation half-li fe of metocloprami de i s approxi matel y 2 to 4 hours.
The cli nical useful ness of the gastrokinetic agents is found in those pati ents who are l ikel y to have
large gastri c flui d volumes, such as parturients, pati ents schedul ed for emergency surgery who
have just eaten, obese pati ents, pati ents with trauma, outpati ents, and those wi th gastroparesis
secondary to di abetes mell i tus.
However, the admini stration of metocl opramide does not guarantee gastri c emptyi ng. Signi fi cant
gastri c fl ui d volume may sti l l be present despite its admi ni strati on. The effect of metocloprami de
on the upper gastroi ntesti nal tract may be offset by concomitant atropine admi ni strati on or pri or
injecti on of opi oids. It wi ll not further reduce gastri c vol ume in pati ents undergoing elective
surgery wi th al ready smal l gastri c volumes. It may not be effective after admi ni strati on of sodi um
ci trate. In contrast, metocl oprami de may be especi al l y effective in reducing the risk of aspi ration
pneumoniti s when combi ned wi th an H
2
receptor antagoni st (for exampl e, rani ti di ne) before
el ecti ve surgery.
As menti oned previ ousl y, the drugs used to al ter gastri c fl ui d pH and vol ume are rel ati vel y free of
si de effects. The riskbenefi t rati o for these drugs in reducing the risk of pul monary sequelae from
aspirati on i s often very favorable. Indeed, the drugs do decrease the number of pati ents at ri sk.
However, none of the drugs or combi nations of drugs i s absolutel y rel iabl e i n preventi ng the risk
of aspi rati on pneumoni tis i n al l pati ents al l of the ti me. Therefore, thei r use does not el iminate the
need for careful anestheti c techniques to protect the ai rway duri ng i nducti on, mai ntenance, and
emergence from anesthesi a.
Ant i emet i cs
There are several groups of pati ents i n whom the anti emetic effects of drugs may be helpful i n
reduci ng nausea and vomi ti ng. Droperi dol, metocl opramide, ondansetron, and dexamethasone,
si ngl y or i n combi nati on, are agents i n common usage.
84
These are pati ents schedul ed for
ophthal mol ogi c surgery, patients wi th a pri or hi story of nausea and vomi ting or moti on sickness,
patients schedul ed for l aparoscopic surgery or gynecol ogi c procedures, and pati ents who are
obese. A risk score for predi cti ng postoperati ve nausea and vomi ting after i nhalati on anesthesia
i denti fi ed four ri sk factors: femal e gender, prior hi story of moti on si ckness or postoperati ve
nausea, nonsmoki ng, and the use of postoperati ve opi oi ds. The i nvesti gators suggested
prophyl acti c anti emetic therapy when two or more of the ri sk factors were present when usi ng
85
Many anesthesiologi sts prefer not to administer anti emetics as part of a
preoperati ve regi men, but bel i eve that antiemeti cs shoul d be administered intravenousl y just
before they are needed at the concl usi on of surgery.
Anticholinergics
Previ ously, antichol inergi c drugs were widel y used when i nhal ati on anestheti cs produced copious
respiratory tract secreti ons and i ntraoperati ve bradycardi a was a frequent danger. The advent of
newer inhal ati on agents has al most compl etel y dispell ed the routine use of anti chol i nergic drugs
for preoperati ve medi cati on. Their routi ne use has been questioned by several authors, who
bel i eve that the same care in selecti on of anti choli nergics shoul d be exhi bi ted as i n the choi ce of
other drugs. Speci fi c i ndi cations for an anti chol inergi c before surgery are (1) anti si alagogue effect
and (2) sedati on and amnesi a (Tabl e 18-15). Uses that are l ess firml y establi shed and not
uni versal ly agreed on i ncl ude the preoperati ve prescripti on of
P.496
anti choli nergics for their vagolyti c action or i n an attempt to decrease gastri c aci d secreti on.
Antisialagogue Effect
Antichol inergi cs have been prescribed in a sel ecti ve fashi on when drying of the upper ai rway is
desi rabl e. For exampl e, when endotracheal intubati on i s contempl ated, an anesthesi ol ogist may
want to reduce secreti ons. In the study by Fali ck and Smi ler, conditi ons were more often rated as
sati sfactory after endotracheal i ntubati on when an antichol inergi c drug had been admini stered.
86

The antisi al agogue effect may be i mportant for i ntraoral operati ons and i nstrumentati ons of the
ai rway such as bronchoscopi c examinati on. Administrati on of anti choli nergi cs may be desi rabl e
before the use of topical anesthesia for the airway to prevent a dil uti onal effect of secreti ons and
to all ow contact of the l ocal anesthetic wi th the mucosa.
Scopol ami ne i s a more potent drying agent than atropine. It is l ess li kel y to i ncrease heart rate
and more l i kel y to produce sedation and amnesi a. Glycopyrrolate is a more potent and longer
acti ng anti si al agogue than atropi ne, wi th l ess l i keli hood of i ncreasing heart rate. Because
gl ycopyrrolate is a quaternary ami ne, i t does not easi l y cross the bl ood-brai n barri er and does not
produce sedation. Antichol i nergi cs are not the onl y drugs that can dry secreti ons. As demonstrated
by the study of Forrest et al , several other drugs and pl acebo (presumabl y a reflection of
apprehensi on) can cause a pati ent to have a dry mouth before operati on
87
(Tabl e 18-16).

TABLE 18-15 Comparison of Some of the Effects of Anticholinergic Drugs
ATROPINE GLYCOPYRROLATE SCOPOLAMINE
Increased heart rate +++ ++ +
Anti si al agogue + ++ +++
Sedati on + 0 +++
0, no effect; +, small effect; ++, moderate effect; +++, l arge effect.
Adapted from Stoel ti ng RK: Pharmacol ogy and Physi ol ogy i n Anestheti c Practi ce.
Phi ladelphi a, JB Li ppincott, 1991.
TABLE 18-16 Incidence of Side-Effects 1 Hour After Preoperative Medication
(Percentage of Patients)
MEDICATION DRY
MOUTH
SLURRED
SPEECH
DIZZY NAUSEATED RELAXED
Pentobarbi tal
(50150 mg)
29 27 10 7 2
Secobarbi tal (50 41 32 8 9 4
Sedation and Amnesia
When sedati on and amnesi a are desi red before operation, scopol ami ne is frequentl y the
anti choli nergic chosen, especial ly in combinati on wi th morphine. Scopol amine and atropine both
cross the bl ood-brai n barri er. Scopolami ne is a much more potent sedati ve and amnesti c drug
than atropi ne. In a study of pati ent acceptance of preoperati ve medi cation, the combi nation of
morphi ne and scopol ami ne was superi or to that of morphi ne and atropi ne.
88
Scopolami ne does not
produce amnesi a i n al l pati ents. It may not be as effecti ve as lorazepam or di azepam in
preventi ng recal l . Scopol amine has an addi ti ve amnesti c effect when combined with
benzodiazepi nes. The study by Frumin et al showed that the combi nati on of diazepam and
scopol amine produced amnesi a more often than di d di azepam al one.
89

Vagolytic Action
Vagolyti c acti on of the antichol i nergi c drugs i s produced through the bl ockade of effects of
acetylchol ine on the si noatrial node. Atropine gi ven intravenousl y i s more potent than
gl ycopyrrolate and scopol ami ne i n i ncreasi ng heart rate. The vagol ytic acti on of the anti choli nergic
drugs i s useful in the preventi on of refl ex bradycardi a duri ng surgery. Bradycardia may resul t from
traction on extraocul ar muscles or abdomi nal vi scera, from carotid si nus sti mulation, or after the
administrati on of repeated doses of i ntravenous succi nylchol ine. The preventi on of refl ex
bradycardia with intramuscul ar doses of the antichol inergi cs is unreli able, gi ven the drug dosages
and ti ming usual ly involved wi th preoperati ve medi cation admini stered on the unit. Many
anesthesiol ogi sts prefer to gi ve atropi ne or gl ycopyrrol ate i ntravenousl y just before surgery and
the anti ci pated bradycardic sti mul us. Atropi ne and gl ycopyrrol ate gi ven i ntravenously i mmedi atel y
before surgery have been equal l y effective in preventing bradycardi a resul ti ng from repeated
doses of succi nylchol ine.
Elevation of Gastric Fluid pH Level
High doses of anti chol i nergics often are needed to alter gastri c fl ui d pH. Even then, when gi ven in
150 mg)
Diazepam (515
mg)
35 20 10 3 12
Hydroxyzi ne (50
150 mg)
45 31 6 2 9
Morphi ne (510
mg)
80 33 15 7 20
Meperi di ne (50
100 mg)
85 45 20 12 25
Pl acebo 34 21 7 12 4
Modi fi ed from Forrest WH, Brown CR, Brown BW et al : Subjecti ve responses to si x
common preoperati ve medi cations. Anesthesi ol ogy 47:241, 1977.
the preoperati ve setti ng, anti choli nergi cs cannot be rel ied on consi stentl y to decrease

gastri c hydrogen i on secreti on.
70
Thi s functi on has l argel y been repl aced by the use of H
2
receptor
antagonists (see Gastric Fl ui d pH and Vol ume secti on).
Side Effects in Anticholinergic Drugs
Scopol ami ne and atropi ne may cause central nervous system toxici ty, the so-call ed central
anti choli nergic syndrome. Thi s is most li kel y to occur after the admi ni strati on of scopolami ne, but
can be seen after hi gh doses of atropi ne. The symptoms of central nervous system toxi city
resul ti ng from anti chol inergi c drugs incl ude del i ri um, restl essness, confusi on, and obtundati on.
El derl y pati ents and pati ents wi th pai n appear to be parti cul arl y susceptibl e. The central nervous
system toxi c effect of anti chol i nergics has been noted to be potentiated by i nhal ati on anesthetics.
Some cl i ni cians have successful l y treated the syndrome after i t occurred wi th 1 to 2 mg of
physostigmi ne i ntravenousl y.
The antichol inergi cs rel ax the l ower esophageal sphi ncter. In theory, after parenteral
administrati on of an anti chol inergi c drug, the risk of pul monary aspi ration of gastri c contents i s
increased. This has yet to be proved as an important cl ini cal issue.
Mydri asi s and cyclopl egia from anti chol i nergi c drugs coul d be unwanted in pati ents wi th gl aucoma
because of resulti ng i ncreased i ntraocul ar pressure. Thi s seems unl i kel y wi th the doses used for
preoperati ve medi cati on. Atropine and gl ycopyrrol ate may be l ess l i kely to i ncrease i ntraocular
pressure than scopolami ne. In pati ents wi th glaucoma, most anesthesi ologists feel safe i n
conti nui ng medi cations for gl aucoma up unti l the ti me of surgery and usi ng atropi ne or
gl ycopyrrolate when necessary (see Chapter 33).
Because anti chol i nergic drugs bl ock vagal acti vi ty, rel axati on of bronchi al smooth muscl e occurs
and respi ratory dead space increases. The magni tude of the i ncrease i n dead space depends on
pri or bronchomotor tone, but increases as large as 25 to 33% have been reported. Anti chol i nergic
drugs cause secreti ons to dry and thicken. In theory, a dose of anti chol i nergi c drug gi ven before
operation coul d l ead to i nspi ssati on of secretions and an increase i n ai rway resi stance. Thi s may
develop i nto more than a theoreti cal i ssue when pati ents wi th di seases such as cysti c fi brosi s are
bei ng consi dered.
Sweat gl ands of the body are i nnervated by the sympathetic nervous system and use chol inergi c
transmi ssi on. Therefore, admi ni strati on of anti chol inergi c agents i nterferes wi th the sweati ng
mechani sm, whi ch may cause body temperature to i ncrease. Thi s si de effect of anti chol i nergi c
medicati on must be considered careful l y i n a chil d wi th a fever.
Atropi ne is more l ikel y than gl ycopyrrol ate or scopol amine to cause an i ncrease in heart rate.
Unwanted i ncreases in heart rate are much more li kel y after i ntravenous admi nistrati on than after
intramuscul ar admi ni strati on. In fact, heart rate may transi ently decrease after i ntramuscul ar
administrati on as a resul t of a peri pheral agonist effect of the anti chol i nergi c agent.
Adr ener gi c Agoni st s
Alpha-2 adrenergic agonists have been used as premedi cants.
90, 91
Cl onidi ne in doses of 2.5 to 5
g/kg has been admini stered preoperati vel y to produce sedati on, reduce maximum all owabl e
concentration, and prevent hypertension and tachycardi a from endotracheal intubati on and
surgi cal sti mul ati on. It has even been used as part of anestheti c techni que to produce i nduced
hypotensi on. Dexmedetomidi ne i s another al pha-2 adrenergic agoni st studi ed for preoperati ve use
to attenuate i ntraoperati ve sympathoadrenal responses.
90
After the admini stration of cl oni dine
preoperati vel y, one i s more li kel y to see episodes of hypotension and bradycardi a duri ng
anesthesia when there are periods of li ttl e surgi cal sti mulation. Furthermore, some
anesthesiol ogi sts ask i f preoperati ve al pha-2 adrenergic agonists are a substi tute for a properly
conducted anestheti c i f appropri ate attenti on i s given to depth of anesthesi a.
P.497
Ot her Dr ugs Gi ven wi t h P r eoper at i ve Medi cat i ons
Although they are not preoperati ve medicati ons i n the stri ct sense, other drugs are often gi ven at
the ti me of preoperati ve medicati on. Exampl es of such drugs are i nsuli n, steroi ds, antibi oti cs, and
methadone for pati ents who are addicted to opioi ds. They may be prescribed by either the
anesthesiol ogi st or the surgeon to be given on the ward or in the operating room i mmediately
pri or to surgery. Regardl ess of these factors, thei r actions may affect the anestheti c, and the
anesthesiol ogi st must be knowledgeable about thei r admini stration and acti ons.
Beta-Blockers
For pati ents with known or suspected coronary artery di sease, preoperative beta-bl ockers may add
to safety in the perioperati ve peri od. Cl ini cal studi es have shown that beta-bl ockers i n this setti ng
have reduced mortali ty and the inci dence of nonfatal myocardi al i nfarcti on after surgery. Because
benefi t has been shown wi th several different beta-bl ockers, i t is probabl y a drug cl ass effect or
hemodynamic effect rather than the resul t of empl oying a speci fi c beta-bl ocker. Contraindicati ons
to preoperative beta-bl ocker therapy i ncl ude known al lergy to beta-bl ockers, second- or thi rd-
degree heart bl ock, congestive heart fai lure, acute bronchospasm, l ow systol i c bl ood pressure
(l ess than 100 mm Hg), slow heart rate (l ess than 60 beats per mi nute), and other hemodynami c
instabil i ty. Many cl ini ci ans use ei ther atenol ol (50 to 100 mil l igrams po dai l y) or metoprolol (25 to
50 mi ll i grams po twice dail y). They are chosen because of thei r l ong acti on and rel ati ve beta-1
sel ecti vi ty. The goals are to achieve a heart rate near 50 to 70 beats per mi nute, whi l e
maintai ni ng a systol ic bl ood pressure greater than 110 mm Hg. The beta-bl ockade i s usual l y
maintai ned throughout the perioperative peri od to achi eve maxi mum effect. Intravenous
metoprol ol may be gi ven just pri or to surgery i f inadequate bl ockade has been achi eved wi th the
oral medi cati ons. The oral beta-bl ockers may be started several days pri or to surgery.
Antibiotics
Antibi oti cs are often admi ni stered i mmedi ately before operation for contami nated, potenti al l y
contami nated, or dirty surgi cal wounds. Prophyl acti c anti bi oti cs may be warranted for cl ean
surgi cal procedures when infecti on woul d be catastrophi c. Other instances for the use of
prophyl acti c anti bi otics include i n the i mmunosuppressed patient, in the aged, or i n pati ents
taking steroids. Antibiotics given i mmedi atel y before surgery are also used for the preventi on of
endocardi ti s.
92
Anti bioti c admini stration comes under the anesthesi ol ogist's purvi ew because of
the desi re to have such agents given i mmediately before exposure to pathogens, whi ch i s just
before the begi nni ng of surgery.
It has been estimated that 60 to 70% of surgi cal pati ents receive anti bi oti cs just before surgery or
i ntraoperati vel y. Cephal ospori ns are the most popular. However, no drug or combi nation of drugs
may be reli ed on to protect agai nst al l potenti al pathogens in all patients for al l types of surgery.
As wi th any other medi cati on, the anesthesi ologi st must know the si de effects and compl i cations
of the anti bi oti cs to be admi ni stered. Some are associ ated with al l ergi c reacti ons, hypotension,

and bronchospasm (e.g., peni ci l li n and vancomycin). Al lergic reactions from cephal ospori n
administrati on have been esti mated to occur i n about 5% of pati ents. Cross-reacti vi ty of the
cephal ospori ns i n patients with a known peni ci l l in all ergy has been esti mated at anywhere from 5
to 20%. The aminogl ycosi des, vancomycin, and the pol ymyxi ns have been i mpl i cated in
nephrotoxi ci ty. In addi ti on, ototoxici ty has resul ted from aminogl ycosi de and vancomyci n
administrati on. Pseudomembranous col i ti s i s a known compli cati on of cli ndamyci n admi ni stration.
Fi nal ly, the ami nogl ycosi des are known to extend the neuromuscul ar bl ocki ng effects of muscl e
rel axants.
Steroids
Steroi d admi ni strati on may be necessary i mmedi atel y before surgery in the patient treated for
hypoadrenocorti cism or i n the patient wi th suppression of the pi tuitary-adrenal axi s owi ng to
P.498
present or previ ous admini stration of corti costeroi ds. It is i mpossi bl e to i dentify the specific
duration of therapy or dose of steroi ds that produces pi tui tary and adrenal suppression. Marked
vari abi l ity among pati ents exists. Certainly, more suppressi on may be expected the hi gher the
dose and the l onger the durati on of therapy. A conservati ve esti mate i s to consi der treatment in
any pati ent who has received corti costeroi d therapy for at l east 1 month in the past 6 to 12
months.
Because of di sease states of the pitui tary-adrenal axi s or i ts suppression from steroi d therapy,
patients may not be able to respond to the stress of surgery. The dose and durati on of
suppl emental steroi d admi ni strati on depend on an esti mate of the stress of the surgi cal procedure
in the peri operati ve period. One regimen i s to administer 25 mg of corti sol preoperati vel y and
then gi ve an intravenous i nfusion of 100 mg of cortisol over the next 12 to 24 hours for adult
patients. Another method i s to admi nister 100 mg of hydrocortisone i ntravenousl y before, duri ng,
and after surgery. Thi s dose is meant to equal the esti mated maxi mum amount of steroi d that
stress coul d produce i n pati ents perioperativel y. When consi deri ng whether to admi ni ster steroi ds
or a hi gher dose of steroi ds, the anesthesi ol ogi st should keep i n mind that the ri skbenefi t rati o i s
usuall y very small .
Insulin
Anesthesi a and surgery may i nterrupt the regul ar meal schedul e and insul in admi ni strati on of
di abeti cs (see Chapter 41). Peri operati ve stress may i ncrease serum gl ucose concentrati ons. A
pl an for peri operati ve i nsul i n and glucose management must be agreed on among the
anesthesiol ogi st, the surgeon, and the endocri nol ogi st i nvol ved in the di abeti c pati ent's care.
There are several methods of doi ng this, none of which has proved superior to the others. One
method is to admini ster one-fourth to one-half of the usual dail y dose of i ntermediate-acti ng
insuli n preoperati vel y in the morni ng of surgery and begi n an i nfusion of glucose-contai ning fl ui d.
A second way is to admini ster no i nsul in or no gl ucose preoperati vel y and to measure serum
gl ucose level s frequentl y duri ng anesthesi a. Regular insul in or glucose i s then admi ni stered
intraoperativel y and postoperati vel y as needed. A thi rd method i s to begi n an i nfusion of insul in
and gl ucose i mmedi atel y preoperati vel y and to check serum glucose l evels frequentl y.
Opi oi d Dependency
Wi thdrawal produced by drug cessati on i s a preoperati ve i ssue i n the pati ent who is taking
methadone or i s dependent on other opi oi ds. There shoul d be an attempt to maintai n opi oi d use at
the usual l evel by conti nui ng methadone or substituti ng other appropri ate agents for methodone.
The anesthesi ol ogi st shoul d be cauti oned about using agoni st-antagonist drugs i n these patients i n
the preoperati ve peri od for fear of produci ng wi thdrawal .
DIFFERENCES IN PREOPERATIVE MEDICATION BETWEEN
PEDIATRIC AND ADULT PATIENTS
Differences between chi l dren and adul ts with regard to preoperati ve medi cation incl ude aspects of
psychol ogi cal preparati on, the emphasi s on oral medi cations when pharmacol ogi c preparati on i s
desi red, and more frequent use of anti chol inergics for thei r vagol yti c acti vi ty. What remai ns the
same i s the need to assess the needs of each chi ld individuall y and to tai l or the psychol ogi cal
preparati on and preoperati ve medi cati on accordi ngl y (see Chapter 44).
P sychol ogi cal Fact or s i n P edi at r i c P at i ent s
Hospi tal admi ssi on and major surgery can produce long-lasti ng psychol ogical effects i n some
chil dren. The hospi tal stay is stressful and ful l of apprehensi on over the short term for al most al l
chil dren. The demeanor and communicati ve efforts of the anesthesi ol ogist can make a di fference
to the chi l d and fami l y who are getti ng ready for a tri p to the operating room, anesthesia, and
surgery.
Age is probabl y the most i mportant aspect when psychol ogi cal preparati on of the pedi atri c pati ent
is consi dered.
93
A baby younger than 6 to 8 months of age i s not emoti onall y upset when
separated from hi s or her mother. Others i n the health care team can substi tute very easi ly.
Preoperati ve preparati on i n thi s age group is often di rected toward other goal s, for example,
obtundation of vagal refl ex responses. However, preschool chi ldren are upset when separated from
thei r mothers and fear the operati ng room. This i s an age when hospi tal ization may be the most
upsetting. It is di fficul t to explai n the forthcoming events to chi ldren i n thi s age group. It is easi er
to communi cate wi th pati ents from age 5 years to adolescence. The anesthesiologi st can expl ain
and offer reassurance about such issues as separation from parents and the home, operati ng room
events, and any of the pati ent' s percei ved fears of surgery and anesthesi a. Adol escent patients
may already be anxi ous and apprehensive. They may al so be worried about l oss of consci ousness,
have a fear of death, or be apprehensi ve about what they wi l l do or say after preoperati ve
sedati on or during anesthesi a. The more fearful chi ld may be di fficul t to i denti fy. Thi s is usual l y
the chi ld who i s qui et during the preoperati ve i ntervi ew and appears nonchalant or even detached.
If these patients can be i denti fi ed before operati on, they are often candi dates for heavy
pharmacol ogic preparati on.
P sychol ogi cal P r epar at i on
For the above reasons, a good preoperati ve vi sit and proper psychol ogi cal preparati on may be
even more i mportant in chi l dren than adul ts. Thi s is an art that i s acquired by the
anesthesiol ogi st. The preoperative vi si t is a ti me of reassurance and expl anati on. It i s an
opportunity to gain the chi ld' s trust. Most anesthesiologi sts wi l l want to i nvol ve the parents when
possi bl e. Some hospi tals have found brochures, motion pi ctures, and sl i de shows to be helpful i n
prepari ng pedi atri c pati ents for the operati ng room. The chil d may want to bri ng a personal
bel ongi ng, such as a stuffed ani mal or bl anket, to the operati ng room for security. Some chi ldren
wi sh to take an acti ve rol e by doi ng such thi ngs as hol di ng the face mask duri ng i nhalation
inducti on of anesthesi a. It may be hel pful in a case wi th supporti ve parents to have them
accompany the chi l d to the

operating room suite after an explanation of events that may occur duri ng i nducti on. It i s common
in many hospitals for a parent to go i nto the operati ng room and stay unti l i nducti on i s compl ete.
Di f f er ences i n P har macol ogi c P r epar at i on
The di scussi on of pharmacologi c preparati on for the pedi atri c pati ent presumes proper
psychol ogi cal preparati on, a sati sfactory operati ng room envi ronment, and preparati on for an
effi ci ent and ti mel y i nducti on of anesthesi a (see Chapter 44).
SedativeHypnotics
As i n adul ts, the sedati vehypnoti c medicati ons are used to reduce apprehensi on, produce
sedati on and amnesia, and to facil i tate smooth i nducti on of anesthesi a when an i nhal ati on method
is to be used. The use of preoperative medi cation is controversi al i n pediatric patients and may
not be compl etel y successful i n as many as 20% of instances. It has not been proved to reduce
unwanted psychol ogi cal outcome after surgery and anesthesi a. Nei ther has it been shown that the
uneventful i nducti on of anesthesi a i s l ess li kel y to produce long-lasti ng psychol ogi cal probl ems i n
chil dren. After 6 months to 1 year of age, the chi l d schedul ed for a surgical procedure may benefi t
from a sedati vehypnoti c drug before surgery. There is some emphasi s on avoidi ng intramuscul ar
injecti ons in chi ldren. The oral route i s often used for preoperati ve medi cati on i n the older chi ld,
whereas i n preschool chi ldren drugs may al so be gi ven rectal l y. Many different sedati vehypnoti c
drugs via di fferent routes (oral , i ntranasal , and rectal ) have been prescri bed for chi l dren before
operati on. Mi dazol am can be given intramuscul arl y (0.05 to 0.2 mg/kg). However, the most
effective and acceptable route for midazol am i s the oral route, achi eved by mi xi ng 0.5 to 0.75
mg/kg wi th fl avored syrup, appl e jui ce, or col a because of i ts bi tter taste.
94
It is effective in
producing sedati on and compli ance, but not usual l y sl eep, i n about 15 mi nutes and l asts for 30 to
60 mi nutes. Oral ketamine 5 to 10 mg has been prescri bed 20 to 30 minutes before i nducti on.
Although often all owi ng smooth separation from parents, oral secretions and preoperati ve or
P.499
postoperative deli ri um can be probl ems. Both ketami ne (3 to 8 mg/kg) and mi dazol am (0.2
mg/kg) can be gi ven usi ng a nasal atomizer, with the caveat that nasal drug admi ni strati on and
bi tter aftertaste are di sadvantageous. Ketami ne (5 mg/kg) and mi dazol am (0.3 to 1.0 mg/kg)
have al so been gi ven rectal l y before i nducti on of anesthesi a. A further opti on i n the pharmacol ogic
preparati on of chi l dren i s the rectal admini stration of methohexi tal (Fi g. 18-9). Methohexital (20
to 30 mg/kg) may be gi ven i mmedi atel y before operati on, using pul se oximetry and whil e the chil d
is sti l l in the parent' s arms. The i ntramuscul ar route i s al so possi bl e.
Opioids
There i s the occasi onal need for opi oid premedi cati on in chi l dren. Methadone has the advantage of
oral admi ni strati on, usual l y prescribed i n the 0.1 to 0.2 mg/kg dose range. Intramuscular
morphi ne and meperidi ne are used, often in combi nati on wi th other premedi cati ons. Intramuscul ar
morphi ne is often seen as part of the pharmacol ogi c preparati on for the chi l d wi th congeni tal heart
di sease. In many hospi tal s, opi oids have been combi ned wi th sedativehypnoti c and
anti choli nergic drugs to make a cocktai l that may be gi ven oral l y for preoperati ve medi cati on.
Transmucosal admi ni strati on of fentanyl (5 to 20 g/kg) appears to be effecti ve i n produci ng
sedati on preoperati vel y. However, transmucosal fentanyl may i ncrease gastri c fl ui d vol ume and
al so i ncrease the i nci dence of ri gi dity, respiratory depressi on, pruri tus, nausea, and vomi ting.
68

Fentanyl (2 g/kg) and sufentani l (3.0 g/kg) gi ven by the intranasal route have been shown to
cal m pedi atri c pati ents preoperati vel y. Agai n, postoperati ve nausea and vomi ti ng, i n addi tion to
respiratory compl i cations, have resul ted i n l ack of enthusi asm for thi s technique.
FIGURE 18-9. Frequency di stri buti on of sleep i nducti on times after rectal i nsti l l ation of
methohexi tal . Pati ents averaged 3.3 years i n age and 15 kg i n body wei ght. (Repri nted from
Liu LMP, Goudsouzi an NG, Li u PL: Rectal methohexi tal premedi cation in chi ldren, a dose-
compari son study. Anesthesi ol ogy 53:343, 1980.)
Anticholinergics
Easi l y i nduced vagal reflexes make anti choli nergics especi all y important i n chi l dren. Bradycardi a
may result from ai rway mani pul ati on, surgical mani pul ati on, or anestheti c drugs such as hal othane
or succi nylchol i ne. Al so, the chi ld' s cardi ac output i s more dependent on heart rate than is the
adult' s. If no contraindicati on exists, most pedi atri c pati ents recei ve atropi ne intravenousl y
immedi ately after i nducti on of anesthesi a and pl acement of an intravenous catheter. If the
intramuscul ar route has been used for atropi ne, i t wi ll often be administered i mmediatel y after the
patient becomes unconsci ous during i nducti on of anesthesi a. Glycopyrrol ate also has been used i n
chil dren i n thi s setti ng. Scopolami ne has a pl ace in premedicati on of the pedi atri c pati ent to
produce sedati on, amnesi a, and dryi ng of the airways. One must be aware of the hazards of
administeri ng an anti choli nergi c to a chi ld wi th a fever or when inspissati on of secreti ons is not
wanted. Fi nal l y, i t has been noted that pati ents wi th Down syndrome appear to be sensiti ve to
atropi ne. This i s especi al l y evi dent wi th the effect on heart rate and mydriasis.
(For i nformati on on Anesthesi a for Ambul atory Surgery, see Chapter 46.)
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> Tabl e of Contents > Secti on IV - Prepari ng for Anesthesi a > Chapter 19 - Anesthesi a for Pati ents wi th Rare
and Coexi sti ng Di seases
Chapter 19
Anesthesia for Patients with Rare and Coexisting
Diseases
Stephen F. Dierdorf
J. Scott Walton
KEY POINTS
The muscl e membrane in pati ents wi th muscular dystrophy has an abnormal
structure and is suscepti ble to damage from succi nylchol ine. Massi ve release of
intracel lular contents, especi al l y potassi um, may occur.
Myotoni c dystrophy produces cardi ac conduction del ay that can manifest as
fi rst-, second-, or thi rd-degree atrioventricul ar heart bl ock.
Patients with myastheni a gravi s are exqui si tel y sensi tive to nondepol ari zi ng
muscle rel axants. Short-acti ng muscl e rel axants and careful objecti ve and
cl i ni cal moni toring of neuromuscul ar functi on are i ndi cated.
Many types of cancer i n addi ti on to smal l cell l ung carci noma can produce
myasthenic syndrome.
Patients with mul tipl e sclerosi s should be advised that they may have an
exacerbation of neurologic symptoms duri ng the peri operati ve period.
Repeated epi sodes of sickl i ng i n pati ents wi th sickl e cel l di sease cause
pul monary hypertension. Pul monary hypertension in si ckl e cel l pati ents i s
associated wi th i ncreased mortal i ty.
Rheumatoi d arthri ti s i s a mul tisystem di sease that causes subcli nical cardi ac
and pul monary dysfuncti on.
Many pati ents wi th rheumatoid arthri tis have si gnifi cant degeneration of the
cervi cal spi ne wi th few neurologi c symptoms. Cervical mani pul ati on duri ng
l aryngoscopy and i ntubati on requi res speci al precauti ons.
Esophageal dysfuncti on i n patients wi th scleroderma or dermatomyositi s
Knowl edge of the pathophysi ol ogy of coexi sti ng diseases and an understandi ng of the i mpl i cati ons
of concomi tant drug therapy are essential for the opti mal management of anesthesia for an
i ndi vi dual pati ent. In many instances, the nature of the coexisting di sease has more i mpact on the
management of anesthesi a than does the actual surgical procedure. A vari ety of rare disorders
may i nfl uence the selecti on and conduct of anesthesia (Tabl e 19-1). Recent advances in mol ecular
geneti cs and bi ol ogy have cl arified the pathophysi ology of many uncommon diseases. These
di scoveries have radi cal l y al tered the treatment of some disorders. Consequentl y,
anesthesiol ogi sts must peri odi cal l y update thei r di agnosti c skil l s and cl i ni cal knowl edge to
recogni ze when addi ti onal eval uati on or treatment may be requi red.
increases the risk of aspi rati on pneumoni ti s.
Patients with epi dermolysi s bul l osa can have undiagnosed myocardial
dysfuncti on.
TABLE 19-1 Coexisting Diseases that Influence Anesthesia Management
MUSCULOSKELETAL
Muscular dystrophy
Myotoni c dystrophy
Fami l i al peri odi c paral ysi s
Myastheni a gravi s
Lambert-Eaton (myastheni c) syndrome
Guil l ai n-Barr syndrome
CENTRAL NERVOUS SYSTEM
Mul ti pl e scl erosi s
Epi l epsy
Parki nson' s disease
Hunti ngton' s di sease
Alzhei mer' s disease
Amyotrophi c lateral scl erosi s
Creutzfel dt-Jakob di sease
ANEMIAS
Nutri ti onal defi ci ency
Hemolytic
Hemoglobi nopathi es
Thalassemi as
COLLAGEN VASCULAR
Rheumatoi d arthri ti s
Systemi c l upus erythematosus
Scl eroderma
MUSCULOSKELETAL DISEASES
Muscul ar Dyst r ophy
The cytoskel eton of the muscl e cel l i s composed of different protei ns such as dystrophi n, merosi n,
utrophi n, syntrophi n, dystrobrevi n, and sarcoglycans. Abnormal muscl e proteins or

insufficient quantities of normal protei ns di mi ni sh the i ntegri ty of the muscl e membrane, maki ng i t
more suscepti ble to damage (Fi g. 19-1). The muscular dystrophi es are diseases associ ated wi th
abnormali ties of the muscle membrane (Tabl e 19-2).
1

Pol ymyosi ti s
SKIN
Epi dermol ysis bul l osa
Pemphi gus
P.503
FIGURE 19-1. Muscl e cel l cytoskeleton. (Repri nted wi th permi ssi on from Duggan DJ, Gorospe
JR, Fani n M et al : Mutations i n the sarcogl ycan genes i n pati ents wi th myopathy. N Engl J
Med 336:618, 1997.)
TABLE 19-2 Types of Muscular Dystrophy
Muscular dystrophi es are characteri zed by a progressi ve, but vari abl e l oss of skel etal muscl e
functi on. Al though many of the presenti ng si gns and symptoms of muscular dystrophy are a resul t
of skel etal muscl e weakness, cardiac and smooth muscl e are also affected. In many types of
muscul ar dystrophy, cardi ac muscle dysfuncti on may be more si gni fi cant than skeletal muscl e
dysfuncti on, and preoperati ve evaluati on of cardi ac function can infl uence peri operative
management.
Recent research has revealed a wide vari ety of unrel ated geneti c defects that produce cli ni cal l y
si mi l ar muscl e di seases. It i s sti ll , however, more cl ini cal ly useful to classi fy muscl e diseases by
cl i ni cal expressi on rather than geneti c origi n (Fi g. 19-2).
Duchenne
Becker
Emery-Drei fuss
Li mb-gi rdl e
Ocul opharyngeal
Fasci oscapul ohumeral
Congeni tal muscul ar dystrophy
FIGURE 19-2. Di stri buti on of predomi nant muscl e weakness i n different types of muscul ar
Duchenne's Muscular Dystrophy
Duchenne' s muscul ar dystrophy i s produced by a geneti c abnormal ity resul ting i n a l ack of
producti on of dystrophi n, a major component of the skeleton of the muscle membrane. Duchenne' s
dystrophy i s characteri zed by pai nl ess degenerati on and atrophy of skel etal muscl e. Thi s di sorder
is a sex-li nked recessi ve trai t cl i ni cal ly evi dent i n boys, al though sensi ti ve testing may reveal
subcl i ni cal abnormal i ti es in carri er femal es. Progressi ve muscl e weakness produces symptoms
between the ages of 2 and 5 years and li mitati on of movement usual l y confi nes the pati ent to a
wheel chai r by 12 years of age. Axi al skel etal muscl e i mbalance produces kyphoscoli osi s that often
requi res operative instrumentation for stabi l izati on. Death i s usuall y secondary to congesti ve
heart fail ure or pneumonia. Aggressi ve treatment of cardiopul monary dysfuncti on has i mproved
survi val for many pati ents unti l the age of 30 years. Serum creati ne ki nase l evels refl ect the
progressi on of the disease. Earl y i n the pati ent' s l i fe the creatine ki nase l evel is i ncreased. Later,
as signi ficant amounts of muscl e have degenerated, the creati ne ki nase level decreases.
Invol vement of cardi ac muscl e i s refl ected by a progressive loss of R-wave ampl itude i n the l ateral
precordial l eads of the

el ectrocardi ogram as the pati ent ages. Routi ne echocardi ography can provide i mportant
information about cardi ac functi on and i s i ndi cated at regul ar i nterval s. Progressi ve l oss of
myocardial ti ssue results in cardi omyopathy, ventricul ar dysrhythmi as, and mi tral regurgi tation.
Treatment of cardiac dysfuncti on may i nclude angiotensin-converting enzyme (ACE) inhi bi tors and
beta-adrenergi c bl ockers.
2

Degenerati on of respiratory muscl es can be measured wi th pul monary functi on testi ng
(spirometry), whi ch reveal s a restri cti ve pulmonary di sease pattern. Di mi ni shed muscl e strength
produces an i neffective cough resulti ng i n retention of pul monary secreti ons, pneumoni a, and
death. Smooth muscle involvement causes i ntesti nal tract hypomoti l ity, delayed gastric emptying,
and gastroparesi s.

Although the geneti c defect that causes Duchenne' s dystrophy i s known, speci fi c genetic therapy
remai ns el usive. Current treatment i s supporti ve and di rected at better nutri ti on and i mprovement
of cardi orespiratory functi on.
Emery-Dreifuss Muscular Dystrophy
Emery-Drei fuss muscular dystrophy i s characterized by contractures of the el bows, ankl es, and
spi ne as wel l as humeropectoral muscle weakness. There are two types of Emery-Drei fuss
dystrophy. The autosomal domi nant type i s caused by a defect i n the cel l nuclear protei n lami n,
whi l e the X-li nked recessi ve type i s caused by a defect i n the nuclear protei n emeri n. The skel etal
muscle mani festati ons are usual l y mi ld, whereas cardi ac conduction defects can be fatal .
3

Impl antabl e defi bril l ati ng pacemakers are often i ndi cated for patients wi th Emery-Drei fuss
muscul ar dystrophy.
Limb-Girdle Muscular Dystrophy
Patients with li mb-gi rdle dystrophy exhibi t weakness of the muscles of the shoul der and pelvic
gi rdles. Cardiomyopathy and atrioventricul ar conducti on defects can occur in pati ents wi th l imb-
gi rdle dystrophy. Al though most cases of l i mb-gi rdle dystrophy are i nheri ted as an autosomal
recessi ve trait, some forms are i nheri ted as autosomal domi nant trai ts. Fifteen di fferent geneti c
dystrophy. A. Duchenne-type and Becker-type. B. Emery-Dreifuss. C. Li mb-gi rdl e. D.
Fasci oscapul ohumeral . E. Di stal . F. Ocul opharyngeal. (Reproduced wi th permi ssi on from the
BMJ Publ i shing Group Emery AEH: BMJ 317:991, 1998.)
P.504
P.505
defects have been di scovered and most cause an abnormal ity in the sarcoglycan protei ns.
Fascioscapulohumeral Muscular Dystrophy
Fasci oscapul ohumeral muscul ar dystrophy is i nheri ted as an autosomal domi nant trai t. Pati ents
with thi s di sease have diverse cli ni cal mani festations. Weakness of the facial , scapul ohumeral ,
anterior ti bi al , and pelvic-gi rdle muscles i s promi nent. Other abnormal i ti es i nclude reti nal vascul ar
di sease, deafness, and neurol ogi c dysfuncti on. Cardi ac conduction defects and dysrhythmi as may
occur.
Oculopharyngeal Muscular Dystrophy
Ocul opharyngeal muscul ar dystrophy typically presents in late adulthood. The pri mary cli ni cal
mani festati ons are ptosi s and dysphagi a. Dysphagia i s secondary to pharyngeal skel etal muscl e
weakness and esophageal smooth muscle dysfunction. Weakness of the muscl es of the head, neck
and arms may al so devel op.
Congenital Muscular Dystrophy
Congeni tal muscular dystrophy i s characterized by earl y onset (i nfancy, i n utero) of muscl e
weakness, mental retardati on, feedi ng diffi culti es, and respi ratory dysfunction. Incl uded in thi s
group of muscul ar dystrophi es are merosin-defici ent muscular dystrophy, Fukuyama muscul ar
dystrophy, Walker-Warburg syndrome, Ul ri ch' s di sease, muscl e-eye-brain (MEB) disease, ri gid
spi ne muscul ar dystrophy, central core disease, myotubul ar myopathy, and nemal ine myopathy.
4

Most of the significant compli cati ons from anesthesi a in pati ents wi th muscular dystrophy are
secondary to the effects of anestheti c drugs on myocardi al and skel etal muscl e. Myocardial
dysfuncti on makes pati ents wi th muscular dystrophy more suscepti ble to the myocardi al
depressant effects of potent inhal ed anestheti cs. There are numerous case reports of cardiac
arrest occurri ng duri ng the i nducti on of anesthesi a. These reports are associ ated wi th
rhabdomyol ysi s and hyperkal emi a and have occurred with volatil e anestheti cs al one or i n
combi nati on with succi nylchol i ne. In view of the weakened muscl e structure of pati ents wi th
muscul ar dystrophy, succi nyl chol i ne may damage the muscle membrane and release intracel lular
contents. Succinyl chol i ne i s best avoi ded i n pati ents wi th muscul ar dystrophy. The effect of
vol ati l e anestheti cs on abnormal skeletal muscle i s not known. It coul d be specul ated that vol ati l e
anesthetics, by rel easi ng calci um from the sarcopl asmi c reticulum, coul d damage the muscl e
membrane and cause rhabdomyol ysi s. Sevofl urane is a l ess-potent sti mulus for rel ease of cal cium
from the sarcoplasmi c reti culum and may be the preferred vol ati l e agent for pati ents wi th
muscul ar dystrophy.
5
Some pati ents wi th muscul ar dystrophy may be susceptibl e to mal i gnant
hyperthermi a, but this i s unpredi ctable.
Nondepolari zing muscl e rel axants can be used although pati ents wi th Duchenne' s muscul ar
dystrophy may have prol onged recovery. The response to mi vacuri um i s, however, normal.
6
The
response of pati ents wi th other forms of muscular dystrophy to nondepolarizing muscl e rel axants
is variabl e and close moni toring of neuromuscular functi on i s indi cated.
Degenerati on of gastroi ntesti nal smooth muscl e wi th hypomoti li ty of the i ntesti nal tract and
del ayed gastric emptyi ng in conjuncti on wi th i mpai red swal l owing i ncreases the ri sk of
peri operative aspi ration of gastri c contents. After surgery, the patient with muscul ar dystrophy
must be closely moni tored for evi dence of pul monary dysfuncti on and retention of pul monary
secretions. Vi gorous respiratory therapy and mechani cal venti l ation may be requi red.
The Myot oni as
The myotoni as are a di verse group of di seases that share a common pathol ogi c feature: myotoni a.
Myotoni a i s the del ayed rel axati on of skel etal muscl e after vol untary contraction. Typicall y, muscl e
rel axants and regi onal anesthesi a wi ll not prevent or treat myotonia. Drugs that alter ion channel
acti vi ty and skel etal muscl e membrane excitabi l ity such as mexi l itene, tocai ni de, and qui ni ne may
rel ax a myotonic contracture. Recent research has identi fi ed a wi de variety of geneti c defects that
produce abnormal iti es in i on channel s i n the muscle membrane (Tabl e 19-3). These defects can
occur in the sodi um, chlori de, and calci um i on channel s.
Myotonic Dystrophy (Steinert's Disease)
Myotoni c dystrophy i s the most common of the myotoni c disorders. Myotoni c dystrophy i s an
autosomal l y domi nant i nheri ted disorder wi th symptoms occurri ng during the second and thi rd
decades of li fe. In addi tion to myotoni a, other cli nical features of myotonic dystrophy i nclude
muscl e degenerati on, cataracts, premature baldi ng, diabetes mell i tus, thyroi d dysfuncti on, adrenal
insuffi ciency, gonadal dystrophy, and

cardi ac conducti on abnormal iti es. Myotoni c dystrophy i s the result of an enl arged tri nucl eoti de
repeat of cytosine, thymine, and guani ne (CTG) on chromosome 19. Thi s defect produces a
decrease i n protei n ki nase that causes a degenerati on of the sarcopl asmic reti cul um.
Cardi ac abnormal i ti es have been wel l descri bed i n pati ents wi th myotonic dystrophy. The
most prominent cardiac di sorders include atrioventricual r conducti on delays (A-V block),
atri al flutter and fi bril l ati on, and ventri cular dysrhythmi as. Fi rst-degree A-V bl ock may actual l y
precede the onset of skel etal muscl e symptoms. Sudden death may be a resul t of the abrupt onset
of third-degree A-V block. Other cardiac abnormal iti es associated wi th myotonic dystrophy i nclude
mi tral val ve prol apse, left ventri cul ar di astol i c dysfuncti on, and cardi ac fai l ure.
7

Pul monary functi on studi es demonstrate a restri cti ve l ung di sease pattern, mi l d arteri al
hypoxemi a, and di mi ni shed ventil atory responses to hypoxi a and hypercapni a. Brai nstem
respiratory control mechanisms may al so be defecti ve. Weakness of the respi ratory muscles
di minishes the effecti veness of cough and may l ead to pneumoni a. Myotoni a of the respi ratory
muscles can produce intense dyspnea requiri ng treatment wi th procai nami de. Al terati on of smooth
muscle functi on produces gastri c atony and i ntesti nal hypomotil i ty. Pharyngeal muscl e weakness
i n conjuncti on wi th del ayed gastri c emptyi ng i ncreases the ri sk of aspi ration of gastri c contents.
Pregnancy often produces an exacerbati on of myotoni c dystrophy that may be secondary to
increased l evel s of progesterone. Congesti ve heart fai l ure is al so more l ikel y to occur duri ng
pregnancy. Cesarean section must often be performed because of uteri ne smooth muscl e
dysfuncti on. Some i nfants of mothers wi th myotoni c dystrophy may devel op congeni tal myotoni c
dystrophy. Congeni tal myotoni c dystrophy i s characteri zed by hypotoni a, respiratory insuffi ciency,
and diffi culty wi th feedi ng. Mental retardati on i s common i n patients with the congenital form of
TABLE 19-3 Classification of Myotonic Dystrophy
Protei n kinase defi ci ency
Myotonic dystrophy
Sodi um channel diseases
Hyperkal emi c peri odi c paral ysi s
Paramyotoni c congenita
Cal cium channel di seases
Hypokal emi c peri odi c paral ysi s
Chl ori de channel di seases
Myotonia congenita (Thomsen)
Recessive myotonia
Unknown defect
Proximal myotoni c dystrophy
P.506
myotoni c dystrophy.
Therapy for myotoni c dystrophy i s di rected at treatment of cardiac dysrhythmi as (pacemaker
implantati on) and surgical therapy for cataracts and gal l bladder disease. Mexi l i tene is effecti ve for
the treatment of myotonia. Treatment wi th growth hormone, selenium, vi tami n E, coenzyme Q,
and dehydroepi androsterone may be effecti ve but are as yet unproven.
Other Myotonias
Other forms of myotonic dystrophy i nclude proxi mal myotoni c myopathy, myotoni c dystrophy type
2, and proxi mal myotoni c dystrophy.
Patients with proxi mal myotonic myopathy have myotoni a, proxi mal muscl e weakness, and
cataracts, but no facial muscl e weakness. Cardi ac dysrhythmi as occur l ess frequentl y than in
patients with myotonic dystrophy.
Myotoni c dystrophy type 2 patients have cl i ni cal manifestati ons si mil ar to myotonic type 1
pati ents but have a di fferent mode of inheritance.
Proxi mal myotoni c dystrophy produces cl i ni cal manifestati ons si mil ar to proxi mal myotonic
myopathy but with more severe muscle degeneration.
8

Consi derations for anesthesi a for patients with myotoni c dystrophy include the presence of cardi ac
and respi ratory muscl e di sease and the abnormal responses to drugs used duri ng anesthesi a.
Succi nylchol i ne produces an exaggerated contracture and i ts use shoul d be avoided (Fi g. 19-3).
The myotoni c response to succi nyl chol i ne can be so severe that venti lation and tracheal i ntubation
are di ffi cul t or i mpossi bl e. Most pati ents wi th myotoni c dystrophy devel op a chroni c myopathy and
the response to nondepolari zi ng muscl e rel axants may be enhanced. It would be prudent to use
short-acti ng muscl e rel axants such as mi vacuri um or ci s-atracurium with cl ose moni toring of the
response. Reversal wi th neostigmine may provoke myotoni a. The response to the peripheral nerve
stimul ator must be carefull y interpreted because muscl e stimul ati on may produce myotonia. The
myotoni c response may be mi sinterpreted as sustai ned tetanus when si gni fi cant neuromuscul ar
bl ockade sti ll exists.
FIGURE 19-3. Admi ni strati on of l ow does of succinyl chol i ne to a pati ent wi th myotoni c
dystrophy produces an exaggerated contracti on of skel etal muscl e. (Reprinted wi th
permi ssi on from Mitchel l MM, Al i HH, Savarese JJ: Myotoni a and neuromuscul ar blocking
drugs. Anesthesi a 49:44, 1978.)
Patients with myotonic dystrophy are sensiti ve to the respi ratory depressant effects of opi oids
(systemic and neuraxi al ), barbi turates, benzodi azepines, and inhal ed anestheti cs. The severi ty of
the respi ratory depressi on paral lel s the progressi on of the di sease and may be the resul t of
depressi on of central respi ratory centers as well as peri pheral muscle effects. In a study of more
than 200 pati ents wi th myotoni c dystrophy undergoi ng surgery, respi ratory compli cati ons were
more l i kely to occur in the earl y postoperati ve peri od after upper abdomi nal surgery or i n those
patients i n whom preoperati ve upper extremi ty weakness was cl inicall y evident.
9

No speci fi c anestheti c technique has been shown to be superi or for pati ents wi th myotonic
dystrophy. Hi gher doses of propofol have been associ ated wi th prol onged recovery. Careful l y
control led propofol infusi ons have been successful l y used for pati ents with myotoni c dystrophy.
Inhaled anesthetics may be used but cl ose monitori ng of cardi ac rhythm and cardiovascular
functi on i s i ndi cated. Postoperative mechani cal ventil ati on shoul d be employed until muscle
strength and function return.
10
Successful regi onal anesthesia has been descri bed for both
chi l dren and adul ts wi th myotonic dystrophy.
11

Skeletal muscle weakness and myotoni a are exacerbated duri ng pregnancy. Labor i s typi cal l y
prol onged and there i s an i ncreased i ncidence of postpartum hemorrhage (placenta accreta).
Spinal and epi dural anesthesi a have been successfull y used for pregnant pati ents.
Fami l i al P er i odi c P ar al ysi s
Geneti c research requi red a recl assi fi cation of the peri odic paralyses and some types of
myotoni as. These di seases have been reclassified as the skel etal muscle channel opathi es.
12
The
skel etal muscl e channelopathies i ncl ude hyperkal emi c and hypokal emi c peri odic paralysi s,
paramyotoni a congenita, and potassi um aggravated myotonia.

Hyperkalemic Periodic Paralysis
Hyperkal emi c peri odi c paral ysi s i s i nheri ted as an autosomal dominant trait that causes a mutation
in the sodi um i on channel. Hyperkal emi c peri odi c paralysi s i s characteri zed by epi sodes of
myotoni a and muscl e weakness that may l ast several hours after exposure to a trigger. Weakness
can occur during rest after strenuous exerci se, infusi ons of potassi um, metabol ic aci dosi s, or
hypothermia. The weakness may be so severe that venti l atory support is requi red. The
hyperkalemia i s often transient, occurri ng onl y at the onset of weakness and potassi um l evels
measured duri ng the attack may be normal or decreased. Treatment consi sts of a low-potassium
di et and the admi nistrati on of thi azi de di ureti cs (Tabl e 19-4).
P.507
TABLE 19-4 Clinical Features of Familial Periodic Paralysis
HYPOKALEMIC
Cal cium channel defect
Potassium l evel <3 mEq/L duri ng symptoms
Precipi tating factors
High gl ucose meal s
Strenuous exerci se
Gl ucose-insuli n infusi ons
Stress
Hypothermi a
Other features
Chronic myopathy with aging
HYPERKALEMIC
Sodi um channel defect
Hypokalemic Periodic Paralysis
Hypokal emi c peri odic paral ysis i s i nheri ted as an autosomal dominant trait that produces a defect
in the cal cium ion channel . Paralysi s may be produced by the i ngesti on of carbohydrates,
strenuous exerci se, and the infusi on of gl ucose and insul in. Paral ysis i s usual ly i ncomplete,
affecti ng the li mbs and trunk, but sparing the di aphragm. Vocal cord paral ysi s can cause
respiratory distress. Low potassi um l evels duri ng acute epi sodes can cause cardiac dysrhythmias.
Treatment consi sts of potassi um i nfusion and the admini stration of acetazol amide and
di chl orphenami de. Chroni c muscl e weakness occurs in most patients with hypokal emi c peri odi c
paral ysi s as they age.
The primary goal of the peri operati ve management of pati ents wi th both forms of peri odi c
paral ysi s is the mai ntenance of normal potassi um l evels and avoidance of events that preci pitate
weakness. If possibl e, any electrolyte abnormal ity should be corrected prior to surgery. These
patients may be sensi tive to nondepol ari zi ng muscle rel axants. Short-acti ng muscl e rel axants are
preferred and the response shoul d be moni tored wi th a peri pheral nerve sti mulator.
Succi nylchol i ne i s best avoided as i ts admi ni strati on may al ter serum potassi um l evels. Metabol ic
changes (aci dosi s and al kal osi s) or medi cations (gl ucose and i nsuli n, diureti cs) that reduce
potassium l evel s may ini ti ate an epi sode of paral ysi s. Since changes in the potassi um l evel may
precede the onset of weakness, serial measurement of potassi um l evels duri ng prol onged surgi cal
procedures and the earl y postoperative peri od shoul d be consi dered. The el ectrocardiogram (ECG)
should be conti nuousl y moni tored for evi dence of potassi um-rel ated dysrhythmias. Other
recommendations i ncl ude the avoi dance of carbohydrate l oads, hypothermi a, and excessi ve
hyperventi lation. Any cause of potassi um depl eti on can produce muscl e weakness i n pati ents wi th
hypokal emi c peri odi c paral ysi s. Hal ogenated i nhal ed anesthetics have been admini stered without
compl i cati on. Regi onal anesthesia has al so been successful l y used.
13
Mal i gnant hyperthermi a has
been associ ated wi th both forms of periodic paral ysi s.
After surgery, adequate muscl e strength must be assured before mechani cal venti l ati on of the
lungs i s disconti nued.
Myast heni a Gr avi s
Myastheni a gravi s i s an autoi mmune disease with anti bodi es di rected agai nst the ni coti ni c
acetylchol ine receptor or other muscle membrane protei ns. Ei ghty-five percent of pati ents wi th
myastheni a gravi s have i dentifiabl e anti acetyl choli ne receptor anti bodi es. The majori ty of
previ ously described seronegative patients have been found to have anti bodi es to muscl e-
specific receptor tyrosi ne ki nase (MuSK).
14
Anti acetylchol ine receptor anti bodi es damage the
postsynapti c muscl e membrane vi a a compl ement-mediated reacti on causing an i ncreased
Potassium level normal or >5.5 mEq/L duri ng symptoms
Precipi tating factors
Rest after exerci se
Potassi um i nfusi ons
Metabol ic aci dosi s
Hypothermi a
Other features
Skel etal muscl e weakness may be local i zed to tongue and eyeli ds
degradati on and decreased formati on of acetyl choli ne receptors. The thymus may play a central
role i n the pathogenesi s of myastheni a gravi s as 90% of patients have hi stologi c abnormal iti es
such as thymoma, thymi c hyperpl asia, or thymic atrophy. Many myastheni c pati ents al so have
anti nucl ear and anti thyroid anti bodi es and other autoi mmune diseases such as systemic l upus
erythematosus, rheumatoi d arthriti s, pernici ous anemi a, and thyroi di ti s i s associated wi th
myastheni a gravi s.
The cli nical hall mark of myastheni a gravi s i s skeletal muscle weakness. Typi cal ly, the weakness i s
aggravated by repeti ti ve muscl e use and there are peri ods of exacerbati on al ternati ng wi th
remission. Any skeletal muscle may be affected, although there is a predil ecti on for muscl es
innervated by cranial nerves. Ini ti al symptoms i ncl ude di pl opi a, dysarthria, dysphagi a, or li mb-
muscle weakness. Although respi ratory i nsuffi ci ency is not a common presenting symptom,
undi agnosed myastheni a gravi s should be incl uded in the differenti al diagnosis of respi ratory
fai l ure.
15
A myastheni c cri sis wil l occur i n 15 to 20% of pati ents during the course of thei r
di sease. Myastheni c cri ses are often preci pitated by pul monary i nfections and resul t in respi ratory
fai l ure requiri ng mechani cal venti l ati on. Potenti al cardi ac mani festati ons of myastheni a gravi s
incl ude focal myocarditi s, atrial fi bri l lation, atri oventri cul ar conduction delay, and l eft ventri cul ar
di astoli c dysfuncti on.
Many conditi ons such as vi ral infecti on, pregnancy, extreme heat, stress, and surgery may initi ate
or exacerbate the symptoms of myasthenia, but the response to such stressors i s unpredi ctabl e.
Some pregnant patients have a remission during pregnancy whil e others (20 to 40%) have
increased symptoms during gestation. Postpartum respi ratory fai l ure can occur. Fi fteen to 20% of
neonates born to myasthenic mothers have transi ent myastheni a from passi ve placental transfer
of anti acetyl chol i ne receptor anti bodi es. Si gns and symptoms of neonatal myastheni a begin 12 to
48 hours after birth and may persi st for several weeks.
There are several types of myasthenia gravis. Disease cl assi fi cation is based on skeletal muscle
groups affected as wel l as the age of onset (Tabl e 19-5). The Osserman stagi ng system i s based
on the severi ty of the di sease. Type I: ocular si gns and symptoms onl y; type IIA: general i zed
muscle weakness;

type IIB: general i zed moderate weakness and/or bul bar dysfunction; type III: acute ful minant
presentation and/or respi ratory dysfuncti on; and type IV: severe, general i zed myastheni a.
P.508
TABLE 19-5 Different Presentations of Myasthenia Gravis
ETIOLOGY ONSET SEX THYMUS COURSE
Neonatal
myasthenia
Passage of
anti bodi es
from
myasthenic
mothers
across the
pl acenta
Neonatal Both
sexes
Normal Transient
Congeni tal
myasthenia
Congeni tal
end-pl ate
pathology,
geneti c,
autosomal
recessi ve
02 yr Mal e >
female
Normal Nonfluctuating,
compati bl e
with long
survi val
The di agnosi s of myastheni a gravi s is based on the cl inical hi story, the edrophonium test,
el ectromyography, and the detecti on of ci rculating antiacetylchol ine receptor anti bodi es. No si ngl e
test, however, i s defi ni ti ve. The admi ni strati on of edrophoni um, for exampl e, can i mprove muscl e
strength i n myasthenic patients and in pati ents wi th other neuromuscul ar disorders.
Treatment modal i ti es i nclude the admi ni strati on of choli nesterase inhi bi tors, corti costeroi ds,
i mmunosuppressants, pl asmapharesi s, and thymectomy. The mai nstay of medi cal therapy i s the
chol i nesterase i nhibi tor pyridosti gmi ne. Chol inesterase i nhi bi tors functi on by effecti vel y i ncreasing
the concentration of acetyl chol i ne at the ni coti ni c postsynapti c membrane. Consi stent control of
myastheni a with chol i nesterase i nhi bitors can be qui te chall engi ng. Underdosi ng wi ll resul t i n
increased muscl e weakness, whereas overdosi ng wi ll produce a chol i nergi c cri sis. Excessi ve
amounts of chol i nesterase i nhibi tors produce abdomi nal crampi ng, sal i vati on, bradycardi a, and
skel etal muscl e weakness that mi mi cs the weakness of myastheni a.
The i mmunosuppressi ve effects of corti costeroi ds produce an improvement in muscl e strength in
myastheni c patients al though the precise mechani sm i s unknown. Hi gh-dose corti costeroi ds may,
however, cause a transi ent increase i n muscl e weakness. Other i mmunosuppresants used for the
treatment of myastheni a include azathi opri ne, cycl ospori ne, cycl ophosphamide, tacrol i mus,
ri tuxi mab, and mycophenol ate mofetil . Pl asmapharesi s removes anti acetyl chol i ne receptor
anti bodi es from the ci rcul ati on and i s effective treatment for pati ents in myasthenic cri sis.
Intravenous immunoglobulin may al so be effective for the treatment of myastheni c cri si s.
The associ ati on between the thymus and myastheni a gravi s has been known for decades. The rol e
of thymectomy for the treatment of myastheni a gravi s is, however, not clearl y establ i shed.
Although a thymoma is a clear indicati on for thymectomy, thymectomy for other myastheni c
patients i s controversial . Thymectomy may be more effective if performed i n the earl y stages of
the disease. Shoul d thymectomy be recommended, the surgi cal approach i s al so controversial . It
is not clear whether wi de surgical exposure through a sternal spl i tti ng approach i s better than a
transcervical or a vi deo-assi sted thorascopi c (VATS) approach. The l ess-invasi ve approaches offer
pattern of
inheri tance
Juveni l e
myasthenia
Autoi mmune
di sorder
220 yr Femal e
> mal e
(4:1)
Hyperpl asi a Sl owl y
progressi ve,
tendency to
rel apse and
remi ssi on
Adult
myasthenia
Autoi mmune
di sorder
2040
yr
Femal e
> mal e
Hyperpl asi a
> thymoma
Maximum
severity wi thin
35 yr
Elderl y
myasthenia
Autoi mmune
di sorder
>40 yr Mal e >
Femal e
Thymoma
(beni gn or
local ly
invasive)
Rapi d
progress,
hi gher
mortal i ty
Reproduced wi th permission from Barka A: Anesthesi a and myasthenia gravis. Can J
Anaesth 39:476, 1992.
fewer postoperati ve compli cati ons, but may resul t in an i ncompl ete resection of the thymus.
16

The primary concern i n anesthesi a for the pati ent wi th myastheni a gravi s i s the potenti al
interaction between the di sease, treatment of the di sease, and neuromuscul ar bl ocki ng drugs.
The uncontrol l ed or poorl y control led myastheni c patient is exqui si tel y sensi tive to
nondepol ari zi ng muscl e rel axants. Small defasicul ati ng doses of nondepolarizers can produce
si gni fi cant respiratory muscl e weakness and respi ratory di stress. It shoul d be anti cipated that any
patient wi th myastheni a, no matter how local i zed, wil l have increased sensi ti vi ty to
nondepol ari zi ng muscle rel axants (Fi g. 19-4). An anestheti c techni que that avoi ds the use of a
muscle relaxant may be

preferred for pati ents with myastheni a gravi s.
17
Condi ti ons sui tabl e for tracheal i ntubati on can be
obtai ned wi th a standard i nducti on techni que (thi opental , propofol ) and the i nhalati on of vol ati l e
halogenated agents. Isofl urane, sevofl urane, and desfl urane depress neuromuscular transmi ssi on
and may provi de enough muscl e rel axati on so that tracheal i ntubati on can be performed wi thout
neuromuscul ar bl ocki ng drugs after an adequate depth of anesthesi a has been attai ned. Adjuvant
drugs such as propofol , opi oids, and li docai ne that blunt responses to laryngosocpy may be useful.
Myastheni a and the chol i nesterase i nhibi tor drugs used to treat myastheni a wi ll i nfluence the
response to both depol ari zi ng and nondepolari zi ng muscl e rel axants. Certai n recommendati ons are
i ndi cated. Pretreatment doses of nondepolari zers and l ong-acti ng nondepolari zing muscl e
rel axants (pancuroni um) shoul d not be used i n myastheni c patients. If addi ti onal muscl e
rel axation is required for the procedure, short-acti ng nondepolari zers i n smal l doses should be
used for myasthenic patients. Close, objective moni toring of neuromuscular transmi ssi on and
cl i ni cal effect is necessary. Atracuri um, ci satracuri um, mi vacuri um, vecuroni um, and rocuroni um
have been used. The response of the myastheni c pati ents to these drugs vari es greatl y. Although
patients with myastheni a have a resi stance to succi nyl choli ne, a dose of 1.5 to 2 mg/kg wil l be
adequate for rapid tracheal intubati on. Preoperati ve admi ni strati on of pyridosti gmi ne, however,
may prol ong the acti on of succinyl choli ne and mi vacuri um.
18

P.509
FIGURE 19-4. Dose-response for vecuronium i n normal patients and pati ents wi th
myastheni a gravi s. (Reprinted with permission from Eisenkraft JB, Book WJ, Paparestas AE:
Sensiti vi ty to vecuroni um i n myasthenia gravis: A dose-responsi ve study. Can J Anaesth
37;301, 1990.)
Adjuvant drugs that may exacerbate muscl e weakness in myasthenic pati ents incl ude
aminogl ycosi de antibi oti cs, pol ymyxi ns, beta-adrenergi c bl ockers, procai nami de, corti costeroi ds,
and phenytoi n. Pati ents with myastheni a gravi s may have central respiratory depressi on and the
respiratory depressant effects of barbi turates, benzodi azepines, opi oi ds, and propofol may be
accentuated. Vi gi lant monitori ng of respiratory functi on i s required.
Most modern anestheti c techniques permi t weani ng from mechani cal venti lation and tracheal
extubati on of myastheni c pati ents soon after surgery.
19
Less-invasi ve surgi cal techni ques for
thymectomy, such as a transcervi cal approach or video-assi sted thoracoscopi c thymectomy,
produce l ess di srupti on of respi ratory function than transsternal thymectomy. Because of the
unpredictabi l ity of postoperative recovery, however, i t woul d be prudent to make preoperati ve
arrangements for postoperati ve venti lation. Ri sk factors that i ncrease the l ikeli hood of
postoperative insuffici ency i ncl ude a l ong durati on of myasthenia, chroni c respiratory disease, and
treatment requi ri ng hi gh doses of pyri dosti gmi ne. The pati ent with myastheni a gravi s can be qui te
chal l engi ng to wean from ventil atory support. Skeletal muscl e strength can vary greatl y duri ng a
short peri od of ti me.
Epi dural analgesi a and anesthesi a can be used for l abor and del i very. Muscl e rel axati on i nduced by
regi onal anesthesi a may, however, compound the weakness caused by myasthenia. Thi s potential
synergi sm necessi tates careful moni toring of the pati ent' s muscl e strength. Ami de local
anesthetics may be better than ester local anestheti cs as the metabol i sm of ami des i s not affected
by choli nesterase acti vi ty. Exacerbati ons of myastheni a must be anti ci pated duri ng pregnancy.
Myast heni c Syndr ome ( Lamber t - Eat on Syndr ome)
The Lambert-Eaton myasthenic syndrome (LEMS) i s a di sorder of neuromuscul ar transmission
associated wi th carcinomas, parti cul arly small cel l carci noma of the lung and lymphoprol i ferati ve
di seases (Tabl e 19-6). The onset of the myastheni c syndrome may actual l y precede the discovery
of the mal ignancy by as much as 5 years. LEMS i s an autoi mmune disease in whi ch
i mmunogl obul i n G (IgG) anti bodi es agai nst vol tage-gated cal ci um channel s (presynaptic) are
produced. In those cases associated wi th carcinoma, the autoanti bodi es are di rected at cal cium
channel s in the tumor. These autoantibodi es, however, cross-react wi th calci um channel s at the
neuromuscul ar juncti on. The resul t i s a decreased rel ease of acetyl choli ne in response to nerve
stimul ati on. Typicall y, the pati ent i s a man, 50 to 70 years of age, compl aini ng of proximal
extremi ty weakness (hi p, shoul der) that markedly affects gai t and the abi li ty to stand and cl i mb
stai rs. Rarely, the cli nical presentati on may be respiratory fail ure. Autonomi c dysfunction, such as
xerostomi a, impotence, orthostatic hypotensi on, consti pati on, and al tered sweati ng responses may
al so devel op.
20

TABLE 19-6 Comparison of Myasthenic Syndrome and Myasthenia Gravis
MYASTHENIC SYNDROME MYASTHENIA GRAVIS
Mani festati ons Proximal limb weakness (arms >
legs)
Extraocular, bul bar, and
faci al muscle weakness
Exerci se improves wi th strength Fati gue wi th exerci se
Muscl e pain common Muscl e pain uncommon
Refl exes absent or decreased Refl exes normal
Treatment of the underl yi ng neoplasm may i mprove the neurologic condi tion. The most effecti ve
drug for the treatment of myastheni c syndrome is 3,4-di ami nopyridi ne. 3,4-di ami nopyridi ne
i mproves synapti c transmi ssi on by openi ng vol tage-gated potassi um channel s, which prol ongs the
acti on potential and i ncreases release of acetyl chol i ne. Si de effects of 3,4-di ami nopyridi ne include
peri oral and di gi tal paresthesi as and sei zures. Immunosuppressi on wi th corti costeroi ds,
azathi opri ne, and cycl ospori ne may also be effective.

Pl asmapharesis and intravenous immunoglobul i n may produce short-term i mprovement.
21

Patients with myastheni c syndrome are sensiti ve to the effects of both depol ari zi ng and
nondepol ari zi ng muscle rel axants. Consequently, doses of these drugs should be reduced and
neuromuscul ar function should be moni tored careful l y. The admini stration of 3,4-di ami nopyridi ne
should be conti nued up to the time of surgery.
Because the myastheni c syndrome is di ffi cul t to diagnose, a hi gh index of suspi ci on shoul d be
maintai ned i f unexpected muscl e weakness occurs in pati ents wi th mal ignant tumors.
Although myastheni c syndrome is most frequentl y associ ated with smal l cell carcinoma of the
lung, muscle weakness can occur wi th other mali gnanci es as wel l .
Gui l l ai n- Bar r Syndr ome ( P ol yr adi cul oneur i t i s)
Guil l ai n-Barr syndrome is the most common cause of acute, flacci d paralysi s. Gui l lai n-Barr
syndrome is an autoimmune di sease tri ggered by a bacteri al or vi ral infecti on. The l ist of
infecti ous tri ggers i s l ong and includes Epstei n-Barr vi rus, hemophil us parai nfl uenza, i nfluenza,
adenovi rus, herpes si mpl ex, vari cel la, human i mmunodefi ciency vi rus, mycoplasma, and
campyl obacter. The i nfection triggers an i mmune response that produces anti bodi es to an antigen
of the infecti ous agent. The anti gen mimi cs an epi tope of the Schwann cel l and the antibodi es
damage myel in nerve sheaths.
Most patients have a hi story of a respi ratory or gastroi ntesti nal infecti on withi n 4 weeks of the
onset of neurol ogi c symptoms. Gui ll ain-Barr syndrome is characterized by the acute or subacute
onset of skel etal muscl e weakness or paral ysis of the l egs. Sensory disturbances such as
paresthesi as often precede the paral ysi s. The paral ysi s typicall y progresses cephalad to include
Gender Mal e > female Femal e > male
Coexi sti ng
pathology
Small cell carci noma of the l ung Thymoma
Response to
muscle rel axants
Sensiti ve to succi nyl choli ne and
nondepol ari zi ng muscl e rel axants
Resi stant to succinyl choli ne
Sensi ti ve to
nondepol ari zi ng muscle
rel axants
Poor response to
anti choli nesterases
Poor response to
anti choli nesterases
Repri nted wi th permi ssi on from Stoel ti ng RK, Di erdorf SF (eds): Anesthesia and Co-
existing Di sease, 3rd ed. New York, Churchi l l Livingstone.
P.510
the muscl es of the trunk and arms. Di fficul ty i n swal l owi ng and i mpaired venti lation secondary to
intercostal muscl e paralysi s can occur. Progressi on occurs over 10 to 12 days, fol l owed by gradual
recovery. The most serious immedi ate probl em is venti l atory insuffi ciency. The vi tal capaci ty
should be measured frequently. If the vital capaci ty decreases to l ess than 15 to 20 mL/kg,
mechani cal venti l ation of the l ungs is i ndi cated. The more rapi d the onset of quadri pl egi a, the
more l i kely the need for venti l atory support. Al though 85% of patients wi th this syndrome achi eve
a good or full recovery, chroni c recurrent neuropathy devel ops i n 3 to 5% of pati ents. Subtypes of
Guil l ai n-Barr syndrome incl ude acute i nflammatory demyel i nati ng pol yneuropathy (AIDP), acute
motor axonal neuropathy (AMAN), acute motor-sensory axonal neuropathy (AMSAN), and Mil l er-
Fi sher syndrome (MFS).
The primary therapy for Gui ll ain-Barr syndrome is i ntensi ve respi ratory care and management of
autonomi c dysfuncti on. Intensi ve cri tical care has reduced mortal ity from Gui ll ain-Barr syndrome
to l ess than 5%. Plasmapharesi s and the admi ni strati on of i ntravenous i mmunogl obul in may hel p
al leviate the harmful effects of the di sordered i mmune response.
22

Autonomic nervous system dysfunction occurs i n many pati ents wi th Gui ll ain-Barr syndrome. Thi s
dysfuncti on can produce wi de fluctuations i n cardiovascular parameters. In a manner si mi l ar to
autonomi c hyperreflexi a, physi cal sti mul ati on can preci pitate hypertensi on, tachycardia, and
cardi ac dysrhythmi as. Appropri ate al pha- and beta-adrenergi c blockade may be requi red. Mi l d
hepati c dysfuncti on may al so devel op i n patients wi th Guil l ai n-Barr syndrome.
Autonomic nervous system dysfunction indicates that compensatory cardiovascular responses may
be absent, resulti ng i n si gnificant hypotension secondary to postural changes, blood loss, or
positi ve airway pressure. On the other hand, noxi ous sti muli such as l aryngoscopy and tracheal
i ntubati on may produce exaggerated increases i n heart rate and bl ood pressure. Di rect-acti ng
vasopressors may be requi red to control bl ood pressure. Cardi ovascul ar functi on shoul d be
careful ly moni tored in the peri operative peri od.
The admi ni strati on of succi nyl chol i ne shoul d be avoi ded because of the danger of drug-i nduced
potassium rel ease and hyperkal emi a. Thi s ri sk may actuall y persist after cl inical recovery from the
di sorder.
23
A nondepol arizing muscl e relaxant wi th mi ni mal cardiovascular effects such as
ci satracurium, vecuroni um, or rocuroni um woul d be a useful choi ce. The sensiti vi ty of pati ents
with Gui ll ain-Barr syndrome to nondepolari zi ng muscl e rel axants, however, may vary from
extreme sensi ti vi ty to resi stance, dependi ng on the phase of the di sease.
24
It i s l ikel y that
mechani cal venti l ation wi ll be requi red duri ng the i mmedi ate postoperati ve period. Pati ents wi th
Guil l ai n-Barr syndrome that have pronounced sensory disturbances may benefi t from the
administrati on of epi dural opi oi ds.
It shoul d be remembered that i t can be very di fficul t to differenti ate Guil l ai n-Barr syndrome from
other neurologi c disorders such as anteri or spinal syndrome or chroni c i nfl ammatory demyel inati ng
pol yneuropathy. Gui ll ain-Barr syndrome can occur after surgery.
CENTRAL NERVOUS SYSTEM DISEASES
Mul t i pl e Scl er osi s
Mul ti pl e scl erosi s i s an acquired di sease of the central nervous system (CNS) characterized by
central nervous system i nflammati on and mul ti pl e si tes of demyel inati on i n the brai n and spi nal
cord. The cause of multi ple scl erosi s i s multi factori al and i nvol ves a complex seri es of
immunol ogic events occurri ng in geneticall y susceptibl e i ndi vi dual s. Initi al l y, a virus or other
agent (? ischemi a) triggers an i nfl ammatory reaction that causes a T-cel lmediated autoi mmune
response to myel i n. Demyel i nati on exposes the axon to harmful factors and i nterferes wi th neural
transmi ssi on. The nerve' s abi li ty to repair i tsel f duri ng the earl y phases of the process expl ains
the rel apsi ng nature of the di sease.
25

The symptoms of mul ti pl e scl erosi s depend on the sites of demyel i nati on i n the brai n and spi nal
cord. Demyel i nati on of the optic tracts produces vi sual di sturbances, whereas demyel inati on of the
ocul omotor pathways resul ts in nystagmus. Lesi ons of the spinal cord produce li mb weakness and
paresthesi as. The legs are affected more than the arms. Bowel retention and urinary inconti nence
are frequent complai nts. Brai nstem i nvol vement can produce dipl opia, tri gemi nal neural gia,
cardi ac dysrhythmi as, and autonomic dysfunction, whi l e alterations i n venti lati on can l ead to
hypoxemi a, apnea, and respi ratory fail ure. The course of multi ple scl erosi s i s characteri zed by
exacerbation of symptoms at unpredi ctabl e i nterval s over a peri od of years. Residual symptoms
eventuall y persist and may l ead to severe di sabi li ty. Three cl ini cal courses are recogni zed:
rel apsi ng-remi tti ng MS (RR-MS), pri mary-progressi ve MS (PP-MS), and secondary-progressi ve MS
(SP-MS). Ten to 20% of patients with multi ple sclerosi s have a relati vel y beni gn course with li ttl e
di sabi l ity. Pregnancy i s associated wi th an i mprovement i n symptoms, but rel apse frequentl y
occurs i n the fi rst three postpartum months.

The di agnosi s of multi ple sclerosi s is based pri mari l y on cl i ni cal determi nants. Cl i ni cal cri teri a
incl ude age of onset between 10 and 50 years, neurologi c si gns and symptoms of CNS white
matter di sease, two or more attacks separated by a month or more, and i nvol vement of two or
more nonconti guous anatomi c areas. Laboratory confi rmation of the di agnosi s can be made by
chemi cal anal ysi s of the cerebrospinal fluid and crani al magnetic resonance i maging (MRI).
Seventy percent of pati ents wi th multi ple sclerosi s have el evated l evel s of IgG in the CSF. An
el evated level of al bumin i n the CSF i s i ndicati ve of blood-brain barrier dysfuncti on. MRI i s a
sensi ti ve diagnosti c tool for mul ti pl e scl erosi s and provides di rect evi dence of the l ocati on of
demyel inated pl aques in the central nervous system. MRI can al so be used as a measure of the
effecti veness of treatment.
Current therapy for multi ple sclerosi s is di rected at modulating the i mmunol ogi c and i nflammatory
responses that damage myel in. Corti costeroi ds (methyl prednisolone) are the pri mary agents for
treatment of an acute exacerbati on of multi ple scl erosi s. Corti costeroi ds have di verse effects that
suppress cel l ul ar i mmune responses. Interferon (IFN) alters the infl ammatory response and
augments natural di sease suppression and has been shown to reduce the rel apse rate. Side effects
of interferon therapy i ncl ude aggravation of spasticity, development of autoanti bodi es, and fl u-l i ke
symptoms. Gl ati ramer i s a mi xture of pol ypepti des that mi mi cs the structure of myel i n and serves
as a decoy for autoanti bodi es. A number of i mmunosuppressants have been studi ed but pati ent
response has been vari able. Mi toxantrone can be used to treat aggressive multi ple sclerosi s.
Mi toxantrone, however, i s cardiotoxi c. Currentl y under investi gati on are therapies di rected at
remyeli nation such as Schwann cel l transplantati on.
26
Symptomati c therapy for some of the
compl i cati ons of mul ti pl e scl erosis i ncl ude di azepam, dantrol ene, and bacl ofen for spasti city.
Pai nful dysesthesi as, toni c sei zures, dysarthria, and ataxi a may be treated wi th carbamazepine.
Nonspeci fi c measures i ncl ude the avoi dance of excessi ve fatigue, emoti onal stress, and
hyperthermia. Demyeli nated nerve fi bers are extremel y sensi ti ve to i ncreases i n temperature. A
temperature increase of 0.5 degrees C can bl ock impul se conducti on i n demyel inated fi bers.
The effect of surgery and anesthesi a on the course of multi ple scl erosi s i s controversi al.
Regi onal and general anesthesi a have been reported to exacerbate mul ti pl e scl erosis, whi le
other reports have found no correl ati on between anesthesia and the course of the di sease. Factors
other than anesthesi a such as i nfection, emoti onal stress, and hyperpyrexi a may contribute to an
increased risk of a peri operati ve exacerbati on. Preoperati vel y, the pati ent shoul d be advi sed that
surgery and anesthesia coul d produce a rel apse despite a wel l -managed anestheti c. Ideall y, the
patient should have a thorough neurologic examinati on before the operation to document
coexi sti ng neurologi c defici ts. After surgery, the exami nati on can be repeated so that pre- and
postoperative fi ndi ngs can be compared.
Although the mechanism is not known, spi nal anesthesi a has been associ ated wi th an exacerbation
of the disease. It could be specul ated that demyel i nated areas of the spi nal cord are more
sensi ti ve to the effects of the local anestheti c causi ng a rel ati ve neurotoxici ty. Further evidence
for this theory is found by the observation that hi gher concentrations of bupi vacaine (0.25%) used
P.511
for l abor epidural analgesia were more li kel y to produce relapse than l ower concentrati ons.
27
With
such a precaution i n mi nd, epidural anal gesia can be safely provided for women during labor.
Neuraxi al l ocal anestheti cs and opi oi ds may al so be i ndicated for the treatment of chroni c,
refractory pai n syndromes i n patients wi th mul tipl e scl erosi s.
Sel ecti on of agents for general anesthesi a should take i nto consi derati on potential interacti ons
with medi cations the patient is recei vi ng. Pati ents bei ng treated wi th corti costeroi ds may requi re
intravenous corti costeroi d suppl ementation duri ng the peri operati ve peri od. Immunosuppressants
can produce cardiotoxi city and subcli ni cal cardi ac dysfuncti on. Bacl ofen can produce an increase
sensi ti vi ty to nondepolari zing muscl e rel axants, whi l e anti convulsants produce resi stance to
nondepol ari zers. In theory, succi nylchol ine could produce an exaggerated rel ease of potassi um,
al though this has not been reported. Autonomi c dysfuncti on caused by mul ti pl e scl erosi s may
exaggerate the hypotensi ve effects of volatil e anestheti cs. Careful monitoring of cardi ovascular
functi on i s indicated. Respi ratory muscl e weakness and respi ratory control dysfuncti on i ncrease
the li kel i hood of the need for suppl emental oxygen and/or mechani cal venti l ati on duri ng the
immedi ate postoperati ve peri od.
28

Epi l epsy
A sei zure is a common mani festati on of many types of CNS di seases. A seizure resul ts from an
excessive discharge of large numbers of neurons that become depol arized in a synchronous
fashi on. Idi opathi c sei zures usual l y begi n during chi l dhood. The sudden onset of seizures in a
young or mi ddl e-aged adul t shoul d arouse suspici on of focal brai n disease, parti cul arly a tumor.
The onset of sei zures after 60 years of age i s usual l y secondary to cerebrovascul ar disease but
can be a resul t of head i njury, tumor, metabol ic di sturbances, or central nervous system i nfecti on.
The onset of sei zures mandates a thorough neurologi c eval uation to determi ne the eti ology.
Advanced neuroimagi ng techni ques provi de powerful di agnosti c tools for the determinati on of
structural causes of epi lepsy. Research i n molecul ar bi ology and genetics has reveal ed that some
forms of epi l epsy are caused by mutations i n ion channel s. The avai labi li ty of new anti seizure
drugs has i ncreased the therapeuti c opti ons for patients wi th epil epsy. Sel ecti ng the ri ght drug or
drugs for the treatment of epi lepsy may require tri al and error to bal ance effi cacy wi th si de
effects.
29

There are more than 40 types of epi l epsy based on several cl ini cal features. The most common
cl assi ficati on i s the Internati onal Classi fi cation of Epi lepti c Seizures (Tabl e 19-7). A descripti on of
the most frequentl y encountered types of sei zures foll ows.
TABLE 19-7 Classification of Seizures
LOCALIZATION-RELATED EPILEPSIES AND SEIZURES
Idi opathi c
Beni gn chi l dhood epi l epsy
Chi ldhood epi lepsy with occipi tal paroxysms
GENERALIZED EPILEPSIES
Idi opathi c
Absence epil epsy
Childhood
Juveni le
Beni gn neonatal convul sions
Myocloni c epil epsy
Neonatal
Juveni le
Grand mal seizures on awakening
Idi opathi c and/or symptomati c
1. Grand Mal Seizures
A grand mal sei zure i s characteri zed by general i zed toni c-cl oni c activity. All respi ratory
acti vi ty i s arrested and a peri od of arteri al hypoxemia ensues. The tonic phase l asts for 20
to 40 seconds and i s fol lowed by the cl oni c phase. In the posti ctal peri od, the pati ent is
lethargi c and confused. Ini ti al therapy i s di rected toward mai ntaini ng arteri al oxygenati on
and stoppi ng the sei zure acti vi ty. Di azepam and thi opental are effective for the treatment of
acute, general i zed seizures. Anti sei zure drugs effective for sei zure control and preventi on
are valproate, phenytoi n, felbamate, carbamazepi ne, and l amotrigi ne (Tabl e 19-8). Epi leptic
patients resi stant to drug therapy may benefit from surgi cal resecti on of a sei zure focus or
vagal nerve stimul ator i mpl antati on.
30

2. Focal Corti cal Sei zure
Focal corti cal sei zure, also known as Jacksonian epil epsy, may be sensory or motor,
depending on the si te of neuronal discharge. There i s usual ly no l oss of consci ousness,
al though the sei zure acti vi ty may spread to produce a grand mal sei zure.

3. Absence Sei zure (Petit Mal)
Absence sei zures, previousl y cal l ed peti t mal seizures, are characteri zed by a bri ef loss of
awareness l asti ng 30 seconds. Additi onal mani festati ons i nclude stari ng, bl inki ng, and rol li ng
of the eyes. There i s an immedi ate resumption of consci ousness. Absence seizures typi cal l y
occur in chi ldren and young adults. Absence sei zures without other sei zure acti vi ty are best
treated wi th ethosuxi mi de. Val proate i s the drug of choice for absence sei zures associ ated
with other seizure activity.
4. Aki neti c Sei zure
Aki netic seizures are characteri zed by a sudden, bri ef l oss of consciousness and l oss of
postural tone. These types of sei zures usual l y occur in chi l dren and can produce severe head
injury from a fal l.
5. Myocl onic Sei zure
Myocl onic sei zures occur as i sol ated cl onic jerks i n response to a sensory sti mul us. In most
West' s syndrome
Lennox-Gestaut syndrome
Myocl oni castati c sei zures
Myocloni c absences
Symptomati c
Nonspeci fi c eti ol ogy
UNDETERMINED EPILEPSIES AND SYNDROMES
Wi th both general i zed and focal sei zures
Neonatal sei zures
Severe myoclonic epilepsy of infancy
Acqui red epil eptic aphasi a
SPECIAL SYNDROMES
Febril e sei zures
Alcohol -rel ated seizures
Modi fi ed wi th permi ssion from Riel a AR: Management of sei zures. Cri t Care Cl i n 5:863,
1989.
P.512
cases a si ngl e group of muscl es i s i nvol ved. Myocl oni c sei zures are often associ ated with
degenerati ve and metabol i c brai n di seases.
6. Psychomotor Sei zure
Psychomotor seizures are seen as an impai rment of consci ousness, inappropri ate motor acts,
hall uci nati ons, amnesi a, and unusual vi sceral symptoms. Thi s type of sei zure is preceded by
an aura.
7. Status Epi l epti cus
Status epil epticus i s defi ned as two consecutive toni c-cl oni c sei zures wi thout regai ni ng
consciousness, or sei zure acti vi ty that i s unabated for 30 mi nutes or more. Status
epi l epti cus can i nclude all types of seizure activity. Grand mal status epi lepti cus is of the
greatest concern because mortali ty can be as hi gh as 20%. Grand mal status epil epti cus
typi cal l y l asts for 48 hours with a sei zure frequency of four to five per hour. As the seizure
progresses, skel etal muscl e activity dimini shes and sei zure acti vi ty may be evi dent onl y on
the electroencephal ogram (EEG). Respi ratory effects of status epil epti cus i ncl ude i nhi biti on
of the respi ratory centers, uncoordi nated skeletal muscle acti vi ty that impai rs venti lati on,
and abnormal autonomic activity that produces bronchoconstri cti on. In addi ti on to the
danger of arteri al hypoxemi a, there i s a hi gh li kel i hood of permanent neuronal damage from
conti nued sei zures. Di azepam or l orazepam are considered the drugs of choi ce for treatment
of status epi l epti cus. Because the effects of the benzodi azepi nes are transient, a l onger
acti ng anti convulsant such as phenytoi n or phenobarbi tal must al so be admi nistered.
Thi opental is quite effecti ve for the i ni tial treatment of status epil epticus, but the effect i s
transi ent. Muscl e rel axants may be requi red to faci l i tate tracheal i ntubati on if a secured
ai rway is necessary. Al though muscl e rel axants wi ll terminate the skeletal muscle
mani festati ons of a sei zure, there i s no effect on sei zure activity in the brai n. On rare
occasions, general anesthesi a with isofl urane or barbi turates may be requi red for treatment
of status epil epti cus.
TABLE 19-8 Anticonvulsant Drugs
DRUG SEIZURE
TYPE
THERAPEUTIC BLOOD
LEVELS (g/mL)
SIDE EFFECTS
Phenobarbi tal Generali zed 1535 Sedati on, i ncreased
drug metaboli sm
Val proate Generali zed 50100 Pancreati ti s, hepati c
Absence dysfuncti on
Fel bamate Generali zed 20140 Insomnia, ataxia,
nausea
Parti al
Phenytoin Generali zed 1020 Gi ngi val hyperpl asi a
Parti al Dermati ti s
Resi stance to NM
bl ockers
Fosphenytoin Generali zed Paresthesi as
Parti al Hypotensi on
Carbamazepine Generali zed 612 Cardi otoxic, hepati ti s
Parti al Resi stance to NM
bl ockers
Lamotri gi ne Generali zed 216 Rash
Parti al Stevens-Johnson
syndrome
Topi ramate Generali zed 410
Parti al
Gabapenti n Generali zed 416 Fati gue, somnol ence
Parti al
Pri mi done Generali zed 612 Nausea, ataxi a
Parti al
Clonazepam Absence 0.010.07 Ataxi a
Ethosuximide Absence 40100 Leuopenia
Erythema multiforme
Leveti racetam Generali zed 545 Dizzi ness, headache
Parti al Somnolence
Patients recei vi ng anti seizure medi cations shoul d be mai ntained on their normal medi cation
regi men unti l the time of surgery. After surgery, medi cations shoul d be gi ven parenteral l y unti l
oral i ntake can be resumed. A decl i ne i n blood level s of anticonvul sant drugs wi l l increase the
li kel ihood of postoperati ve sei zures.
In the management of anesthesi a for the patient with a sei zure disorder, the potenti al infl uence of
anti convul sants on the response to anesthesi a must be consi dered. Conversel y, an anesthesi a
technique shoul d be used that wi ll not i ncrease the l ikel i hood of sei zure acti vi ty. Because
anti convul sant drugs affect the l i ver and neuromuscul ar systems, the potential for si gni fi cant drug
interactions certainly exi sts. Sti mul ati on of the hepati c mi crosomal enzymes by anti convul sants
may i ncrease the magni tude of biotransformati on of anestheti c drugs. Increased bi otransformation
of vol ati l e hal ogenated anestheti cs may i ncrease the ri sk of organ toxi ci ty. Other known si de
effects of anticonvul sants i nclude l eukopeni a, anemi a, and hepatiti s from phenytoi n; pancreati tis,
hepati c fail ure, and coagulopathy from val proate; apl asti c anemi a, cardi otoxi ci ty, and
hypothyroi di sm from carbamazepine; leukopenia from felbamate; and rash and hypersensi tivity
from lamotri gine.
31

Although most inhaled anesthetics, i ncl udi ng ni trous oxide, have been reported to produce seizure
acti vi ty, such activity during the admini stration of isofl urane, sevoflurane, and desflurane i s
extremel y rare. In general , these anestheti cs produce a dose-dependent depressi on of EEG
acti vi ty. The use of ketami ne is controversi al . Ketamine has been shown to produce sei zure
acti vi ty i n pati ents with known seizure disorders. Simil arl y, methohexi tal may produce seizure
acti vi ty. It woul d seem reasonable to avoi d the use of ketamine and methohexital for pati ents wi th
sei zure di sorders when al ternati ve drugs such as thi opental , propofol , and benzodi azepi nes are
avai l abl e. Propofol has a more depressant effect on the EEG than thi opental and has been shown
to i ncrease the sei zure threshold in patients receiving el ectroconvul sive therapy.
Potent opi oids such as fentanyl , sufentani l , and al fentani l may produce myocl onic acti vi ty or chest
wal l rigi di ty that can be confused wi th sei zure acti vi ty. In cl i ni cal doses, opioi d i nduced sei zures
are unl i kel y. Prol onged admi ni strati on of

large doses of fentanyl (200 to 400 g/kg) or sufentanil (40 to 160 g/kg) may produce seizures
and shoul d be used wi th cauti on i n patients with sei zure di sorders.
Patients recei vi ng phenytoi n or carbamazepi ne exhi bi t resi stance to nondepolari zi ng muscl e
rel axants.
P ar ki nson' s Di sease
Parki nson' s di sease, one of the most common disabli ng neurol ogic diseases, affects 1% of the
Oxycarbazepi ne Parti al 1035 Hyponatremi a, di pl opi a
Somnolence
Ti agabi ne Parti al Tremor, depressi on
Zonisami de Generali zed 1040 Anorexi a
Parti al Decreased cogni tion
P.513
popul ati on over 60 years of age. Parkinson' s disease i s a degenerati ve di sease of the central
nervous system caused by l oss of dopami nergi c fi bers i n the basal gangl i a of the brai n. The
characteri sti c pathol ogi c feature i s destructi on of dopami ne-contai ning nerve cell s i n the
substanti a ni gra of the basal gangl i a. Lewy bodi es, a hal l mark of the pathol ogy of Parki nson' s
di sease, are protei naceous cytoplasmi c cel l inclusi ons. Theori es of the eti ol ogy of Parki nson' s
di sease i ncl ude mitochondri al dysfunction wi th disordered oxidati ve metaboli sm, exci totoxici ty
(persi stent acti vation of glutamatergi c receptors), i nadequate neurotrophic support, and exposure
to toxi ns (pesti ci des, herbi ci des, i ndustri al chemi cal s, or vi ral i nfection).
32
Other than the wel l -
known postencephal i ti c Parki nson' s disease, however, there i s l ittle evidence that Parki nson' s
di sease is caused by a virus.
The cli nical effects of Parki nson' s di sease are caused by dopami ne defi ci ency. Dopami ne defici ency
increases activity of gamma-aminobutyri c aci d (GABA). GABA i nhi bits thal ami c and brai nstem
nucl ei, whi ch suppress corti cal motor activity, thereby causi ng tremor, aki nesia, and gai t and
posture abnormal iti es. The most characteri sti c cli ni cal features of Parki nson' s di sease are resting
tremor, cogwheel ri gi di ty of the extremiti es, bradyki nesi a, shuffl i ng gai t, stooped posture, and
faci al i mmobi l ity. These features are al l secondary to di mi ni shed i nhi biti on of the extrapyrami dal
motor system as a resul t of depl eti on of dopami ne from the basal gangl ia. Other features that
occur in pati ents wi th Parkinson' s di sease are seborrhea, si alorrhea, orthostati c hypotension,
bl adder dysfuncti on, pupi l lary abnormal i ti es, diaphragmati c spasm, ocul ogyri c cri ses, dementia,
and mental depressi on.
The treatment of Parki nson' s di sease is di rected toward increasi ng dopami ne level s i n the brain
but preventi ng the adverse peripheral effects of dopami ne. Levodopa i s the si ngl e most effecti ve
therapy for pati ents wi th Parki nson' s disease. When admi ni stered orall y, however, l evodopa is
converted to dopami ne and causes side effects such as nausea, vomi ting, and hypotensi on. To
avoi d such si de effects, l evodopa i s admi ni stered in combinati on wi th a peri pheral decarboxyl ase
i nhi bi tor (carbi dopa). Cardi ovascul ar side effects of levodopa i ncl ude depl etion of myocardial
norepi nephri ne stores, peri pheral vasoconstri cti on, hypovolemia, and orthostati c hypotensi on.
Although levodopa has si gni fi cantl y reduced morbi di ty and mortali ty from Parkinson' s di sease,
motor fluctuati ons causi ng si gni fi cant di sabi l ity occur in l evodopa treated pati ents. There is al so
some evi dence that l evodopa may accel erate the pathol ogi c process that causes Parki nson' s
disease. In an effort to del ay the use of l evodopa, other drugs such as selegi l ine, dopamine
agoni sts, amantadi ne, COMT inhi bi tors, and apomorphi ne have been used as i ni ti al treatment
drugs.
33
Anti chol i nergi c

drugs (tri hexyphenidyl, benztropi ne) are effecti ve because they counteract loss of inhi bi ti on of
chol i nergi c neurons. Anti chol i nergi cs can worsen dementia and are reserved for younger pati ents
in the earl y phases of Parki nson' s di sease. Amantadi ne is a glutamate receptor antagoni st and
may exert a neuroprotecti ve effect on neurons i n the basal gangl i a. Dopami ne receptor agoni sts
(bromocri ptine, pergol ide, prami pexole, ropi ni role) exert their effect on dopami ne receptors i n the
brai n. Si de effects of dopami ne agoni sts i ncl ude pulmonary and retroperi toneal fi brosi s,
erythromelal gia, and Raynaud' s phenomenon. Sel egi l i ne i s a sel ecti ve MAO-B inhi bi tor that
decreases the metabol ism of dopami ne. COMT inhi bi tors (entacapone, tolcapone) prevent the
degradati on of l evodopa. Many of the aforementi oned types of drugs, al though not entirely
successful as sole agents for the treatment of Parki nson' s disease, are effecti ve i n combi nation
wi th l evodopa. Therapi es directed at neuroprotecti on with a vari ety of agents (coenzyme Q10,
creati ne, vi tami n E) are under study. Pati ents with advanced drug-resistant Parki nson' s di sease
may benefit from surgical implantati on of deep brai n stimul ators.
34

Management of anesthesi a i s usual l y determined by potenti al interacti on between anesthesi a
drugs and anti -Parki nson medi cati ons and the severi ty of neurol ogi c impai rment. The pati ent' s
medicati ons shoul d be admini stered on the morni ng of surgery. The half-li fe of l evodopa i s short
and interruption of therapy for more than 6 to 12 hours can resul t in severe skeletal muscle
ri gidi ty that i nterferes with venti lation. Dopami ne antagoni sts such as phenothi azi nes, droperi dol,
P.514
and metocl oprami de shoul d be avoi ded. Al fentanil and fentanyl may produce acute dystoni c
reacti ons i n pati ents wi th Parki nson' di sease. Al though ketami ne coul d produce an exaggerated
sympatheti c nervous system response wi th resul tant tachycardi a and hypertension, i t has been
used wi thout diffi culty in pati ents wi th Parki nson' s di sease. The l i kel ihood of coexi sti ng heart
di sease i n el derly pati ents wi th Parki nson' s disease, however, makes the use of ketami ne less
attracti ve. There are no reports of adverse responses to isofl urane, sevoflurane, or desflurane in
patients with Parki nson' s disease. Although defi ni ti ve studi es of anesthesi a for patients recei vi ng
sel egil i ne have not been performed, cl i ni cal experi ence i ndi cates that anesthesi a is usual l y
uneventful . There have been reports of agi tati on, muscl e ri gi di ty, and hyperthermi a in pati ents
recei vi ng meperi di ne and sel egi l i ne. Pati ents wi th Parki nson' s di sease who are bei ng treated wi th
dopamine agonists may be at risk for neurol epti c mali gnant syndrome. Apomorphi ne i s a dopamine
agoni st that can be admi ni stered subcutaneousl y or intravenousl y i n the peri operati ve period i f
oral l evodopa cannot be admini stered.
Autonomic dysfunction is common in pati ents wi th Parkinson' s disease. Gastroi ntesti nal
dysfuncti on i s mani fested by excessi ve sal i vati on, dysphagi a, and esophageal dysfuncti on.
Consequently, the pati ent with Parki nson' s disease should be consi dered to be at risk for
aspirati on pneumoni ti s. The most consi stent cardi ovascul ar abnormali ty i s orthostati c hypotension.
The di sease process undoubtedl y contri butes to hypotensi on, whi ch is further compounded by the
tendency for anti -Parki nson drugs to cause peripheral vasodi l ati on. Pati ents wi th Parkinson' s
di sease woul d be more l i kel y to devel op exaggerated decreases i n blood pressure in response to
inhaled hal ogenated anestheti cs.
Peri operative respi ratory compli cati ons are common i n pati ents with Parki nson' s disease.
35
Upper
ai rway obstructi on may occur as a resul t of poor coordi nation of upper ai rway muscl es secondary
to neurotransmi tter imbal ance caused by the di sease process or i nduced by the admi ni strati on of
anti dopami nergi c drugs. Some Parki nson' s pati ents with upper ai rway obstructi on may respond to
the admini stration of anti -Parki nson drugs.
In the postoperati ve period, pati ents wi th Parkinson's di sease are susceptibl e to mental confusion
and even hall uci nati ons. These al terati ons in mental functi on may not appear unti l the day after
surgery. The pati ent and the pati ent's caregi ver shoul d be advised of thi s possi bil i ty.
Hunt i ngt on' s Di sease
Hunti ngton' s disease i s a neurodegenerative disease caused by severe neuronal atrophy i n the
corpus stri atum and l ater the cortex. Huntington' s di sease is one of the tri nucl eoti de repeat
di sorders. An i ncrease in cytosi ne, adeni ne, and guani ne (CAG) repeat sequences on chromosome
4 causes the genetic defect that causes Huntington' s di sease. Thi s gene encodes for the huntingti n
protei n. Although the function of the hunti ngtin protein i s not known, i ntranuclear incl usi ons of
hunti ngti n and ubi qui tin are found i n neurons that eventuall y di e. Hunti ngton' s disease i s a
heri tabl e di sorder that is transmi tted as an autosomal domi nant trai t. Identificati on of the
Hunti ngton' s gene provi des a rel i abl e techni que for predi cti ve testi ng; however, the delayed
nature of the cl i ni cal manifestati ons of the disease presents l egal and ethical concerns about earl y
predi cti ve testing.
36

The hal lmark cl i ni cal features are choreiform movements and dementi a. Onset i s typicall y between
the ages of 35 and 40 years, although a juveni le form may devel op as earl y as 5 years of age.
Although chorea i s the most common movement di sorder, athetosi s and dystonia also occur.
Movement abnormal iti es can i nvol ve the extremi ti es, trunk, face, eyes, oropharynx, and
respiratory muscl es. The di sease progresses for several years and mental depressi on makes
suici de a frequent occurrence. Death usuall y resul ts from malnutriti on and aspi rati on pneumoni ti s.
The durati on of Hunti ngton' s disease averages 17 years from the ti me of di agnosi s to death.
There i s no specific therapy for Hunti ngton' s di sease. Pharmacotherapy i s di rected at rel i ef of
mental depressi on and control of movement disorders. Drugs that reduce dopami nergic
transmi ssi on such as phenothi azines, butyrophenones, and thi oxanthi nes or drugs that depl ete
dopami ne such as tetrabenzamine and reserpi ne reduce the severi ty of chorea. Sel ecti ve serotoni n
reuptake i nhibi tors (SSRIs) such as fluoxitene, sertral i ne, and paroxitene are the primary drugs
for treatment of depression.
37

Many of the mani festations of Huntington' s disease are typi cal of pati ents wi th neurodegenerative
di sorders. As the disease progresses, the pharyngeal muscles become dysfuncti onal and the risk of
aspi rati on pneumoni tis increases. Appropri ate antiaspirati on maneuvers should be used.
If preoperati ve and postoperative sedation are necessary, the butyrophenones or phenothi azi nes
are logi cal choices. Cases of neurol epti c mali gnant syndrome in pati ents wi th Hunti ngton's di sease
are most l i kel y secondary to the admi nistrati on of neurol epti c drugs rather than i ntri nsi c effects of
Hunti ngton' s di sease. Although there are no speci fi c contrai ndi cati ons to the use of inhaled or
intravenous anestheti cs, recovery from propofol may be faster than from other intravenous
hypnoti cs. Short-acti ng neuromuscul ar bl ocking drugs woul d be preferabl e to l onger acti ng
rel axants. Decreased pl asma chol i nesterase acti vi ty may prol ong the rel axant effects of
succi nyl choli ne and mi vacurium. Although reported experi ence wi th regi onal anesthesi a is sparse,
spi nal anesthesi a has been successful l y admini stered.

As for any pati ent wi th a progressi ve neurol ogi c di sease, del ayed emergence and an i ncreased
li kel ihood of respi ratory compl i cati ons must be anti cipated i n the i mmedi ate postoperati ve peri od.
Al zhei mer ' s Di sease
Alzhei mer' s di sease i s the major cause of dementi a in the Uni ted States and the major reason that
patients are admitted to nursi ng homes. The incidence of Alzhei mer' s di sease is 1% i n 60 year
ol ds and 30% i n 85 year ol ds. Al though dementia i s caused by more than 60 di sorders,
Alzhei mer' s di sease i s responsibl e for 50 to 60% of the cases. Dementi a i s characteri zed by
intel l ectual and cogniti ve deteri orati on that impai rs soci al functi on. Memory impairment and
language deteri orati on occur earl y in the di sease process. Motor and sensory abnormali ties, gait
di sturbances, seizures, agi tation, and psychosi s are l ater features of the di sease. Any systemic
cause of dementia must be elimi nated before the di agnosi s of Al zheimer' s i s made. Laboratory
testi ng for thyroi d dysfunction, infecti on, and heavy metal exposure may be i ndi cated. Computed
tomography (CT), MRI, and posi tron emi ssi on tomography (PET) are hel pful i n differenti ati ng
Alzhei mer' s from other causes of dementi a.
The deposi ti on of beta-amyl oi d pepti de appears to be central to the process of degenerati on and
neuronal death. The pathol ogi c features of Al zhei mer' s such as neurofibri ll ary tangl es and neuri tic
pl aques are secondary to beta-amyl oi d deposi ti on. Different geneti c patterns may expl ain
vari ati ons in cl i ni cal presentati on and age of onset. To date, no effecti ve anti amyl oi d therapi es are
avai labl e.
Treatment of Al zhei mer' s di sease i s directed i n four areas: neuroprotection, chol i nesterase
i nhi bi tors, psychopharmacol ogi c agents to i mprove behavior, and heal th mai ntenance.
38

Neuroprotective therapies under i nvesti gati on i ncl ude vitami n E, selegi l ine, memanti ne, and anti -
infl ammatory agents. The admi ni strati on of choli nesterase inhi bi tors i s now consi dered standard of
care treatment for pati ents wi th Al zhei mer' s di sease. The three most commonl y used
chol i nesterase i nhibi tors are donepezi l, ri vasti gmi ne, and gal antamine. Chol i nesterase i nhibi tors
improve the pati ent's abi li ty to perform dail y li ving activiti es and may i mprove cogni ti on. Si de
effects of choli nesterase inhi bi tors i ncl ude nausea, vomiti ng, bradycardia, syncope, and fati gue.
Appropri ate psychotropi c drugs can be used to treat psychosi s and depression. Treatment of the
medi cal and nutri ti onal problems of a neurodegenerati ve disease and the elderly pati ent are
i ndi cated to reduce morbi di ty and mortal ity.
Sel ecti on of anesthetic drugs and techni ques for pati ents wi th Al zhei mer' s di sease i s gui ded by the
pati ent' s general physi ol ogi c conditi on, the degree of neurol ogic deteri orati on, and the potenti al
for i nteracti on between anestheti cs and medi cations the patient is recei vi ng. Because of dementi a,
P.515
these pati ents are l i kel y to be disori ented and uncooperative preoperati vel y. Sedati ve
preoperati ve drugs are rarel y i ndi cated as further mental confusion coul d resul t. Anestheti cs
known to result i n rapi d recovery, such as propofol , desfl urane, and sevofl urane are advantageous
because they permit a rapi d return to the patient' s preoperative state. If an antichol i nergi c is
requi red, gl ycopyrrol ate, which does not cross the blood-brain barrier, i s preferabl e to atropi ne or
scopol amine. An anti chol inergi c drug that crosses the blood-brain barrier could exacerbate the
dementia. Patients recei vi ng chol i nesterase i nhi bitors may have a prol onged response to
succi nyl choli ne and mi vacuri um. The pati ent' s preoperati ve drug l i st shoul d be revi ewed for the
possi bi li ty of i nteracti ons wi th anesthetics.
Amyot r ophi c Lat er al Scl er osi s
Amyotrophi c lateral scl erosi s (ALS) is a degenerati ve di sease of motor cel l s (anteri or horn cel l s)
throughout the central nervous system. Progression of the di sease i s relentl ess and death usuall y
fol l ows withi n 3 to 5 years of di agnosi s. Ten percent of ALS pati ents, however, survi ve for 10
years. Upper and l ower motor neurons are involved, although l ower motor neurons are affected
first. The cause of ALS i s unknown, but proposed causes i ncl ude glutamate excitotoxi city, free
radi cal stress, i mpai red neural protei n repai r, vi ral or prion infecti ons, heavy metal exposures, or
an autoi mmune response. Al though the si mi l arity between ALS and pol i omyeli tis i s striking, there
is no increase i n the i nci dence of ALS i n postpol io pati ents. Five to 10% of the cases of ALS are
heredi tary.
39

The si gns and symptoms of ALS refl ect the upper and l ower motor neuron dysfunction. Ini ti al
symptoms are weakness, atrophy, and skel etal muscl e fasci culation, often beginni ng in the
intrinsic muscl es of the hand. Deep tendon refl exes are i nappropriately bri sk. As the di sease
progresses, the atrophy and weakness involve most skel etal muscl es, i ncluding those of the
tongue, pharynx, larynx, and chest. Dysarthria and dysphagia are a resul t of bul bar i nvol vement.
Pul monary functi on tests demonstrate a decrease in vi tal capacity, maxi mal voluntary ventil ati on,
and di mi ni shed expi ratory muscl e function. In rare instances, the i ni ti al presentati on of ALS may
be respiratory fail ure. Eventual l y, respiratory fail ure devel ops i n al l pati ents wi th ALS and
venti l atory support i s requi red. Al though mechani cal venti l ation can prol ong l i fe, many pati ents
with ALS do not opt for aggressi ve ventil atory management because of the futil i ty of l ife-
prolongi ng measures. Intell ectual and cogni ti ve functi on i s preserved.
40
Pati ents wi th ALS have
evidence of autonomi c dysfuncti on as evi denced by an increased resti ng heart rate, orthostati c
hypotensi on, and elevated l evels of epi nephri ne and norepi nephri ne. There may be a decreased R-
R interval vari ati on on the ECG and a decreased heart rate response to atropi ne. The cause of
death for pati ents wi th ALS i s usual ly respi ratory fai lure. Sudden death from ci rcul atory col l apse
frequently occurs in venti l ator-dependent pati ents wi th ALS.
Ri l uzol e, an anti glutamate drug, i s the onl y speci fi c drug approved for the treatment of ALS.
Although not curati ve, ril uzol e may modestl y prol ong survival and del ay the need for
tracheostomy. Si de effects of ril uzole i ncl ude dizzi ness and hepatic dysfunction. Investi gati ons of
other drug therapi es have been unproducti ve.
41
Creatine therapy has been shown to produce some
benefit in a mouse model of ALS. Al though si mil ar effi cacy has not yet been shown i n humans,
many ALS pati ents take creatine suppl ements. Pal l iative care may i ncl ude ventil atory and
nutriti onal support and medicati ons for the rel ief of muscl e cramps and fasi culations.
Neuromuscul ar transmission is markedl y abnormal i n pati ents wi th ALS and these pati ents can be
very sensi tive to nondepol ari zi ng muscle rel axants. As with other pati ents wi th l ower motor
neuron di sease, ALS pati ents shoul d be consi dered vul nerabl e to hyperkalemia i n response to
succi nyl choli ne. Bulbar involvement wi th dysfuncti on of pharyngeal muscl es predi sposes pati ents
with ALS to pul monary aspi ration. The need for postoperati ve ventil atory support is hi ghl y l i kely
for these pati ents. There is no evidence that a speci fi c anestheti c drug or combinati on of drugs i s
best for patients with ALS. Subcl inical autonomi c dysfuncti on can produce very
P.516
exaggerated decreases i n cardi ovascul ar functi on i n response to anesthesi a.
42

Cr eut zf el dt - J akob Di sease
Creutzfeldt-Jakob di sease (CJD) i s one of three disorders that constitute the cl ass of di seases
known as the human spongi form encephal opathi es. The other two di seases in thi s group are kuru
and Gerstmann-Straussl er syndrome. Pathol ogi cal l y these di seases are characteri zed by
vacuol ati on of brai n ti ssue and neuronal l oss. Creutzfel dt-Jakob di sease i s caused by a pri on. A
pri on i s a smal l proteinaceous i nfectious agent that modifi es nuclei c aci ds. Most cases of CJD are
sporadi c al though some are heredi tary. Iatrogenic transmission of CJD has been l i nked to
contami nated dural graft materi al, the use of contami nated surgi cal i nstruments, corneal
transpl ants, and pool ed human growth hormone. Although CJD was previ ously consi dered to be a
rare form of dementia, the discovery of transmi ssi on of another pri on di sease (bovi ne spongi form
encephal opathy, mad cow di sease) from cows to humans in the mid 1990s catapul ted CJD to
media promi nence. This di sease i s termed variant CJD (vCJD) and it differs cl inicall y from cl assi c
CJD.
43
The typical cl i ni cal characteristics of classi c CJD are subacute dementi a, myoclonus, and
EEG changes. The EEG pattern is relatively characteri sti c wi th diffuse, sl ow activity, and peri odic
compl exes. Progressive l oss of cogni tive and neurol ogi c functi on occurs. Pati ents wi th vCJD
present at an earli er age wi th psychi atric features such as dysphori a, wi thdrawal, anxi ety, and
insomnia. Neurol ogi c features devel op 1 to 2 months after the psychi atric changes commence.
44

Presumabl y, transmission of vCJD i s by the ingestion of contami nated animal products. Accurate
epi demi ologi c studi es are di ffi cul t because the i ncubation peri od is several years. Scrapi e and
chroni c wasti ng di sease (mule and elk) are other ani mal forms of spongi form encephalopathy. The
ri sk of transmi ssi on of these di seases to humans i s unknown.
Creutzfeldt-Jakob is a transmissibl e di sease and appropri ate precautions must be observed when
administeri ng anesthesia. Hi gh-ri sk pati ent tissues incl ude brai n, spi nal cord, cerebrospinal fl uid,
and lymphoi d tissue. Human to human transmission vi a bl ood transfusion has occurred. Si ngle-use
anesthesia suppl i es, incl uding facemasks, breathi ng circui ts, l aryngoscopes, and tracheal tubes,
shoul d be empl oyed.
45

Patients with degenerati ve neurologic di seases are prone to aspi rate gastri c contents because they
have i mpaired swall owi ng function and decreased acti vi ty of l aryngeal reflexes. Appropri ate anti -
aspi rati on precauti ons are i ndi cated duri ng anesthesi a. Because l ower motor neuron dysfuncti on
occurs i n CJD pati ents, the use of succi nyl choli ne shoul d be avoi ded. The autonomi c and
peri pheral nervous systems may be adversel y affected, whi ch may result i n abnormal
cardi ovascul ar responses to anesthesia and vasoacti ve drugs.
ANEMIAS
Anemi a i s defined as an absolute or rel ati ve defi ciency i n the concentrati on of circul ati ng
functi onal red bl ood cel l s. Anemi as can be cl assi fi ed as nutri tional , hemol yti c, and geneti c
(hemogl obinopathi es, thal assemi as) (Tabl e 19-9).
TABLE 19-9 Types of Anemia
NUTRITIONAL
Iron defi ci ency
Vitami n B12 defi ci ency
Foli c aci d defi ciency
Chronic il l ness
HEMOLYTIC
Regardl ess of the cause of the anemi a, compensatory physi ol ogi c mechani sms devel op to offset
the decreased oxygen carryi ng capaci ty of the blood. In a heal thy person, symptoms do not
develop until the hemoglobi n l evel decreases below 7 g/dL. Symptoms are vari abl e and depend on
other concurrent disease processes. Physiol ogi c compensation incl udes i ncreased pl asma vol ume,
increased cardi ac output, and increased l evel s of red bl ood cel l 2,3-di phosphogl ycerate (Tabl e 19-
10). Because el derl y pati ents with chronic anemia have an i ncreased pl asma volume, transfusion
of whol e bl ood i n these pati ents may resul t in congesti ve heart failure. Similarly, the myocardial
depressant effects of anestheti cs may be exaggerated for pati ents wi th i ncreased cardi ac output at
rest as compensati on for anemi a.
Concern about the transmission of blood-borne i nfections has greatl y infl uenced the peri operative
use of bl ood products. Tradi ti onal hematocrit l evel s that have tri ggered the need for bl ood
transfusion have been radi cal ly al tered and there i s no uni versall y accepted hematocri t l evel that
demands transfusi on. The pati ent's physi ol ogi c status and coexi sti ng di seases must be factored
into a subjecti ve deci si on.
Nut r i t i onal Def i ci ency Anemi as
The three pri mary causes of nutri tional defi ciency anemi a are i ron defi ci ency, vi tami n B
12

defici ency, and fol i c aci d defi ci ency. Chroni c il l ness, as wel l as poor di etary i ntake, can result i n
nutritional deficiency anemia.
Spherocytosis
Gl ucose-6-phosphate dehydrogenase defi ciency
Immune-mediated
Drug-induced ABO incompatibi l i ty
GENETIC
Hemoglobi n S (si ckle cel l )
THALASSEMIAS
Thalassemi a major (Cooley' s anemi a)
Thalassemi a i ntermedi a
Thalassemi a mi nor
TABLE 19-10 Compensatory Mechanisms to Increase Oxygen Delivery with Chronic
Anemia
Increased cardi ac output
Increased red bl ood cel l 2,3-di phosphoglycerate
Increased P-50
Increased pl asma volume
Decreased bl ood vi scosi ty
Iron defi ci ency anemi a produces the typical mi crocyti c, hypochromic red bl ood cel l . Iron deficiency
anemi a may be an absol ute defi ciency secondary to decreased oral i ntake or a rel ati ve defi ci ency
caused by a rapi d turnover of red

bl ood cel ls (e.g., chroni c blood loss, hemol ysis). Measuri ng the hemogl obi n and serum ferri tin
l evel s i s a rapi d and effecti ve method for di fferenti ati ng true i ron defi ci ency anemi a from other
causes. Severe iron defi ciency anemi a can resul t i n respi ratory di stress, congestive heart fai lure,
thrombocytopeni a, and neurol ogi c abnormal iti es.
Megal obl asti c anemi a can be caused by vi tami n B
12
(cobal ami n) defi ci ency, fol ate defi ci ency, or
refractory bone marrow disease. Absorpti on of vitami n B
12
by the gastrointesti nal tract depends on
producti on of i ntrinsi c factor, a glycoprotei n produced by gastri c parietal cel l s. Atrophy of the
gastri c mucosa causes vitami n B
12
defi ci ency and megal obl asti c anemia. Chronic gastriti s and
gastri c atrophy may be caused by autoanti bodi es to gastri c pari etal cel l s. In additi on to
megal obl asti c anemi a, vi tami n B
12
defi ci ency can i nterfere with myel i nati on and produce nervous
system dysfunction. In adul ts, this i s mani fested by a peri pheral neuropathy secondary to
degenerati on of the lateral and posteri or spinal cord col umns. The neuropathy is evi denced by
symmetri c l oss of propriocepti on and vi bratory sensati on, especi all y i n the l ower extremi ti es.
Admi ni strati on of parenteral vi tami n B
12
reverses both the hematol ogi c and neurol ogi c changes in
adults. Congeni tal vitami n B
12
defi ci ency, however, produces severe neurol ogi c changes that can
onl y be parti al l y reversed wi th therapy. The coexi sti ng neuropathy of vi tamin B
12
defi ci ency must
be consi dered when regi onal anesthesia or peripheral nerve bl ocks mi ght be used. The cl inical
si gni fi cance of the effects of nitrous oxi de on vi tami n B
12
metabol ism is controversi al . Ni trous
oxi de i nacti vates the vi tami n B
12
component of methi onine synthetase and prol onged exposure to
ni trous oxide resul ts i n megal oblasti c anemi a and neurol ogi c changes simil ar to those that occur
with pernici ous anemi a. Rel ati vel y short exposures to ni trous oxi de have also been reported to
produce megal obl asti c changes. Whether the durati on of exposure to nitrous oxi de obtai ned duri ng
the course of a normal anestheti c produces such changes i n humans has not been establ ished. The
issue of ni trous oxi de causi ng postoperative neurologi c dysfuncti on is very controversial and case
reports of neuropathy li nked to i ntraoperative ni trous oxide exposure have i ncreased. Whether
these reports i nfluence the future use of ni trous oxi de is not cl ear.
Foli c aci d defi ciency also produces megal obl asti c anemi a. Al though peri pheral neuropathy may
occur, i t i s not as common as with vitamin B
12
defi ci ency. The admi ni stration of fol i c aci d duri ng
early pregnancy markedly reduces the ri sk of neural tube defects i n infants. Causes of fol i c aci d
defici ency i ncl ude al cohol ism, pregnancy, and mal absorpti on syndromes. Methotrexate, phenytoi n,
and ethanol are among the drugs known to interfere wi th fol ic aci d absorpti on.
Hemol yt i c Anemi as
The normal li fe span of an erythrocyte i s 120 days. Abnormal i ti es in the erythrocyte may resul t in
the premature destructi on of the cel l (hemolysi s). Causes of hemol ytic anemia i ncl ude structural
erythrocyte abnormalities, enzyme defi cienci es, and i mmune hemol ytic anemias.
Hereditary Spherocytosis
Spherocytosis, el l iptocytosi s, pyropoi ki locytosi s, and stomatocytosis are the four types of
heredi tary red cel l membrane defects resul ti ng i n abnormal l y shaped red bl ood cel l s.
Heredi tary spherocytosi s is the most common of the red bl ood cel l membrane defects producing
hemol ysi s. Spherocytosi s i s a disorder of the protei ns (spectri n) of the red bl ood cel l cytoskel eton
in which the red blood cel l i s more rounded, more fragi l e, and more suscepti ble to hemol ysi s than
the normal , bi concave red bl ood cell . As a resul t of this i ncreased fragi l ity, the spl een destroys
the abnormal red bl ood cel ls and a chroni c anemi a ensues. Chol eli thi asi s from chroni c hemol ysi s
and elevation of the serum bi l irubi n occur frequentl y i n patients with heredi tary spherocytosi s.
Patients with heredi tary spherocytosis may have hemolyti c cri ses accompani ed by anemi a,
vomi ti ng, and abdomi nal pai n. These cri ses may be tri ggered by i nfection or fol ic aci d defi ci ency.
Heredi tary spherocytosi s is treated by splenectomy, whi ch i s usual ly delayed unti l the pati ent i s 6
P.517
years of age or ol der. Spl enectomy before that age i s associ ated wi th a high i ncidence of bacteri al
infecti ons, especi al l y those secondary to pneumococcus. Before splenectomy, most pati ents
requi re a foli c aci d suppl ement owi ng to excessi ve uti l izati on of fol ic aci d for red blood cel l
producti on. Transfusi on i s rarel y necessary because adequate compensatory mechani sms for
chroni c anemi a have devel oped i n these pati ents.
Glucose-6-Phosphate Dehydrogenase Deficiency
Gl ucose-6-phosphate dehydrogenase (G6PD) defici ency i s the most common enzymopathy in
humans and affl i cts 400 mi l li on people worl dwide. G6PD defi ci ency may confer malarial resi stance
and the di stri buti on of thi s vari ant parall els the geographic di stri buti on of malari a. Afri can
Ameri cans, Afri cans, Asi ans, and Medi terranean popul ati ons are susceptibl e to the abnormal ity. In
patients with G6PD defici ency, G6PD acti vi ty decreases by 50% duri ng the 120 day li fe span of the
red bl ood cel l . G6PD i ni ti ates the hexose monophosphate shunt. Thi s shunt produces ni cotinami de-
adeni ne di nucl eoti de phosphate (NADPH). Without NADPH, the red bl ood cell i s suscepti ble to
damage by oxi dati on. A defi ci ency of G6PD resul ts i n decreased l evel s of glutathi one when the red
bl ood cel l i s exposed to oxi dants. Thi s i ncreases the ri gidi ty of the red bl ood cel l membrane and
accel erates cl earance of the cell from the ci rculati on. In severe forms of G6PD defi ci ency,
oxi dati on produces denaturati on of gl obi n chai ns and causes intravascul ar hemolysi s. Gl utathi one
synthetase i s another enzyme of the hexose monophosphate shunt, and defici ency of thi s enzyme
may also produce anemi a.
There are a number of drugs that accentuate the destruction of erythrocytes i n patients with G6PD
defici ency, i ncl udi ng anal gesi cs, anti bi oti cs, sulfonami des, and anti malarial s (Tabl e 19-11). There
is consi derabl e vari abil i ty i n the hemol yti c response to drugs; many drugs (e.g., aspi rin) cause
hemol ysi s onl y i n very hi gh doses. Pati ents with G6PD defi ci ency are unabl e to reduce the
methemogl obi n produced by sodi um ni trate; therefore sodi um ni troprussi de and pri locai ne shoul d
not be admini stered. Characteristicall y, the cri si s begi ns 2 to 5 days

after drug admi ni stration. The hemolyti c episode is usual l y sel f-li mi ted because onl y the ol der red
bl ood cel ls are affected. Bacteri al i nfections can al so tri gger hemol ytic epi sodes. Presumabl y, the
oxi dants produced by acti ve whi te blood cel l s may hemolyze suscepti ble red bl ood cel l s.
Anestheti c drugs have not been i mpli cated as hemol yti c agents; however, earl y postoperati ve
evidence of hemol ysis might i ndi cate a G6PD defi ci ency.
P.518
TABLE 19-11 Drugs that Produce Hemolysis in Patients with Glucose-6-Phosphate
Dehydrogenase Deficiency
Phenaceti n Nal idi xi c aci d
Aspi ri n (hi gh doses) Isoni azi d
Penici l li n Pri maqui ne
Streptomyci n Quinine
Chl oramphenical Quinidi ne
Sul facetami de Doxorubi ci n
Pyruvate Kinase Deficiency
Pyruvate kinase i s a glycol ytic enzyme of the Embden-Meyerhof pathway. Thi s pathway converts
gl ucose to l actate and i s the primary pathway for adenosi ne tri phosphate synthesis i n the red
bl ood cel l . A defi ci ency of pyruvate ki nase produces a potassium l eak from red bl ood cel l s,
increasi ng thei r ri gi dity and accel erati ng destructi on i n the spl een. Pyruvate kinase defi ciency i s
responsi bl e for 95% of the defici ency syndromes i n the Embden-Meyerhof pathway, whereas
defi ci ency of gl ucose phosphate i somerase accounts for 4%.
Cli nicall y, these patients exhibi t anemi a, premature chol el ithi asi s, and spl enomegaly. The degree
of anemi a vari es from a very mi ld anemi a to a severe, transfusion dependent anemi a. The cl i ni cal
features resembl e those for pati ents wi th spherocytosi s. There are no speci al consi derati ons for
anesthesia other than those for any pati ent wi th chronic anemia.
Immune Hemolytic Anemia
The i mmune hemol ytic anemias are characterized by i mmunol ogic al terati ons i n the red bl ood cel l
membrane and are caused by drugs, disease, or erythrocyte sensi ti zation. There are three types of
immune hemol yti c anemi a: autoi mmune hemol ysis, drug-induced i mmune hemolysi s, and
al loi mmune hemol ysis (erythrocyte sensiti zati on).
46
Autoi mmune hemol ytic anemia i ncl udes warm
and col d anti body hemol yti c anemi a. Cold autoi mmune hemol ytic anemi a i s of speci al concern to
the anesthesi ol ogi st because of the l i kel ihood that the col d operati ng room environment and
hypothermia duri ng cardi opul monary bypass may i ni ti ate a hemolyti c cri si s. Col d hemaggl uti ni n
di sease i s caused by IgM autoantibodi es that react with the I anti gen of red bl ood cel l s.
Mai ntai ning a warm environment i s essenti al for preventi on of hemolysi s. Pl asmapheresi s to
reduce the ti ter of col d anti body is recommended before hypothermi c procedures such as
cardi opul monary bypass. Col l agen vascul ar di seases, neopl asi a, and i nfections produce immune
hemol yti c anemi as by a vari ety of mechanisms i ncl udi ng warm and col d anti body-medi ated
hemol ysi s.
There are three types of drug-induced i mmune hemolysi s: autoanti body type, hapten-induced
type, and i mmune compl ex type. Hemol ysi s i nduced by al pha-methyl dopa i s of the autoi mmune
type medi ated by an IgG anti body that does not fi x compl ement. The hapten-induced type i s
characteri sti c of the response to penici ll i n and other anti bioti cs. The i mmune complex type of
reacti on can occur after the admi ni strati on of quini dine, qui ni ne, sul fonami des, isoni azid,
phenaceti n, acetami nophen, cephalosporins, tetracycl ine, hydralazi ne, and hydrochl orothi azi de.
The classi c exampl e of all oimmune hemolysi s (erythrocyte sensi tizati on) is hemolyti c disease of
the newborn produced by Rh sensi ti zation. An Rh-negati ve mother wi th Rh anti bodi es produces
hemol ysi s i n an Rh-positi ve fetus. Di fferences i n fetal and maternal ABO groups may also cause
hemol ysi s. Thi s is, however, unusual because A and B anti bodi es are of the IgM cl ass and do not
Sul fani li mi de Methylene bl ue
Sul fapyri di ne Ni trofurantoi n
readil y cross the pl acenta.
Hemogl obi nopat hi es
There are more than 300 different hemogl obi nopthi es descri bed i n the l iterature. Most are quite
rare and may never be encountered by an anesthesi ol ogi st during his or her career. Si ckle cel l
di seases are the most common hemogl obinopathi es in the Uni ted States. An esti mated 8 to 10% of
Afri can Americans have the sickl e cel l trai t, and 1 i n 400 has si ckle cel l anemi a.
Sickle Cell Disease
Normal hemoglobi n i s composed of four gl obi n pol ypepti de uni ts arranged in a tetramer. There are
four globin proteins i n normal human hemogl obi n desi gnated: al pha (), beta (), del ta (),
gamma (). In adul t hemogl obi n the tetramer
2
2
predomi nates and i s cal l ed hemogl obi n A.
Hemoglobi n F (tetramer
2
2
) predominates i n fetal and neonatal li fe. In si ckl e cel l di sease an
abnormal globi n i s produced and i s desi gnated
s
and the tetramer
2
2
s
i s hemogl obi n S. The
s

gl obin is abnormal in that val i ne i s substi tuted for gl utami c aci d i n the si xth amino aci d posi tion.
Thi s abnormali ty causes the hemogl obi n to aggregate and form a pol ymer when exposed to low
concentrations of oxygen. The formation of pol ymeri c hemogl obi n strands within the erythrocyte
causes the red bl ood cel l to si ckle. As the sickl e prone cel l passes through the microci rcul ati on,
the cel l i s exposed to progressivel y lower oxygen tensi ons. The deformed si ckle cel ls can occlude
smal l vessel s causi ng reduced blood flow and stasi s. The si ckl ed erythrocyte may return to a
normal shape when reexposed to hi gher oxygen tensi ons. Permanent al terations to the cell
membrane do occur and worsen wi th each cycl e of si ckli ng, resul ting i n earl y removal of the red
bl ood cel l from the circul ati on. Erythrocyte l ife span i s onl y 12 to 17 days i n si ckle cel l disease
compared to the normal 120 days. The altered red bl ood cell membrane increases the adhesi on of
si ckl e cel l s to the vascul ar endotheli um. This adhesi on acti vates coagulati on and rel eases
inflammatory mediators. Hemolysis of al tered erythrocytes with rel ease of free hemogl obin causes
oxi dant i njury to ti ssues and decreases ni tri c oxide level s. The basi s of mul tipl e organ system
damage i n si ckl e cel l di sease is vascul ar occl usion, ti ssue i schemi a, infarction, hypercoagul abi l ity,
thrombosi s, and i nflammati on.
The defi ni tive diagnosis of si ckle cel l disease i s made wi th hemogl obi n electrophoresis. This test
not onl y detects hemoglobin S but al so reveal s any other types of hemoglobi n present.
Clinical Manifestations. The cl inical mani festations of si ckle cel l disease can devel op i n any
organ system (Tabl e 19-12). The most frequent mani festation is pai n. A pai nful episode is
thought to be because of ti ssue i schemi a and usual ly affects the back, chest, extremi ties, and
abdomen. The severi ty of pai nful events may range from annoying to severe and di sabl i ng.
Parenteral narcoti c anal gesics are the mai nstay of therapy but may be suppl emented wi th non-
steroidal anti -infl ammatory drugs (NSAIDs). Suppl emental oxygen and intravenous fl uids are
administered to maxi mi ze ti ssue oxygenati on. The term crisi s i s used to descri be pai nful
epi sodes that coi ncide with li fe-threatening events. Cri ses that may be seen i n sickl e cell di sease
are: spl eni c sequestrati on, aplasti c anemi a, ri ght upper quadrant syndrome, and acute chest
syndrome. The concentrati on of hemoglobi n F may be predi cti ve of cl i ni cal mani festations as
increased l evel s of hemogl obi n F decrease the l ikeli hood of cl i ni cal events.
TABLE 19-12 Clinical Manifestations of Sickle Cell Disease
HEMATOLOGIC
Hemolytic anemia
Aplasti c anemi a
SPLEEN
Infarcti on
Splenic sequestrati on occurs when there is a dramati c accelerati on of erythrocyte trappi ng in an
enl arged spl een. The removal of l arge numbers of erythrocytes causes the hematocri t to fal l
preci pi tousl y. Hypovol emia and shock may devel op. Left upper quadrant pai n i s a promi nent
symptom. Infusion of fluids and red bl ood cel l s must be performed to restore the i ntravascular
vol ume and hematocri t. Spl enectomy is often performed foll owing the acute episode to prevent
recurrence.

An apl astic crisi s occurs when there is a failure of reti cul ocyte formati on. The hi gh turnover rate
Hypospl eni sm
Splenic sequestration
CENTRAL NERVOUS SYSTEM
Stroke
Hemorrhage
Aneurysm
Meningi ti s
MUSCULOSKELETAL
Pai nful episodes
Bone marrow hyperpl asi a
Avascul ar necrosi s (hi p and shoul der)
Osteomyel i ti s
Bone infarcts
CARDIAC
Cardi omegal y
RENAL
Papi ll ary necrosis
Gl omerul ar scl erosis
Renal fail ure
PULMONARY
Acute chest syndrome
Pul monary infarction
Fi brosis
Asthma
Pul monary hypertension
Thromboembol ism
Pneumonia
GENITOURINARY
Pri api sm
Infecti on
HEPATOBILIARY
Ri ght upper quadrant syndrome
Hepati ti s
Cirrhosi s
Cholel i thiasis
Cholestasi s
Jaundice
IMMUNE SYSTEM
Immunosuppressi on
PSYCHOSOCIAL
Depressi on
Anxi ety
Substance abuse
P.519
of erythrocytes i n si ckl e cel l di sease resul ts in a rapi d worseni ng of anemi a when erythrocyte
formation i s i nterrupted. Symptoms of an apl asti c cri si s are nonspecific and are rel ated to severe
anemi a. Transfusi on i s performed to mai ntai n an adequate hematocrit until reti cul ocyte formati on
returns to normal .
Ri ght upper quadrant syndrome is heral ded by pai n i n the ri ght upper quadrant. Fever, jaundi ce,
and li ver fai lure fol l ow. The ri ght upper quadrant pai n may represent hepati c i schemi a,
chol ecysti ti s, chol angi ti s, or ischemi a of other visceral organs. Transfusi on wil l reduce the
concentration of hemogl obi n S and opti mi ze the hematocrit. Intravenous fl ui ds, anal gesics,
anti bi oti cs, and suppl emental oxygen are usual l y requi red.
Acute chest syndrome (ACS) is characteri zed by chest pai n, dyspnea, fever, and acute pul monary
hypertensi on. ACS may be fatal . Transfusi on or exchange transfusi on i s performed to mai ntain the
hematocri t at 30%. Suppl emental oxygen, anti bioti cs, and i nhal ed bronchodi lators are
administered as required.
Sickl e cell di sease al so produces chroni c cardiac, pul monary, and renal dysfuncti on. Cor
pul monale may result from chroni c hypoxemi a, pul monary fi brosi s, and pul monary
hypertensi on. Cardiac dysfuncti on is characteri zed by systol i c and di astol i c dysfuncti on. The renal
medul l a i s vul nerable to i nfarction and there may be an inabi l ity to concentrate the urine. Other
systemi c effects of si ckle cel l disease i ncl ude chol eli thi asi s (chroni c hemol ysis), cerebral
i nfarcti on, and pri api sm.
47, 48

There are at l east 40 vari ants of S hemogl obinopathy. Pati ents with SA hemogl obin (si ckl e cel l
trai t) usuall y have a normal l i fe expectancy and few compl i cations. Hemoglobin l evel s are normal
and si ckl i ng occurs onl y under extreme physi ol ogi c conditi ons. Although the ri sk of anesthesi a i s
smal l , there have been some reports of death i n the peri operati ve peri od i n pati ents wi th si ckl e
cel l trai t. Hemogl obi n C al so results from a mutation of the gl obin at the 6
t h
amino aci d posi tion.
Lysi ne is substituted for gl utamic acid. Some pati ents have both the si ckl e cel l gene and the
hemogl obi n C gene (hemogl obi n SC). Hemoglobin S may al so be combined with thal assemia trait
resul ti ng in hemogl obin S-thal assemi a trai t. The severi ty of sickl e cell di sease from worst to l east
i s: SS > S-thal assemi a > SC > CC > SA (Table 19-13).
TABLE 19-13 Common Hemoglobin S Variants
HEMOGLOBIN SS HEMOGLOBIN SC HEMOGLOBIN SA
Hemoglobi n l evel
(g/dL)
78 912 1315
Li fe expectancy
(years)
30 Sli ghtl y reduced Normal
Propensity for
si ckl ing
++++ ++ +
Cl i ni cal features Vaso-occl usi ve
crises
Vaso-occl usi ve
crises
Few, under physi ol ogi c
condi ti ons
Spl eni c i nfarcti on Reti nal
thrombosi s

Treatment. Al though the exact mol ecul ar defect of S hemogl obi n has been known for over 50
years, there i s no specific correcti ve therapy. Supporti ve therapy has i mproved, increasi ng
survi val , so that many patients with SS disease live more than 50 years. In some cases bone
marrow transplantati on may be curative, especi al l y when performed i n earl y chi l dhood. Because of
the ri sks of bone marrow transpl antation, thi s therapy i s reserved for very severe cases.
49
An
unaffected si bl ing i s usual ly required for donor matchi ng.
Preventi ve treatment i s begun as soon as the diagnosis i s made. Pati ents should be referred to
centers that provi de a mul ti di sci pli nary approach for routine and urgent care. Dai ly oral peni ci l li n
i s begun i n i nfancy as prophyl axi s agai nst pneumococcal sepsis. Patients recei vi ng frequent
transfusions should be moni tored for i ron overl oad. Li ver biopsy i s the most common method of
moni tori ng the effects of excessive iron. If i ron overl oad occurs, chelation therapy must be
insti tuted to prevent cardiomyopathy and ci rrhosi s. Hydroxyurea is often admi ni stered to i ncrease
producti on of hemogl obi n F and reduce the l ikel i hood of si ckl ing.
Management of Anesthesia. Surgery i s frequentl y requi red for pati ents wi th sickl e cell di sease.
Operations commonly performed on these pati ents i nclude chol ecystectomy, l i ver bi opsy,
spl enectomy, tonsi ll ectomy, hi p replacement, and obstetric procedures. It i s ideal for the
anesthesiol ogi st, hematol ogi st, and

surgeon to interact closely when sickl e cel l pati ents requi re surgery. Prevention of condi ti ons that
favor sickl i ng i s the basi s for recommendati ons regardi ng peri operati ve management. Adequate
oxygenati on, avoidance of excessi ve oxygen consumpti on, assurance of adequate oxygen-carryi ng
capaci ty, and avoidance of vascul ar stasis are imperati ve. Normothermi a shoul d be achi eved as
this minimi zes oxygen consumpti on. Hypothermia may cause peri pheral vasoconstriction and
vascul ar stasi s; whereas hyperthermi a accel erates hemoglobi n S pol ymeri zati on. A warm ambient
temperature suppl emented wi th forced ai r warmi ng i s desi red. Vascular stasi s i s mi ni mi zed wi th
adequate hydrati on and anti cipation of intraoperative volume l oss. Use of the tourniquet should be
reserved for those operations where its use i s essenti al for the success of the surgery.
The hemogl obi n and hematocri t shoul d be measured preoperativel y. Adequate oxygen carryi ng
capaci ty i s maintai ned by transfusi on to keep the hematocrit at 30%. Exchange transfusi on may
be used to keep the hematocrit at 30% and reduce the concentrati on of hemogl obin S to 30 to
40%. Exchange transfusi on i s the preferred method for patient preparati on for cardiopul monary
bypass (Tabl e 19-14).
Hepatomegal y Femoral head
necrosi s

Ski n ul cerati on
P.520
TABLE 19-14 Symptom-Based Preoperative Evaluation in Sickle Cell Disease Patients
for Major Surgery
Drugs commonly used for anesthesi a do not have any si gni fi cant direct effects on the si ckli ng
process. The anesthetic techni que may i nfluence outcome i f i t produces hypoxemi a, vascul ar
stasi s, and reduced cardiac output. Regi onal anesthesi a has been successful l y employed for
surgery, l abor and del i very, and pai n management. Pai n management of pati ents wi th sickl e cell
di sease i n the postoperative period can be qui te chall engi ng. A vari ety of techni ques, i ncl udi ng
opi oi ds (morphi ne), nonnarcoti c analgesi cs, and regi onal anesthesi a have been used.
Close moni toring of the si ckle cel l pati ent during the postoperati ve peri od for pul monary
compl i cati ons and aggressive treatment wi th suppl emental oxygen i s necessary as hypoxemi a may
be the pri mary tri gger of acute chest syndrome. Acute chest syndrome during the earl y
postoperati ve peri od produces si gnifi cant morbi di ty and mortal ity.
50, 51

Thalassemia
The thalassemias are a group of geneticall y transmi tted (autosomal recessi ve) anemi as caused by
insuffi cient producti on of one of the gl obi n pol ypeptide components of hemogl obin. Al though there
are four gl obi n chai ns (, , , ), and thal assemi as are the most common. Thal assemi a genes
are most preval ent i n the Mediterranean regi on, the Middl e East, India, Southeast Asi a, and
malari al zones. The carrier i nci dence in these areas i s 2.4 to 15%.
There are three promi nent cl inical features of thalassemia: anemi a, hemol ysis, and marked
hyperplasia of the bone marrow. The anemia i s mi crocyti c and hypochromi c and can be profound.
In addi tion to anemia, there is unbal anced production of globi n pairs. In thal assemi a, there i s
inadequate production of gl obin, but normal producti on of gl obin. The excess gl obins are
poorl y sol ubl e and preci pi tate to form i ncl usion bodi es i n erythroi d precursor cell s. The excess
gl obins are highly reacti ve and cause free radi cal cell ul ar injury. Many erythrocytes fai l to mature
and others are destroyed by the spl een and reticuloendotheli al system. Splenomegal y,
hepatomegaly, cholel ithiasis, and jaundi ce are common. Anemi a causes a vi gorous secreti on of
erythropoi eti n that produces bone marrow hyperpl asi a. Bone marrow hyperplasia causes skel etal
abnormali ties such as retarded growth, fractures, and facial dysmorphi sm. Extramedul lary marrow
develops in the pl eura, si nuses, epi dural space, and pleural cavities. Spontaneous bl eedi ng from
extramedul l ary marrow i s common and can cause hemothorax, epi dural hematoma, and
epi staxi s.
52

All patients
Hemogl obi n and hematocri t
Hemoglobin > 9 gm/dL or hematocrit > 28% or exchange transfusion planned
Hemoglobi n electrophoresis
Cardiac symptoms or History of acute chest syndrome or Dyspnea on exertion
El ectrocardiogram
Echocardiogram
Chest radi ograph
Renal Dysfunction
Serum electrolytes
BUN
Creati nine
Hepatic Dysfunction
Pl atel et count
PT/PTT, INR
Fi bri nogen
Change in Neurologic Status
Crani al MRI
Transcranial Doppler
A wi de vari ety of cl inical phenotypes are mani fest, from very mild anemia to very severe anemia.
The anemi a i n thal assemi a major (Cool ey' s anemi a) is severe and often l ife threateni ng.
thal assemi a mi nor produces a mi ld anemi a of i ron defi ci ency. thal assemi a intermedi a is an
intermedi ate form of thal assemi a that usuall y does not require transfusi on. thal assemi a
produces a mi l d hemol ytic anemia (Tabl e 19-15).
Treatment of thalassemi a i s based on the severity of the anemi a. Thalassemia major must be
treated aggressi vel y to reduce

compl i cati ons and prol ong l i fe. Bone marrow transplantati on may cure thal assemi a and can be
undertaken after 2 years of age if the i l lness i s li kel y to be severe. Thalassemia major pati ents
who do not quali fy for or fai l bone marrow transplantati on wil l require transfusi on therapy. Three
transfusion protocol s are empl oyed: pal l iative transfusi on, hypertransfusi on, and supertransfusi on.
Pal li ati ve transfusion is used to treat only severe compl icati ons of anemi a. Extramedul l ary
erythropoi esi s is not suppressed by pal li ati ve transfusion. Pal l iati ve transfusi on i s generall y
practi ced i n areas where there i s poor access to medi cal care. The goal of hypertransfusion is to
maintai n a hemogl obin l evel of 9 to 10 grams/dL. Transfusi on i s required every 3 to 4 weeks.
Extramedull ary erythropoi esi s i s substanti al l y reduced. Supertransfusi on i s used to mai ntain a
hemoglobi n l evel greater that 12 grams/dL i n an effort to suppress al l erythropoi esi s. Frequent
bl ood transfusi on predi ctabl y causes hemosi derosis. Chelation therapy with deferoxami ne or
deferi prone i s requi red to reduce the li kel ihood of cardi ac and hepati c i ron toxi ci ty (ci rrhosi s).
Management of Anesthesia. Anestheti c consi derati ons depend on the severi ty of the anemia.
Hemosi derosis i s l ikel y in pati ents receiving regul ar transfusi on therapy. A preoperative
echocardi ogram may be i ndi cated i f there i s any suggestion of cardi ac dysfuncti on. Extramedul lary
erythropoi esi s can produce hyperpl asi a of the faci al bones and narrowing of the nasal passages
and make di rect l aryngoscopy and tracheal i ntubati on di ffi cul t. Epi dural , spi nal , and i ntrapl eural
TABLE 19-15 Thalassemic Syndromes
HEMOGLOBIN BART'S HYDROPS FETALIS (FATAL IN UTERO)
Thalassemi a hemogl obin Bart' s i s a
4
globi n tetramer that i s produced because of
compl ete l ack of gl obin producti on
Thalassemia Major
Homozygous
0
-thal assemi a

Severe
+
-thal assemi a

Heterozygous
0
-thal assemi a

Severe
+
-thal assemi a

Thalassemia Intermedia
Homozygous
Known as hemoglobi n H di sease. Hgb H i s a 4 gl obi n tetramer produced because of a
rel ati ve l ack of gl obin
Heterozygous
Severe
+
-thal assemi a

Mi l d
+
-thal assemi a

Thalassemia Minor Mil d reducti ons in and gl obin producti on
Note:
0
indi cates none of that type of gl obi n i s produced.
+
indi cates a subnormal amount of that globi n i s produced.
P.521
anesthesia are rel ati vel y contraindicated as the presence of extramedul l ary bone marrow in these
si tes i ncreases the l ikel i hood of bleedi ng and hematoma formation. Massive bleedi ng into the
epi dural and pl eural spaces can occur. Pati ents receiving pal l iative transfusi on therapy are at
greater ri sk for extramedull ary erythropoi esi s than those recei vi ng hyper-transfusion therapy.
COLLAGEN VASCULAR DISEASES
A number of di seases are cl assified as the coll agen vascular diseases or connective tissue di seases
(Tabl e 19-16). The four most common disorders of this group are rheumatoi d arthriti s, systemi c
lupus erythematosus, scl eroderma, and dermatomyositi s/polymyositi s. Although many such
pati ents can be categori zed as havi ng discrete di sease syndromes, many others wi th col l agen
vascul ar di seases are consi dered to have overlap syndromes (al so termed mi xed connective ti ssue
di seases) with features of di fferent col lagen vascul ar di seases, and cannot be conveni ently
cl assi fied. The etiol ogy of the col l agen vascular diseases i s unknown, al though the i mmune system
is cl earl y i nvol ved i n the cascade of pathologi c events that cause cl i ni cal mani festati ons of the
di seases. Al though al l of these diseases have effects on joi nts, each has di ffuse systemi c effects
as wel l . The al terati ons in joint functi on and systemi c effects wi l l both have si gni fi cant i mpact on
the management of anesthesia.
Rheumat oi d Ar t hr i t i s
Rheumatoi d arthri ti s i s a chroni c infl ammatory di sease characteri zed by a symmetric
pol yarthropathy and significant systemi c involvement. Al though the etiol ogy of rheumatoi d
arthri tis i s not known, the pathogenesi s has been deli neated. An as yet unknown anti gen provokes
a cel lular immune response i n whi ch monocytes, macrophages, and fi brobl asts rel ease cytoki nes
(TNF-tumor necrosi s factor and interleuki n-1). These cytoki nes ini ti ate an infl ammatory cascade
that damages synovi al and joi nt tissue. B lymphocyte dysregulation causes addi tional damage vi a
complement fixati on.
53
The presence of rheumatoi d factor (IgM) in 75% of pati ents wi th
rheumatoi d arthriti s supports the concept of rheumatoi d arthri ti s as an autoi mmune di sease. The
pathologi c changes of rheumatoi d arthri ti s begin wi th cell ul ar hyperplasia of the synovium
followed by invasion of the synovium by lymphocytes, pl asma cel ls, and fi broblasts. Ulti matel y,
the carti l age and articul ar surfaces are destroyed.
The hands and wrists are involved fi rst, particularl y the metacarpophalangeal and i nterphal angeal
joi nts. In the lower extremi ty, the knee is i nvol ved most frequentl y. Compressi on of l ower
extremi ty peri pheral nerves by the deformed knee can produce paresis and sensory loss over the
lower leg. The upper cervi cal spine i s affected i n nearl y 80% of patients wi th rheumatoi d arthriti s.
Instabil i ty of the upper cervical spi ne can mani fest as atl antoaxi al instabil i ty, crani al settl i ng, and
TABLE 19-16 Collagen Vascular Diseases
Rheumatoi d arthriti s
Lupus
Systemi c l upus erythematosus
Drug-induced lupus
Di scoi d l upus
Scl eroderma
Progressi ve systemic scl erosi s
CREST syndrome (cal ci nosis cuti s, Raynaud' s phenomenon, esophageal dysfuncti on,
scl erodactyly, tel angectasi a)
Focal scl eroderma
Pol ymyosi ti s/dermatomyosi ti s
Overlap syndromes
subaxial instabil i ty. Pl ai n radi ography and CT of the cervi cal spi ne wi ll demonstrate the bony
changes of rheumatoi d arthriti s. MRI i s better suited to the study of the bony and soft ti ssue
changes on the spi nal cord. The degree of cord compressi on, however, may not correl ate wi th the
patient' s symptoms. Al though a very rare event, spinal cord damage after l aryngoscopy and
tracheal i ntubati on has been reported.
54
Intradural cord compression secondary to rheumatoi d
nodul es or pannus formation can al so occur. Rheumatoid arthri tis commonl y affects the joi nts of
the larynx, resul ting i n li mi tati on of vocal cord movement and general i zed erythema and edema of
the laryngeal mucosa that may progress to ai rway obstruction. Arthri ti c changes i n the
temporomandibular joi nts also occur. Al l of these abnormal iti es can compl icate laryngoscopy and
tracheal i ntubati on.
Extra-arti cul ar and systemi c mani festations of rheumatoid arthri tis are di verse (Tabl e 19-17).
Peri cardi tis occurs i n nearl y one-third of pati ents wi th rheumatoid arthri tis and can produce
constri cti ve peri carditi s or cardiac tamponade. Although cardiac tamponade devel ops in onl y a
smal l proportion of pati ents with rheumatoi d arthri ti s, rheumatoid arthri tis i s more l i kel y to cause
tamponade than systemi c l upus erythematosus. Cardi ovascul ar disease i s a common cause of
mortal i ty i n pati ents wi th rheumatoi d arthriti s and there i s a hi gh incidence of subcl i ni cal cardiac
dysfuncti on.
55
Cardi ovascul ar effects include myocardi ti s, coronary arteri tis, pul monary
hypertensi on, di astol i c dysfuncti on, dysrhythmi as, and aorti tis (aorti c root di l ati on, aorti c
insuffi ciency). Pul monary changes are common and i ncl ude pl eural effusi ons, pul monary nodul es,
intersti ti al lung disease, obstructive lung disease, and restri cti ve l ung disease. Several of the
anti rheumati c drugs can cause or accentuate pul monary dysfunction. Renal fai l ure is a common
cause of death i n patients wi th rheumatoi d arthriti s. Renal dysfuncti on may be secondary to
vascul i ti s, amyl oi dosi s, and anti -rheumati c drugs.
TABLE 19-17 Extra-Articular Manifestations of Rheumatoid Arthritis
Skin
Raynaud' s phenomenon
Di gi tal necrosi s
Eyes
Scl eri ti s
Corneal ul cerati on
Lung
Pleural effusion
Pulmonary fibrosis
Heart
Pericardi ti s
Cardi ac tamponade
Coronary arteri ti s
Aortic insufficiency
Kidney
Interstiti al fi brosi s
Gl omerulonephri tis
Amyl oi d deposi ti on
Peripheral Nervous System
Compressi on syndromes
Mononeuri ti s
Central Nervous System
Dural nodul es
Necroti zi ng vascul i ti s
Liver
Hepatiti s

Mi l d anemi a i s present i n al most all patients wi th rheumatoi d arthriti s. The anemi a may be
secondary to a cytoki ne-induced decrease i n erythropoi esi s or may resul t from si de effects of drug
therapy. Fel ty' s syndrome is the cl i ni cal complex of rheumatoi d arthri ti s, l eukopeni a, and
hepatospl enomegaly.
Neurologi c compl i cati ons of rheumatoid arthri tis i ncl ude peripheral nerve compressi on (carpal
tunnel syndrome) and cervical nerve root compressi on. Mononeuriti s mul tipl ex i s presumed to be
caused by deposi ti on of i mmune compl exes i n bl ood vessel s supplying the affected nerves.
Rheumatoi d vascul iti s may affect cerebral bl ood vessel s, produci ng a cerebral necroti zi ng
vascul i ti s.
There i s no treatment that cures rheumatoi d arthriti s. The goal s for therapy are i nducti on of a
remi ssi on, i mproved functi on, and mai ntenance of a remi ssion. There are three groups of drugs
used to treat rheumatoi d arthri ti s: NSAIDs, corticosteroi ds, and di sease-modi fying antirheumati c
drugs (DMARDs). Si nce NSAIDs do not affect the course of the di sease, they are used i n
conjunction with DMARDs. Corti costeroi ds are potent anti -infl ammatory and anti -immune drugs,
but the side effects associ ated with long-term treatment li mit thei r useful ness. DMARDS are now
the fi rst li ne of therapy for the earl y treatment of rheumatoi d arthri ti s. Methotrexate has proven
to be very effecti ve and i s often the i ni ti al drug of choice. Other synthetic DMARDs i ncl ude
lefl unomi de, cycl ospori ne, azathi opri ne, gol d, sul fasal azine, minocycl ine, and hydroxychl oroqui ne.
Bi ol ogi c DMARDs that i nhi bit TNF-al pha i ncl ude i nfli xi mab, etanercept, and adali mumab. Anakinra
inhi bits i nterl euki n-1. The primary si de effect of the bi ol ogi c DMARDs i s an i ncreased suscepti bi l ity
to i nfecti on.
56
Most of the drugs used for the treatment of rheumatoi d arthri ti s have si gni fi cant
si de effects that may li mi t thei r use (Tabl e 19-18). Surgical procedures such as synovectomy,
tenol ysis, and joi nt repl acement are performed to reli eve pai n and restore joint function.
Blood
Anemi a
Leukopenia
P.522
TABLE 19-18 Adverse Effects of Drugs Used to Treat Collagen Vascular Diseases
DRUG EFFECT
Immunosuppressants
Methotrexate Hepatotoxi ci ty, anemia, l eukopeni a
Azathioprine Bi li ary stasi s, l eukopeni a
Cycl ospori ne Renal dysfunction, hypertensi on
Hypomagnesemi a
Cyclophosphami de Leukopeni a, hemorrhagi c cysti ti s
Inhi bi ti on of pseudochol i nesterase
Lefl unomi de Hepatoxici ty, wei ght l oss, hypertensi on
TNF Antagonists
Etanercept Bacteri al i nfecti ons, tubercul osi s
Infl iximab Lymphoma, heart fai lure
Adal i mumab
Interleukin-1 Antagonists
Anaki nra Infecti on, ski n i rri tation
Corticosteroids Hypertensi on, fl ui d retenti on
Osteoporosi s, i nfecti on
Aspirin Pl atel et dysfuncti on, pepti c ul cer
Hepati c dysfuncti on, hypersensiti vi ty
NSAIDs Pepti c ul cer, hypertensi on, hypergl ycemi a, leukopeni a
COX-2 inhibitors Renal dysfunction
Gold Aplasti c anemi a, dermati ti s, nephri ti s
Antimalarials Myopathy, retinopathy
Penicillamine Gl omerul onephri tis, myastheni a, apl astic anemi a
Because rheumatoi d arthriti s i s a multi system disease and the cli ni cal manifestati ons are so
di verse, i ndi vi dual i zed preoperati ve eval uation is i mportant i n the identi fi cation of systemi c
effects.
The joint effects of rheumatoi d arthriti s, including arthri ti c changes in the temporomandi bul ar
joi nts, cri coarytenoi d joi nts, and cervi cal spine, can render ri gid, direct l aryngoscopy and
tracheal intubati on very di fficul t. The mobil i ty of these joi nts shoul d be eval uated before surgery
so that a pl an for airway management can be formul ated. If atl antoaxi al i nstabi li ty exists, fl exion
of the neck may compress the spi nal cord. Neck pai n radi ati ng to the occi put may be the fi rst si gn
of cervi cal spine involvement. Patients wi th symptoms or evi dence of cervi cal cord compression
can be fitted with a cervical col lar preoperati vel y to mi ni mize the ri sk of overmanipulation of the
neck duri ng surgery. Many pati ents with rheumatoi d arthriti s, however, are asymptomati c with
respect to cervi cal spi ne disease (Fi g. 19-5). Preoperati ve i magi ng (radi ography, CT, MRI) may be
i ndi cated i f the degree of cervical involvement i s unknown. Al though there have been no
documented reports of spi nal cord damage i n patients wi th rheumatoi d arthri ti s undergoing
tracheal i ntubati on for elective surgery, al l eged neurol ogi c damage after l aryngoscopy has been
the source of l iti gation agai nst anesthesi ol ogi sts. Any preoperati ve evi dence of neurol ogi c functi on
shoul d be documented before surgery. To minimize the risk of neurol ogi c damage duri ng tracheal
intubati on, awake, fi beropti c l aryngoscopy may be the best means of performi ng tracheal
intubati on i n patients wi th si gni fi cant cervical spi ne involvement. Because pati ents wi th
rheumatoi d arthriti s undergo repeated anestheti cs, i t i s qui te helpful i f the technique of airway
management i s cl earl y documented in the pati ent' s medi cal record. Progressi on of the rheumatoi d

process may, however, al ter joi nt functi on to the extent that neck moti on may dimi ni sh wi th ti me
and render a previ ousl y successful i ntubation technique usel ess. Cri ocoarytenoi d arthri ti s produces
erythema and edema of the vocal cords. Invol vement of the cri coarytenoi d joi nts reduces the si ze
of the glotti c i nl et and necessi tates the use of a small er than predi cted tracheal tube. Exaggerated
postextubati on edema and stri dor may occur.
P.523
The degree of cardi opul monary i nvol vement by the rheumatoid process infl uences the sel ection of
the type of anesthesi a. Functional evaluati on of the heart and l ungs i s necessary i f the cli ni cal
hi story suggests dysfuncti on. It may be di fficul t to determi ne i f the dysfuncti on i s secondary to
rheumatoi d arthriti s or other common causes of cardiopul monary di sease such as arteri osclerosi s
or smoki ng. The need for postoperati ve venti l atory support shoul d be anti ci pated i f severe
pul monary disease i s present.
Medi cati ons that the patient i s recei vi ng i nfluence the management of anesthesi a. Corticosteroi d
suppl ementati on may be necessary duri ng the peri operati ve peri od. Aspi ri n and other anti -
infl ammatory drugs i nterfere with platelet functi on and cl otti ng may be abnormal . Many
rheumatoi d medi cati ons suppress red blood cell formation and anemi a i s common. Drug i nduced
hepati c and renal dysfuncti on may be present.
Restri cti on of joint mobil i ty necessi tates careful posi tioni ng of the pati ent duri ng the operati on.
The extremiti es should be posi tioned to mi ni mi ze the ri sk of neurovascul ar compressi on and
further joi nt i njury. Preoperati ve eval uation of joi nt moti on wi l l hel p determi ne how the
extremi ti es shoul d be posi ti oned.
Rheumatoi d arthri ti s i s a mul tisystem di sease. Potenti al joi nt disabil i ti es have been wel l
documented in the medical l i terature and are often obvious. More si gni fi cant and l ess evi dent are
the effects on the spi nal cord, heart, l ungs, ki dneys, and li ver. The type and severi ty of systemic
dysfuncti on must be considered when pl anni ng an anestheti c for patients with rheumatoi d
arthri tis.
57, 58

Syst emi c Lupus Er yt hemat osus
Systemi c l upus erythematosus (SLE) is an autoimmune di sease wi th diverse cli ni cal and
immunol ogic mani festati ons. The eti ol ogy of SLE i s unknown, but appears to be a compl ex
interaction between genetic suscepti bi li ty and hormonal and envi ronmental factors. Pati ents with
SLE produce autoanti bodi es pri mari l y to DNA, but al so RNA polymerase, cardi ol ipi n, and ri bosomal
phosphoproteins. Some of the cl ini cal mani festati ons of SLE may be the result of the production of
an autoanti body hi ghl y speci fi c for a si ngl e protein wi thi n an organ.
59

The cli nical mani festati ons of SLE are di verse. The most common presenting features are
pol yarthriti s and dermati ti s. The arthri tis i s ol i goarti cul ar and migratory. Any joint may be
invol ved incl uding the cervi cal spi ne. The cl assic mal ar rash i s present i n onl y one-third of SLE
patients. Renal di sease i s a common cause of morbi dity and mortali ty i n pati ents with SLE.
Protei nuri a, hypertensi on, and decreased creatinine clearance are the usual mani festations of SLE
nephri ti s. Of pati ents wi th SLE, 10 to 20% devel op end-stage renal di sease and require di al ysi s or
transpl antati on. Central nervous system involvement occurs i n 50% of patients wi th SLE and i s a
resul t of vascul opathy. CNS mani festati ons i nclude sei zures, stroke, dementia, psychosi s, myel i ti s,
and peri pheral neuropathy. The crani al MRI may demonstrate vascul ar lesi ons, but i s not adequate
for pati ents wi th di ffuse cerebral di sease.
60

SLE produces a di ffuse serosi ti s that mani fests as pl euri ti s and peri cardi ti s. Al though 60% of SLE
patients have a peri cardial effusi on, cardi ac tamponade i s uncommon. In rare cases, cardi ac
tamponade may be the presenti ng si gn of SLE. Myocardi tis, cardi ac conduction abnormal iti es,
ventri cul ar dysfuncti on, and coronary arteri tis can occur i n pati ents with SLE.
61
A noninfecti ous
endocardi ti s (Libman-Sacks endocardi tis) often affects the mi tral val ve and can produce mi tral
insuffi ciency. Effecti ve treatment of SLE has i mproved survi val , but has increased the li kel i hood of
ischemi c heart di sease. Pul monary effects of SLE include pleural effusi on, pneumoni ti s, pul monary
hypertensi on, and al veol ar hemorrhage. There i s a hi gh i nci dence of pulmonary hypertensi on i n
FIGURE 19-5. Magneti c resonance imagi ng of a cervi cal spine i n a patient with rheumatoi d
arthri tis. Al though the patient had no neurol ogi c symptoms, there is severe spi nal stenosis i n
the upper cervi cal spi ne.
SLE pati ents who have Raynaud' s phenomenon. Pati ents wi th SLE are suscepti bl e to i nfection that
may present as pneumoni a or adul t respiratory di stress syndrome. Pul monary functi on studi es
typi cal l y demonstrate a restri cti ve l ung di sease pattern and a decreased di ffusi ng capaci ty.
Patients with SLE may have cricoarytenoi d arthriti s that can manifest as hoarseness, stri dor, or
ai rway obstructi on.
Nearl y one-thi rd of patients wi th SLE have detectable anti phosphol i pi d anti bodi es and may have
thromboembol i c compl i cations. Lupoi d hepati tis typi cal ly occurs i n young women wi th SLE. Other
potential ly seri ous mani festations of SLE i ncl ude peritoni ti s, pancreati tis, bowel i schemia, and
protei n-losi ng enteropathy.
There i s no specific etiol ogi c therapy for SLE. Despi te the di verse effects of SLE and the lack of
specific therapy, current regi mens have improved survival . NSAIDs are used for mi l d arthri ti s.
Antimal ari al s (hydroxychl oroqui ne) control arthri ti s and exert anti thrombotic effects.
Corti costeroids are effecti ve for moderate and severe SLE, but toxi city l i mi ts the dose.
Immunosuppressants such as methotrexate, azathi opri ne, cycl ophosphamide, and mycophenol ate
mofeti l are effective and permi t lower dosages of corti costeroi ds. The potenti al for si de effects
from any of the drugs used to treat SLE i s si gnifi cant and can result i n morbi dity.
62

Drug-induced l upus may be caused by procai nami de, qui ni di ne, hydral azi ne, methyl dopa,
enal apri l , captopri l, cl oni dine, i soni azi d, or mi nocycli ne. Drug-induced l upus may be caused by
reacti ve drug metabol i tes and reacti ve T cel ls. The cli ni cal manifestati ons of drug-induced l upus
are general ly mi l d and

incl ude arthral gia, fever, anemi a, and leukopeni a. These effects typi cal ly resolve wi thi n 4 weeks of
di sconti nuati on of the drug.
Careful preoperati ve eval uati on of the patient wi th SLE is necessary because of the di verse
systemi c effects of the di sease. Preoperati ve chest radi ography, echocardi ography, or pul monary
functi on testing may be necessary if the cli nical hi story suggests dysfuncti on. Anesthesi a
management i s infl uenced not onl y by the degree of organ dysfunction, but also by the drugs used
to treat SLE. Al though there are no speci fi c contrai ndi cati ons to a particul ar type of anesthetic,
myocardial dysfuncti on wi l l certai nl y i nfl uence the choice of anestheti c and the type of
intraoperative moni tors. Because renal dysfuncti on i s so common, renal function should be
quantified preoperati vel y i f there i s any suggesti on of a recent change i n renal function. Although
mi nor abnormal iti es i n hepati c functi on are present i n many patients wi th SLE, these changes are
not usuall y si gni fi cant. Pati ents with SLE are at i ncreased ri sk for postoperati ve i nfections.
Arthriti c involvement of the cervi cal spi ne is unusual i n pati ents wi th SLE and tracheal i ntubati on
is not general l y di ffi cul t. The potential for laryngeal involvement and upper ai rway obstructi on
does, however, requi re cl i ni cal eval uati on of l aryngeal functi on. Shoul d postextubation laryngeal
edema or stri dor occur, i ntravenous admini stration of corti costeroi ds i s effecti ve for al l evi ati on of
symptoms.
Drugs administered to the pati ent for treatment of SLE may also infl uence the management of
anesthesia. Patients recei vi ng corti costeroi ds may require i ntraoperati ve admi ni strati on of
corti costeroi ds. Cycl ophosphami de i nhi bi ts pl asma chol i nesterase and may prolong the response to
succi nyl choli ne and mi vacurium.
Scl er oder ma
Scl eroderma (systemi c sclerosi s) i s characterized by excessi ve deposi ti on of col l agen and fi brosi s
in the ski n and internal organs. The eti ology of scleroderma is unknown. Infectious or
envi ronmental tri gger agents have been proposed. Al terati ons i n the functi on of fi brobl asts,
endothel i al cel l s, and T and B l ymphocytes resul t i n exaggerated deposi ti on of coll agen,
infl ammati on, obl iteration of smal l arteri es and arteri ol es, and ulti matel y fi brosi s and atrophy of
organs. Endothel ial cel l i njury may be the earl iest mani festation of scl eroderma. The endothel ial
P.524
cel ls appear to be defi ci ent i n intri nsi c vasodil ators whi le havi ng i ncreased l evels of the potent
vasoconstri ctor endothel i n-1. Increased acti vi ty of connective ti ssue growth factor (CTGF) and
transformi ng growth factor-beta (TGF-) may be responsi bl e for the deposi ti on of l arge amounts
of col lagen.
63

The manifestati ons of scl eroderma are most evi dent i n the skin, whi ch becomes thi ckened and
swol len. Eventuall y, the ski n becomes atrophi c and smal l arteri es are obli terated. The ski n
becomes fi broti c and taut and produces severe restri cti on of joi nt mobi l ity. Raynaud' s
phenomenon i s present in 85% of pati ents wi th scl eroderma and i s often the presenting symptom.
The same pathol ogi c process that affects the vascul ar system i n the skin affects smal l blood
vessel s in other organs as wel l. Lung i nvol vement occurs in 80% of pati ents wi th scl eroderma and
is characterized by i ntersti ti al fi brosi s, pul monary hypertensi on, and an impaired diffusing
capaci ty. These changes in conjuncti on wi th the effects of chroni c aspirati on pneumoni tis produce
a restrictive lung disease. The onset of pulmonary hypertensi on i s an ominous prognosti c si gn.
64

Myocardi al fibrosi s occurs in 70 to 80% of patients with scl eroderma, al though only 25% have
cl i ni cal symptoms. Echocardiography may reveal a decreased ejecti on fracti on and impai red left
ventri cul ar fi l l ing. Degenerati on of cardiac conducti ng ti ssue may cause conduction defects and
cardi ac dysrhythmi as. Peri cardi tis with effusi on i s very common.
Renal dysfunction is relativel y common i n patients wi th scl eroderma. Thi s dysfuncti on i s secondary
to pathol ogi c changes i n the renal vascul ature si mi l ar to the changes in the di gi tal arteri es that
produce Raynaud' s phenomenon. Renal dysfuncti on can be so severe that a scl eroderma renal
crisi s develops wi th hypertensi on, reti nopathy, and a rapi d deteri orati on in renal functi on.
Gastroi ntesti nal motil i ty i s decreased and i s very pronounced in the esophagus. The frequent
epi sodes of gastroesophageal refl ux and aspi rati on pneumoni ti s exacerbate pulmonary
dysfuncti on. Invol vement of the col on and smal l intestine may resul t in pseudoobstruction.
Currentl y, the therapy for scl eroderma is l i mi ted to the treatment of speci fi c organ dysfuncti on,
immunosuppressants (corti costeroi ds, methotrexate, cycl ophosphamide, anti thymocyte gl obuli n),
and decreasi ng coll agen production (peni ci ll ami ne). Vasodi lators such as calci um channel bl ockers,
ACE inhi bi tors, and prostacycl i n anal ogs are frequently used for the treatment of cardiac
dysfuncti on, pul monary hypertensi on, and Raynaud's phenomenon.
65

Scl eroderma, li ke other col lagen vascul ar di seases, is a mul ti organ disease with many systemi c
mani festati ons. The al tered organ systems must be thoroughl y eval uated so that a l ogi cal pl an for
anesthesia can be sel ected. There are no speci fi c contraindicati ons to the use of any type of
anesthesia, al though the selecti on must be gui ded by the degree of organ dysfuncti on.
Tracheal i ntubation can be qui te di ffi cul t. Fibrotic and taut facial skin can markedly hi nder acti ve
and passi ve mobi l i ty of the temporomandibul ar joints. Awake fi beropti c-assi sted l aryngoscopy and
tracheal intubati on may be required; tracheostomy may be necessary in severel y affected
patients. Orotracheal i ntubati on i s preferred as the fragi l ity of the nasal mucosa i ncreases the ri sk
of severe nasal hemorrhage from nasotracheal intubati on.
The pati ent wi th scl eroderma i s at ri sk for aspirati on pneumoni tis during the i nducti on of
anesthesia owi ng to the high i ncidence of esophageal dysmoti l i ty and gastroesophageal refl ux.
Appropri ate measures to mi nimize the ri sk of acid aspirati on, such as the use of hi stami ne-2
bl ockers and oral antacids, may be i ndi cated.
Chronic arterial hypoxemia i s often present because of restri cti on of l ung expansi on and i mpai red
oxygen diffusion. Controlled ventilation with an increased oxygen concentrati on i s usual ly
necessary. Compromi sed myocardi al functi on and decreased coronary vascul ar reserve often
necessitate the use of invasi ve cardi ovascul ar moni tori ng because the response to inhal ed
anestheti cs may be exaggerated. Transesophageal echocardi ography can provi de valuabl e
information about cardi ac function, al though passage of the probe may be di ffi cul t because of
esophageal stri cture. Venous access can be di ffi cul t and a venous cutdown or central venous
catheterizati on may be required. Muscle involvement may i ncrease the sensi tivity to muscl e
rel axants and short-acti ng neuromuscul ar bl ockers shoul d be used.
Regi onal anesthesia may be admi ni stered to pati ents wi th scl eroderma, al though the response to
local anestheti cs may be prol onged. The anesthesi ol ogi st is often consul ted as to the effi cacy of
sympatheti c blockade for the treatment of vasospasm secondary to Raynaud' s phenomenon.
Stel late gangli on

bl ockade, however, may produce deleteri ous effects on contral ateral bl ood fl ow i n patients wi th
scl eroderma. Intractabl e ischemic l i mb pain may necessi tate l ong-term pai n management.
P ol ymyosi t i s/ Der mat omyosi t i s
Three di seases compri se the infl ammatory myopathi es: polymyositi s, dermatomyosi ti s, and
incl usi on-body myositi s. Cl inical features common to these three di seases are severe muscle
weakness, and noni nfecti ous muscle infl ammation. The etiol ogy of these di seases i s unknown;
however, many of the processes that cause the i nfl ammation have been del i neated.
Dermatomyosi tis i s the result of an anti body i nduced compl ement acti vati on that l yses muscle
capil l ari es and causes muscl e necrosis. Muscl e fi ber necrosi s i n pol ymyosi ti s and i ncl usion-body
myosi tis i s caused by cytotoxic T cel ls.
66

Common presenting symptoms of polymyositis are muscle pai n, tenderness, and proxi mal muscle
weakness. Patients with dermatomyosi sits have skin manifestati ons that may precede the muscl e
weakness. The ski n rash of dermatomyosi tis i s characterized by a purpl ish discol orati on of the
eyeli ds (heli otrope rash), peri orbi tal edema, erythematous l esi ons on the knuckles and a sun-
sensi ti ve rash on the face, neck, and chest. Inclusion-body myositi s typicall y presents with
weakness of the quadri ceps and ankl e dorsiflexors in men over 50 years of age. Although the
pathogeni c processes of these di seases are different, the effects on the heart and lungs are
si mi l ar. Of pati ents wi th pol ymyosi ti s and dermatomyosi ti s, 50% have evidence of pul monary
di sease. Pul monary mani festati ons i ncl ude intersti ti al lung di sease, bronchopneumonia, and
al veoli tis. Aspi rati on i s one of the most common compl icati ons of pol ymyosi tis. Intrinsi c l ung
di sease and thoraci c muscle weakness produce a restri cti ve l ung di sease and decreased di ffusi ng
capaci ty. Myocardi al fi brosis can resul t i n congesti ve heart fai l ure and cardi ac dysrhythmi as.
The most effecti ve treatment for the i nfl ammatory myopathi es are corti costeroi ds (predni sone).
Patients that do not respond to corticosteroi ds are treated with immunosuppressants such as
azathi opri ne, methotrexate, cycl ophosphamide, cycl ospori ne, and mycophenol ate mofeti l.
Intravenous immunoglobul i n and total body l ymphocyte i rradiation have been recommended for
patients resi stant to other forms of therapy.
67

Mobi li ty of the temporomandibular joints and cervi cal spi ne is usual ly adequate i n patients with
pol ymyosi ti s. Some pati ents, however, have restri cted mobi li ty that can make di rect l aryngoscopy
di fficul t. Adequate mouth and neck mobil i ty must be ascertai ned before i nducti on of anesthesi a.
Awake fl exi ble fiberopti c laryngoscopy and tracheal i ntubati on may be requi red for those pati ents
with restri cted neck mobil i ty and i nadequate mouth openi ng.
Dysphagi a and gastroesophageal reflux are very common and there i s an i ncreased li kel i hood of
aspi rati on pneumoni tis. Appropri ate precauti ons to minimize the risk of aspi rati on of gastri c
contents shoul d be taken duri ng the peri operati ve period. Gastroi ntesti nal perforations that
necessitate surgi cal interventi on are rel atively common i n pati ents with pol ymyosi tis.
Although the typi cal el ectromyographic changes of pol ymyosi ti s suggest the potential for
hyperkalemia after succinyl choli ne, succi nyl chol ine has been admi ni stered to patients wi th
pol ymyosi ti s wi thout compli cation.
68
Prol onged neuromuscul ar blockade may occur after the
administrati on of nondepol ari zi ng muscle rel axants. This prol onged response may be secondary to
the myopathy or an i nteracti on between the muscle rel axant and i mmunosuppressants. The
reported experi ence wi th anesthesia for pati ents wi th i nfl ammatory myopathi es i s very l imited and
P.525
general izations from a few case reports must be i nterpreted wi th cauti on. It shoul d be anti ci pated
that consi derable vari ati on i n response to muscl e rel axants wil l occur. It woul d seem to be prudent
to avoi d the administrati on of succi nyl choli ne and to use short-acti ng nondepolari zing muscl e
rel axants such as mivacuri um, ci satracuri um, and rocuroni um.
The degree of cardi opul monary dysfuncti on i nfluences the choi ce of anesthesi a and sel ecti on of
intraoperative moni tors. Further preoperati ve eval uati on of cardiopulmonary function may be
requi red if the cli nical hi story suggests deteri orati on i n cardi ac or pul monary functi on. Because of
the preoperati ve muscle weakness, postoperative ventilatory support may be necessary.
SKIN DISORDERS
Most pri mary di seases of the ski n are l ocali zed and cause few systemi c effects or compl i cations
duri ng the admi ni strati on of anesthesi a. Two bli steri ng ski n disorders, however, can resul t in
compl i cati ons duri ng anesthesi a: epi dermol ysis bul losa and pemphi gus.
Epi der mol ysi s Bul l osa
Epi dermol ysis i s a rare ski n di sorder that can be i nheri ted or acqui red. Pati ents wi th heri table
forms have abnormal iti es that cause defects in the anchori ng systems of ski n layers. The acqui red
forms are autoimmune disorders in which autoantibodi es are produced that destroy the basement
membrane of the ski n and mucosa. The end resul t i s the loss or absence of normal intercel l ul ar
bri dges and separation of skin l ayers (Fi g. 19-6). The separati on of the ski n layers resul ts i n
intradermal fl ui d accumul ati on and bullae formation. Even minor ski n trauma produces ski n
bl i sters. Lateral sheari ng forces appli ed to the ski n are especial ly damagi ng. Pressure appl i ed
perpendi cul ar to the skin i s not as hazardous. Although there are 25 subtypes of epi dermol ysis
bul losa, these di sorders can be categori zed into three groups dependi ng on where the actual skin
separati on occurs: epidermolyti c (epi dermol ysi s si mpl ex), junctional , and dermolyti c
(epi dermol ysis bul l osa dystrophica). Although seri ous compli cati ons from skin and mucosal loss
can occur wi th any form of epidermolysi s, the si mpl ex form i s general ly beni gn. Pati ents wi th the
juncti onal form rarely survi ve beyond earl y chi ldhood. Laryngeal i nvol vement is unusual , but is
most l ikely to occur with the juncti onal type.
Epi dermol ysis dystrophi ca is caused by a defect in type VII coll agen. This form produces
FIGURE 19-6. The ultrastructure for the zones of the ski n. The di agram demonstrates where
ski n separation occurs in the di fferent types of epidermolysi s bul l osa. (Reproduced wi th
permi ssi on from Uitto J, Christiano AM: Molecul ar geneti cs of the cutaneous basement
membrane zone. J Cli n Invest 90;687, 1992; copyright of the Ameri can Soci ety for Cl i ni cal
Investi gati on.)
severe scarri ng of the fi ngers and toes wi th pseudosyndactyl y formati on and ankyl osi s of the
interphalangeal joints and resorption of the metacarpals and metatarsal s (Fi g. 19-7). Mal i gnant
degenerati on of the skin i s common. Invol vement of the esophageal mucosa i s present i n most
patients, resul ti ng in dysphagia and esophageal strictures that contri bute to poor nutri ti on.
69

Secondary infecti on of bul lae wi th staphyl ococcus aureus or beta hemol ytic streptococcus is
frequent. Glomerul onephri ti s may be secondary to streptococcal infecti on. Hypoal buminemi a,
secondary to nephri ti s, protein l oss i nto bul lae, and poor nutri ti on, i s usual . Other consequences
of chroni c i nfecti on and malnutriti on are anemi a and cardi omyopathy. Mi tral val ve prol apse may
occur. Hypopl asi a of tooth enamel resul ts in carious degenerati on of the teeth and the need for
extensi ve dental restorati ons. Diseases associ ated with epidermolysi s bul l osa incl ude porphyri a

cutanea tarda, amyl oi dosi s, mul ti pl e myel oma, di abetes mel li tus, and hypercoagulation. Pati ents
with epidermolysi s bul l osa dystrophica rarely survive beyond the thi rd decade of l i fe.
P.526
Medi cal therapy for epi dermol ysi s bul losa has not been very successful . Phenytoi n, a col lagenase
inhi bitor, may produce short-term improvement. Corti costeroi ds are not effecti ve. Coverage of
denuded ski n wi th cul tured human ski n preparati ons may be effecti ve. Surgi cal therapy is di rected
at preservati on and i mprovement of hand function.
It i s cri ti cal that trauma to the ski n and mucous membranes be avoi ded or mi ni mi zed duri ng the
i ntraoperati ve peri od. Trauma from adhesi ve tape, bl ood pressure cuffs, and adhesive ECG
el ectrodes can cause bul lae formati on. The bl ood pressure cuff shoul d be padded wi th l oose cotton
dressi ng. Intravascul ar catheters should be anchored with sutures or a gauze dressing rather than
adhesi ve tape. Trauma from a facemask may be reduced by l ubri cati on of the mask and the
patient' s face. Use of upper airway i nstruments, i ncl udi ng oropharyngeal and nasopharyngeal
FIGURE 19-7. Epi dermol ysi s bul losa. A: Bull ous l esi on of the finger of a neonate wi th
epi dermol ysi s. B: Hands of an ol der chi l d wi th epi dermol ysis progressi on to produce severe
scarri ng and pseudosyndactyl y. (Courtesy of James E. Bennett, MD, Di vi si on of Pl asti c
Surgery, Indiana Uni versi ty School of Medi ci ne, Indi anapol is, IN.)
ai rways, should be kept to a minimum because the squamous epi theli al l i ni ng of the oropharynx
and esophagus i s suscepti ble to bul l ous formation. Fri cti onal trauma to the oropharynx may resul t
in the formation of l arge intraoral bull ae, airway obstructi on, and extensive hemorrhage from
denuded mucosa. For si mi lar reasons, i nserti on of an esophageal stethoscope shoul d be avoi ded.
Laryngeal i nvol vement i n pati ents with epidermolysi s bul l osa dystrophi ca i s rare. If tracheal
intubati on i s requi red, the l aryngoscope and tracheal tube shoul d be wel l l ubri cated to reduce
fri cti on agai nst the oropharyngeal mucosa. Scarri ng of the oral cavi ty can cause mi crostomi a and
immobil i ty of the tongue, whi ch i ncreases the diffi culty of tracheal i ntubation. Fi beroptic-assi sted
tracheal i ntubati on may be required. Al though the safety of tracheal intubati on has been
establ i shed for patients wi th epi dermol ysis bull osa dystrophi ca, si mi l ar safety has not been
establ i shed for patients wi th the juncti onal form. The juncti onal form affects al l mucosa, including
the respiratory epithel i um. The types of surgi cal procedures (i ntra-abdomi nal) requi red in i nfants
with the juncti onal type, however, usual l y mandate tracheal i ntubati on.
Surgical procedures for patients with epi dermolysi s are usual l y peri pheral and involve the hands.
Ketamine is very useful for such superfi cial procedures because it provides good anal gesi a and
usuall y does not require suppl emental i nhalati on anesthesia. There are, however, no
contrai ndi cations to inhal ed anestheti cs. Porphyria cutanea tarda, often associated wi th
epi dermol ysi s bul l osa, does not have the same impli cati ons for anesthesi a as acute i ntermi ttent
porphyri a. Regi onal anesthesia, i ncl udi ng spi nal , epi dural , and brachi al plexus anesthesi a, has
been used successfull y for pati ents wi th epidermolysi s bul l osa.
Despi te al l the potenti al compl icati ons wi th anesthesia for pati ents wi th epidermolysi s bul l osa,
appropriate intraoperati ve management is associ ated wi th surpri si ngl y few compli cations. Thi s is
especial ly true when care is provided at a center experienced wi th the management of pati ents
with epidermolysi s bul l osa.
70, 71

P emphi gus
Pemphi gus i s a vesicul obul lous di sease that may i nvol ve extensi ve areas of the skin and mucous
membranes. Pemphigus is an autoimmune disease i n whi ch IgG anti bodi es attack the desmosomal
protei ns desmoglei n 3 and desmoglei n 1, l eadi ng to di srupti on of cell adhesion and separati on of
epi thel ial l ayers. A growi ng number of drugs have been i mpl i cated i n the cause or exacerbati on of
pemphi gus. These drugs i ncl ude penici ll ami ne, cephal ospori ns, ACE i nhibi tors, phenobarbi tal ,
propranol ol , l evodopa, pi roxi cam, and ni fedi pi ne.
There are several types of pemphi gus i ncl udi ng pemphi gus vul gari s, pemphi gus fol i aceus,
pemphi gus vegetans, pemphi gus erythematosus, and paraneopl asti c pemphi gus.
72
Pemphigus
vul gari s is the most common type and the most cl i ni cal ly significant for the anesthesi ol ogi st
because of the occurrence of oral lesions. Oral l esi ons devel op in 50 to 70% of pati ents with
pemphi gus vul gari s and usual ly precede the cutaneous l esions. Lesi ons of the pharynx, l arynx,
esophagus, conjuncti va, urethra, cervix, and anus can develop. Extensive

oropharyngeal l esi ons may make eati ng pai nful to the extent that mal nutri tion occurs. Skin
denudati on and bul l ae formation can resul t i n si gni fi cant fluid and protei n l osses and the ri sk of
secondary bacterial i nfection is great. As wi th epi dermol ysi s bul losa, lateral sheari ng force i s more
l i kel y to produce bul l ae than pressure exerted perpendi cul ar to the ski n surface. Systemic
corti costeroi ds are the most effecti ve therapy for pemphigus vulgaris. Improvement may be seen
within days of corti costeroi d therapy wi th ful l heali ng in 6 to 8 weeks. Adjuvant
immunosuppressants such as azathiopri ne, cycl ophosphamide, methotrexate, and mycophenol ate
mofeti l can be used to reduce corticosteroi d doses and si de effects.
73

Paraneopl astic pemphi gus i s an autoi mmune di sease associated wi th a number of mal ignant
tumors, especi all y l ymphomas and l eukemias. IgG anti bodi es are produced that react to
desmogl ein 3 and 1. Oral and cutaneous l esi ons occur in most pati ents. Obstructive respi ratory
fai l ure may resul t from infl ammati on and sloughi ng of the tracheobronchial mucosa.
74

Pemphi gus fol iaceus (superfi cial pemphigus) i s a l ess-severe form of pemphigus in which skin
separati on occurs near the epi theli al surface; the oral mucosa i s not affected. Pemphi gus foli aceus
P.527
can, however, be fatal i f not treated. Pemphi gus erythematosus (Senear-Usher syndrome) i s a
superfi cial form of pemphigus wi th erythematous hyperkeratoti c l esi ons over the nose and mal ar
areas; the oral cavi ty i s not involved.
Preoperati ve drug therapy and the extreme fragil i ty of the mucous membranes are the pri mary
concerns for the management of anesthesi a for patients wi th pemphigus. Corti costeroi d
suppl ementati on wi l l be necessary duri ng the peri operati ve period. Management of the ai rway and
tracheal i ntubati on shoul d be performed as descri bed for pati ents wi th epidermolysi s bull osa.
Ketami ne and regi onal anesthesi a have been used successfull y for patients wi th pemphi gus.
75

There are no speci fi c contrai ndi cati ons to the use of any i nhal ed or i ntravenous anesthetics;
however, potenti al side effects of treatment drugs and i nteracti ons wi th anestheti cs must be
consi dered. Methotrexate produces hepatorenal dysfuncti on and bone marrow suppressi on, and
cycl ophosphamide may prol ong the acti on of succi nyl chol i ne and mi vacuri um by i nhi biti ng
chol i nesterase acti vi ty.
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> Tabl e of Contents > Secti on IV - Prepari ng for Anesthesi a > Chapter 20 - Mal i gnant Hyperthermi a and Other
Pharmacogeneti c Di sorders
Chapter 20
Malignant Hyperthermia and Other
Pharmacogenetic Disorders
Henry Rosenberg
Barbara W. Brandom
Nyamkhishig Sambuughin
Jeffrey E. Fletcher
KEY POINTS
Mal i gnant hyperthermi a syndrome (MH) i s an uncommon pharmacogeneti c
di sorder of skeletal muscle. Thi s means several thi ngs: (a) MH i s inherited. (b)
The syndrome i s i nduced by pharmacologi c agents i n al most all cases. A few
cases have been documented to resul t from exercise and heat exposure. (c) The
pathophysi ol ogy i nvol ves bi ochemical changes i n skeletal muscle physi ol ogy
resul ti ng in hypermetabol i sm. (d) The i nci dence i s approximatel y one i n 10,000
general anestheti cs i n the general population.
Unexpected elevation of end-ti dal carbon di oxi de in the absence of equipment
malfunction is the most sensiti ve and speci fi c si gn of MH. Other si gns of MH
incl ude tachycardi a, tachypnea, aci dosi s, muscl e ri gi di ty, and rhabdomyol ysi s.
MH may occur at any time i n the course of an anestheti c from induction to
emergence.
Masseter muscle ri gi dity after succi nyl chol ine is more common in chi l dren than
adults. It i s predi cti ve of MH susceptibi l ity in up to 25% of cases and i s
associated wi th myogl obi nuri a. Tri gger agents shoul d be di sconti nued after
masseter muscl e ri gi dity.
Sudden cardi ac arrest in a young mal e duri ng general anesthesi a, wi th or
without succi nyl choli ne, is l i kel y a result of hyperkalemia i n a pati ent wi th an
occul t myopathy, especi al l y Duchenne muscul ar dystrophy.
Disorders that predi spose pati ents to MH include central core di sease and rarer
forms of myotoni a (e.g., hypokal emi c peri odi c paralysi s).
Tri gger agents for MH i nclude all potent inhalation agents and succi nyl choli ne.
Many i nheri ted di sorders have si gnifi cant impl icati ons for anestheti c management. In this chapter
we di scuss those di sorders that are preci pitated by drugs often administered by anesthesi ol ogists.
In some cases, such as the porphyri as, the i ll ness may be induced by agents other than
anesthetics. In other enzymati c di sorders, such as pseudochol inesterase abnormal iti es, it woul d be
unl i kel y for a pati ent to have any probl ems until he or she i s exposed to the depol ari zi ng
neuromuscul ar bl ocki ng agent succi nylchol ine. Mali gnant hyperthermi a (MH) or mal ignant
hyperpyrexia i s perhaps the most significant i nheri ted di sorder tri ggered by exposure to anestheti c
drugs.
MALIGNANT HYPERTHERMIA
Mal ignant hyperthermi a was fi rst formall y descri bed i n 1960 i n Lancet
1
by Denborough and Lovel l
and subsequentl y i n The Bri ti sh Journal of Anaesthesi a.
2
That fi rst case report l ai d the foundati on
for much of our understandi ng of the cl i ni cal presentati ons of MH. The pati ent was a young man
who clai med that several of hi s rel ati ves died wi thout apparent cause duri ng anesthesia. He was
anesthetized wi th hal othane and devel oped tachycardi a, hot sweaty skin, peripheral mottl ing, and
cyanosis. Earl y recogni tion and symptomati c treatment saved hi m. It became apparent that thi s
new syndrome had the foll owi ng elements: pati ents were otherwi se healthy unless exposed to an
anesthetic agent, temperature elevati on was a hall mark, a heritable or genetic component was
present, and a hi gh mortali ty rate was l ikel y. In additi on, wi th earl y recogniti on and treatment i t
was possi bl e to abort the mal ignant effects of the syndrome.
The gol d standard test for di agnosti c testi ng i s the caffei ne halothane
contracture test (of freshl y bi opsi ed muscl e) wherein muscl e i s exposed to
incremental doses of caffei ne or to hal othane.
The essenti al poi nts in treatment are the immedi ate disconti nuati on of tri gger
agents, hyperventi l ati on, admi ni strati on of dantrolene in doses of 2.5 mg/kg,
repeated prn to si gns of MH, and cool i ng by al l routes avai l abl e (especial ly
nasogastri c l avage, treatment of hyperkal emia i n a standard fashi on). Fol l owing
an MH episode the pati ent shoul d be treated wi th dantrolene for at l east 36
hours.
Preventi on of MH and avoi dance of medi col egal acti on consi sts of obtai ni ng a
thorough hi story rel ated to anesthetic compl i cati ons, avoi di ng MH tri gger agents
in suscepti bles and thei r rel ati ves, havi ng dantrol ene immedi atel y

avai l abl e, and moni tori ng body temperature duri ng general anesthesi a.
P.530
MH suscepti bil i ty i s i nheri ted i n an autosomal dominant pattern in humans.
Admi ni strati on of tri ggeri ng agents such as al l halogenated an aesthetic agents
and/or succi nyl choli ne leads to an uncontrol led release of free cal ci um from the
sarcoplasmi c reticulum of skel etal muscl e. Several genes have been li nked to
MH, wi th mutations found i n three, the ryanodi ne receptor gene, the
di hydropyri di ne receptor gene, and the gene that elaborates the sodi um channel
of muscle. In humans, over 18 mutati ons have been found to be causal for MH.
Mutations i n these genes al ter the functi on of the calci um channel l eading to
increased cal cium rel ease from the sarcopl asmi c reti cul um. There are many
other DNA vari ants whose significance i s yet to be determi ned.
The associ ati on between porci ne stress syndrome (PSS) or pal e soft exudative porksyndrome
and MH was described in the earl y 1970s, thus provi ding an ani mal model for MH.
3
Porcine breeds
such as the Landrace, Poland Chi na, and Pietrai n show the classi c presentati ons of MH when
potent i nhal ati on agents and/or succi nyl choli ne are admi ni stered. During the 1970s, many more
cl i ni cal presentati ons of MH were reported. The devel opment of an i n vi tro diagnosti c test was
suggested by Kal ow et al based on exposure of a skeletal muscle bi opsy speci men to caffeine and
then hal othane.
4
In 1975, Harri son reported that dantrol ene coul d be effecti ve i n treati ng and
preventi ng MH i n pi gs.
5
By 1979, a suffi ci ent number of cases were descri bed showi ng that
intravenous dantrolene could successful ly reverse the human form of MH, and the drug was
approved for use by the U.S. Food and Drug Admi ni strati on (FDA). In the 1980s, lay organizati ons
in the Uni ted States, Canada, and Great Britain were formed to di ssemi nate i nformati on to
patients affected by MH as well as to enhance awareness of the syndrome among physi ci ans.
Appli cati on of the muscl e bi opsy diagnosti c halothanecaffei ne contracture test was standardi zed
and a regi stry for MH was created i n the Uni ted States i n the late 1980s. In addi tion, a vari ety of
other tests for di agnosi ng MH were introduced, many of whi ch subsequentl y were found to be of
li ttl e or no vali di ty.
A major step forward occurred i n 1985, when Lopez and coll eagues di rectl y demonstrated an
increased i ntracell ul ar concentration of cal ci um i on i n muscl e from MH-suscepti bl e pi gs and
humans.
6
The i ntracell ular cal ci um concentrati on dramati cal ly i ncreased duri ng an MH cri si s and
was reversed by the admi ni strati on of dantrolene.
In the 1990s molecul ar bi ologic techni ques were appl ied to identi fy the genes associ ated with MH
suscepti bi l ity. It i s anti cipated that better understandi ng of the geneti c substrate of the
pathophysi ol ogy of MH wi ll resul t in a l ess i nvasi ve di agnostic test than the contracture tests used
at present. In the 1990s epidemiol ogi c informati on hel ped to di fferenti ate MH from other li fe-
threatening anestheti c compl i cations. It was appreci ated that some deaths in chi l dren formerl y
attri buted to MH were reall y the resul t of destructi on of muscl e cel l s that occurred during
anesthesia with vol ati l e agents and succi nylchol ine i n patients wi th unrecogni zed myopathies,
specificall y the dystrophi nopathi es, Duchenne and Becker muscul ar dystrophy.
7

Cl i ni cal P r esent at i ons
As our knowl edge of MH has grown, the definiti on of MH has changed. At first, MH was
thought i n al l cases to be a heritable syndrome consi sti ng of an extremel y elevated body
temperature, skel etal muscl e ri gi dity, and aci dosi s associ ated wi th a high mortal ity rate. However,
MH shoul d be thought of i n terms of i ts underlying pathophysiol ogi c characteri sti cs. MH i s a
hypermetaboli c di sorder of skel etal muscl e wi th varied presentati ons, dependi ng on speci es,
breed, and tri ggeri ng agents. An i mportant pathophysi ol ogi c process in thi s di sorder i s
intracel lular hypercal cemi a in skeletal muscle. Intracel l ul ar hypercalcemi a activates metaboli c
pathways that resul t i n adenosi ne tri phosphate depl etion, aci dosis, membrane destructi on, and
cel l death. Al though a heri tabl e component is present i n many cases, it i s not invari ably apparent
from patient fami ly hi story. In addi ti on, di sorders that may have symptoms and si gns si mi lar to
those of MH, such as neurol eptic mal i gnant syndrome (NMS), and heat stroke may not have an
i nheri ted basi s.
Classic Malignant Hyperthermia
Mal ignant hyperthermi a may present i n several ways. In almost all cases, the first
mani festati ons of the syndrome occur i n the operati ng room. However, MH also may occur in
the recovery room or (rarely) even later. In the classi c case, the i niti al signs of tachycardi a and
tachypnea resul t from sympatheti c nervous system sti mul ati on secondary to underl yi ng
hypermetabol i sm and hypercarbi a deri ved pri mari l y from the skeletal muscle. Because many
patients recei ve neuromuscul ar bl ockers and control l ed venti lation during general anesthesia,
tachypnea usuall y i s not recogni zed. Shortly after the i ncrease in heart rate, an increase i n blood
pressure occurs, often associ ated wi th ventri cul ar dysrhythmias i nduced by sympatheti c nervous
system sti mulation resul ti ng from hypercarbia or caused by hyperkalemia or catechol ami ne
rel ease. Thereafter, muscl e rigi di ty or an i ncrease i n muscle tone may become apparent. Increase
i n body temperature, at a rate of 1 to 2C every 5 mi nutes, fol lows. Wi th the i ncrease i n
metaboli sm, the pati ent may break through the neuromuscul ar bl ockade. At the same ti me, the
CO
2

absorbent becomes acti vated and warm to the touch (because the reacti on with CO
2
is
exothermi c). The pati ent wi l l displ ay peri pheral mottli ng and, on occasion, sweating and cyanosis.
Bl ood gas anal ysi s usual l y reveals hypercarbi a wi th respi ratory and metabol i c acidosis wi thout
marked oxygen desaturati on. Elevation of end-ti dal CO
2
is one of the earl iest most sensi ti ve and
specific si gns of MH. However, vi gorous hyperventi l ation may mask such hypercarbi a and del ay
the diagnosis.
8
A mi xed venous bl ood sampl e wi l l show even more dramati c evi dence of CO
2

retention and metabol ic aci dosi s.
9
Hyperkalemia, hypercalcemi a, l actaci demi a, and myogl obi nuri a
are characteri sti c. An i ncrease in creati ne kinase (CK) level s i s dramatic, often exceedi ng 20,000
uni ts in the first 12 to 24 hours. Death resul ts unl ess the syndrome i s promptly treated. Even wi th
treatment and survival , the patient is at ri sk for l ife-threatening myogl obi nuric renal fail ure and
di ssemi nated i ntravascul ar coagul ati on. Another signi fi cant cl inical probl em i s recrudescence of
the syndrome wi thi n the first 24 to 36 hours.
10, 11
If succi nylchol ine i s used during i nducti on of
anesthesia, an accelerati on of the mani festations of MH may occur such that tachycardi a,
hypertensi on, marked temperature el evati on, and dysrhythmias are seen over the course of 5 to
10 mi nutes. However, a compl etel y normal response to succi nyl chol i ne does not rul e out the
subsequent devel opment of MH when potent volatil e agents are used.
Masseter Muscle Rigidity
Ri gi dity of the jaw muscl es after admi ni strati on of succi nylchol ine i s referred to as masseter
muscle ri gidi ty (MMR) or masseter spasm. The associ ati on of thi s phenomenon wi th MH was
underl i ned by many case reports of MMR precedi ng MH.
12, 13
Al though MMR probabl y occurs i n
patients of al l ages, i t i s di sti nctl y most common i n chil dren and young adul ts. MMR occurs i n
about 1% of chi l dren induced wi th hal othane prior to admi ni strati on of succi nylchol ine. Several
studi es have shown a peak age inci dence at 8 to 12 years of age. Characteri sti cal ly, anesthesi a i s
induced by i nhalation of hal othane or sevofl urane, after whi ch succinyl choli ne is admi ni stered.
Snappi ng of the jaw or ri gi di ty on opening of the jaw is seen. Although l ess common MMR may
fol l ow induction wi th thi opental or propofol pri or to succi nyl choli ne admini stration. However, thi s
ri gi di ty can be overcome wi th effort and usual l y abates withi n 2 to 3 mi nutes. Repeat doses of
succi nyl choli ne do not rel ieve the probl em nor do non-depol arizing relaxants. A peripheral nerve
stimul ator usual ly reveal s fl acci d paral ysis. However, increased tone of other muscles also may be
noted. Tachycardi a and dysrhythmias are not i nfrequent. Only i n rare cases does frank MH
supervene immedi atel y after MMR. More commonly (if the anestheti c i s conti nued wi th a tri ggeri ng
agent), the i ni tial signs of MH appear i n 20 mi nutes or more. If the anestheti c i s disconti nued, the
patient usuall y recovers uneventful l y. However, within 4 to 12 hours, myogl obi nuri a occurs and CK
el evati on i s detected.
Muscl e bi opsy with caffei nehalothane contracture testing has shown that approxi mately 25% of
patients who experi ence MMR are al so suscepti bl e to MH.
14, 15
Therefore, one may elect to
di sconti nue anesthesi a and postpone surgery after an epi sode of MMR. If surgery must be
conti nued, it shoul d be wi th nontri ggeri ng anesthetics and the use of end-ti dal CO
2
and core
temperature monitori ng. The i ssue of whether to give dantrol ene after an epi sode of MMR i s
unresol ved. Dantrol ene i s most useful onl y when there i s a cl ear di agnosi s of MH. When MMR i s
accompani ed by ri gi di ty of chest or li mb, MH is more l ikely to fol low than after i sol ated jaw
ri gi di ty.
16, 17

The di fferential di agnosis of MMR consists of the fol lowi ng: (1) myotonic syndrome, (2)
temporomandi bul ar joi nt dysfuncti on, (3) underdosi ng with succi nylchol ine, (4) not al lowi ng
suffi ci ent ti me for succi nylchol i ne to act before i ntubation, (5) i ncreased resti ng tensi on after
succi nyl choli ne in the presence of fever or el evated plasma epinephrine. A vari ety of reports have
shown that succi nylchol ine i ncreases jaw muscl e tone i n pati ents wi th normal muscl e.
18
Thi s
normal agonistic effect of succi nylchol ine, further i ncreased by temperature
19
and epi nephri ne i n
the presence of hal othane, may account for some cases of MMR. Si gns of temporomandibular
P.531
dysfuncti on as well as myotonia shoul d be sought fol l owi ng the MMR epi sode. If ri gi di ty precl udi ng
laryngoscopy occurred wi thout temporomandi bul ar joi nt dysfuncti on, the pati ent shoul d be
eval uated by a neurol ogi st for the presence of occul t myopathy and counsel ed regardi ng the need
for a muscl e bi opsy and diagnosti c contracture test to eval uate MH suscepti bil i ty. It i s i ncumbent
on the anesthesi ol ogist to al ert the pati ent to the possibi l ity that MH may fol low i n subsequent
procedures.
MMR has been shown in both retrospecti ve as wel l as prospecti ve studies to occur in as many as 1
in 100 chi ldren anesthetized wi th hal othane and given succinyl choli ne. A retrospecti ve study based
on the i nformati on suppl i ed to the Danish Mal i gnant Hyperthermia Regi stry found that the
inci dence of MMR was 1 in 12,000 (incl udi ng adul ts and chil dren).
20
A prospecti ve study found
MMR i n 1 of 500 chi ldren who recei ved hal othane and then i ntravenous succi nyl choli ne.
21

Our advi ce regardi ng MMR is as foll ows:
1. When i t occurs, the anesthesi ologist shoul d, i f at all possi ble, disconti nue the anesthetic and
postpone surgery. If end-ti dal CO
2
moni toring and dantrol ene are avai labl e and the
anesthesiol ogi st i s experi enced i n managing MH, he or she may el ect to conti nue wi th a
nontri ggeri ng anesthetic.
2. After epi sodes of MMR, the pati ent shoul d be observed careful l y for a period of 12 to 24
hours for myogl obinuria and si gns of MH. Admi ni strati on of 1 to 2 mg/kg of dantrol ene
should be consi dered.
3. The fami l y shoul d be i nformed of the episode of MMR and i ts impl icati ons.
4. Creati ne ki nase l evel s shoul d be checked 6, 12, and 24 hours after the epi sode. If the CK
level i s sti ll grossl y el evated at 12 hours, additional samples shoul d be drawn unti l i t begi ns
to return to normal.
5. If the CK l evel is greater than 20,000 IU i n the peri operative peri od and a concomi tant
myopathy i s not present, the diagnosis of MH is very likely.
22
If contracture test resul ts are
within normal l i mi ts after an epi sode of MMR, we currently do not recommend that other
fami l y members undergo testi ng, but advi se that succi nyl choli ne be avoi ded i n future
anesthetics for that pati ent.
A study by Li ttl eford et al
23
has shown that aci dosi s and rhabdomyolysi s occur when anesthesia i s
conti nued with a volatil e i nhal ati on agent after MMR, although ful mi nant MH may not occur. MMR
has been documented most frequently i n associati on with succi nylchol ine, al though i t may occur
after induction with any anesthetic agent, i ntravenous or inhal ati on, before succinyl choli ne
administrati on.
24
Hence, pedi atric anesthesi ologi sts avoi d the use of succi nylchol ine except on
specific i ndi cati on. (See al so Myodystrophies Exacerbated by Anesthesi a section.)
Lat e Onset of MH and Myogl obi nur i a
Mal ignant hyperthermi a may occur i n the postoperati ve peri od, usual ly wi thi n the first few hours
of recovery from anesthesia. The characteri sti c tachycardi a, tachypnea, hypertension, and
dysrhythmi as i ndicate that an episode of MH may be about to foll ow. Myogl obi nuri a may occur
without an

obvi ous i ncrease in metabol ism.
25
Succinyl chol i ne may cause rhabdomyol ysis i n pati ents who have
other muscl e di sorders that may not be cl i ni cal l y obvi ous on cursory exami nati on.
7, 26, 27

Myogl obinuria may resul t from i nteracti ons wi th other drugs such as i nhibi tors of cholesterol
formation.
28
The presence of myogl obi nuri a mandates that the pati ent be referred to a neurol ogist
for further i nvesti gati on.
Myodyst r ophi es Exacer bat ed by Anest hesi a: Rel at i on t o
P.532
Mal i gnant Hyper t her mi a
Patients sufferi ng from muscul ar dystrophy, Duchenne or Becker' s, are at risk to devel op
hyperkalemic cardiac arrest after admi ni strati on of succinyl chol i ne. The same may occur
fol l owing admi ni strati on of volatil e anestheti c agents onl y. These adverse events were fi rst
bel i eved to represent a form of MH.
29, 30
It now appears that the pathophysi ology of the
hyperkalemic epi sodes and MH i s different. Case reports col l ected by the Mal i gnant Hyperthermi a
Associ ati on of the United States (MHAUS) and the North American MH Regi stry indicate that when
an apparently healthy chi ld experi ences a sudden unexpected cardi ac arrest on induction of
anesthesia, once hypoxemi a and venti l atory problems are ruled out, hyperkalemia shoul d be
consi dered. Of 29 patients wi th such a presentati on, 60% died. In 50% there was evidence of
undi agnosed myopathy (usuall y muscul ar dystrophy).
7
The treatment of hyperkal emi c arrests
incl udes admi ni strati on of cal ci um chloride, gl ucose, insul in, bicarbonate, and hyperventi l ati on.
In 1993 and i n 1994 the package insert for succi nyl choli ne was modified to warn agai nst routi ne
use of succi nylchol ine i n chil dren. Of course, in speci al ci rcumstances, such as airway emergenci es
and the presence of a ful l stomach, succi nyl choli ne may stil l be appropri ate. However,
administrati on of rapi d-acti ng nondepolari zing neuromuscul ar bl ockers i n these si tuati ons may be
an appropri ate alternati ve to use of succinyl chol i ne.
Central core di sease (CCD) i s a congeni tal myopathy characteri zed by muscl e weakness. CCD
is general ly i nheri ted i n an autosomal dominant manner, al though a few fami l ies wi th
autosomal recessi ve i nheri tance and many sporadi c cases have been reported.
31
Mutati ons that
predi spose to central core di sease, simi lar to MH, are usual l y associ ated with the ryanodi ne
receptor gene. Many cases of MH have been reported i n patients wi th CCD. Therefore, precautions
regardi ng MH must be taken for al l patients wi th central core disease.
32

The myotoni as are a vari ed set of disorders resul ti ng from abnormal iti es i n either the sodium or
chlori de channel of muscl e. The common pathophysiologi c process i s prolonged depol ari zati on of
the muscl e membrane fol lowi ng activation. Pati ents wi th any of these di sorders wi ll di splay muscle
contractures after succinyl choli ne. Hypokalemic periodic paralysi s and a rare form of myotoni a,
myotoni a fl uctuans, have been l i nked to MH suscepti bi li ty by the hal othanecaffei ne contracture
test.
33, 34

Ki ng or Ki ng-Denborough syndrome i s a rare myopathy characteri zed by cryptorchi dism, markedly
sl anted eyes, low-set ears, pectus deformi ty, scoli osi s, small stature, and hypotoni a. Several
patients with this di sorder have been diagnosed as MH susceptibl e both cli nicall y and by muscle
bi opsy.
35, 36
Skel etal abnormal iti es such as osteogenesis i mperfecta
37
and the Schwartz-Jampel
38

syndrome myotoni a have been associ ated with si gns of MH. Metaboli sm i s i ncreased in pati ents
with osteogenesi s imperfecta because of the bone di sease. Fever duri ng anesthesi a is common i n
these pati ents. The Schwartz-Jampel syndrome i s an autosomal recessi ve myotonic-li ke condi ti on
with osteoarti cular deformi ties. Fever i s common i n these patients because of conti nuous muscl e
acti vi ty. In both these condi ti ons, associ ati on wi th MH is sporadic. Despi te a few wel l -documented
cases of MH in pati ents wi th osteogenesi s imperfecta, we (and others
39
) have not confirmed MH
suscepti bi l ity i n three cases of osteogenesis i mperfecta tested wi th the halothanecaffei ne
contracture test. Inhal ati on anestheti cs have been admi nistered wi thout compli cati on to many
patients with osteogenesis i mperfecta. But we have found typical contractures i n one other muscl e
bi opsy from a pati ent wi th osteogenesi s i mperfecta.
Syndr omes wi t h a Cl i ni cal Resembl ance t o MH
Pheochromocytoma may be mi staken for MH because i t presents wi th tachycardi a, hypertensi on,
and fever duri ng anesthesi a. However, pheochromocytoma does not predi spose to MH.
40

Thyrotoxicosi s could al so be mi staken for MH. Carbon di oxi de production is l ower i n these
endocri ne di sorders than i n MH. Hypertensi on i s greater i n pheochromocytoma than in
thyrotoxi cosi s, and even less i n MH. Nei ther endocri ne cri si s i s associ ated with muscl e ri gi dity as
in MH. Metabol ic aci dosi s i s general ly not present duri ng thyrotoxi cosi s and not as great during
pheochromocytoma as during MH. Thyroid crisis di d not tri gger MH even i n suscepti bl e pi gs.
41

Sepsi s is most often confused wi th MH. Pati ents undergoi ng urinary tract surgery; ear, nose, and
throat surgery; or appendectomy for appendi ci tis can and wi l l devel op fever and someti mes
acidosis in the PACU. Hyperkal emi a may al so appear duri ng epi sodes of sepsi s. Unl i ke MH,
however, muscl e ri gi dity is uncommon, al though ri gors may be mi staken for ri gi di ty. In addi ti on,
si gns of sepsis are treated effecti vel y with nonsteroidal anti -infl ammatory agents and anti bi oti cs.
MH wi l l not respond to such nonspeci fi c therapy. Dantrolene may often be associated wi th acute
reducti on of fever. Thi s, however, i s al so nonspeci fi c. Di fferenti ating sepsis from MH is often not
possi bl e cli ni cal l y.
Hypoxi c encephal opathy i s characteri zed by fai l ure to awaken from anesthesi a, posturi ng and
opi sthotonus, and hyperthermi a. It has been mi staken for MH. The di agnosi s is based on the
cl i ni cal presentati on.
Mi tochondri al myopathi es resembl e MH. Defects wi thi n the mi tochondrial genome affect oxi dative
phosphoryl ati on and resul t i n i mpai red producti on of ATP. These disorders have many
mani festati ons, usual ly presenti ng at an earl y age wi th central nervous system (CNS) and muscl e
pathology. Fai lure to thrive, developmental delays, muscle weakness, and cardiomyopathy may be
present. El evated serum lactate and pyruvate are found on l aboratory exami nation. There does not
appear to be a rel ati on between the mi tochondrial myopathi es and MH. However, respi ratory
depressi on i s often seen foll owing anesthesi a. Succi nyl choli ne is best avoi ded i n these pati ents
because of the potenti al for hyperkal emi a. There is i nsuffi ci ent evidence i n the li terature to
characteri ze the response to potent vol ati le agents.
42

Peri odi c paral yses are i nheri ted disorders characteri zed by marked muscl e weakness and paral ysi s
resul ti ng from smal l devi ati ons i n potassi um concentrati ons. The di sorders are i nheri ted and resul t
from mutati ons i n the gene that elaborates the sodium channel or the calci um channel of skel etal
muscle.
In hypokal emi c peri odi c paral ysi s, the pati ent i s exqui si tely sensiti ve to l owered potassium as may
occur wi th admini stration of a glucose load or fasti ng. As menti oned earl ier, there has been a
rel ati on to MH descri bed i n some pati ents.
33

In hyperkal emi c periodi c paral ysi s smal l increases i n potassium wil l l ead to muscl e weakness and
paral ysi s. A rel ati on to MH suscepti bi li ty has not been descri bed. In al most al l cases

the pati ent wi ll rel ate a fami ly hi story of muscl e weakness and paral ysi s under condi tions where
there i s a change i n serum potassi um.
Mal i gnant Hyper t her mi a Out si de t he Oper at i ng Room
The often-repeated observati on that an MH-li ke syndrome can occur in certai n pi g breeds i n
response to stressful si tuati ons supports the suggesti on that MH may occur outsi de the operati ng
room i n humans. Gronert et al have descri bed a pati ent who had epi sodi c fevers and whose muscl e
produced a contracture consi stent wi th MH suscepti bil i ty.
43
The fevers were control l ed by
dantrol ene. A mi nori ty of exercise-induced rhabdomyol ysi s and heat stroke cases are al so rel ated
to MH. Mutati ons i n the RYR1 receptor gene, known to be causati ve of MH, have been found in a
patient who di ed of heat stroke
44
and i n some pati ents wi th exercise-induced rhabdomyol ysi s.
45

In 1997 Tobi n and associ ates documented an apparent awake epi sode of fatal MH i n a 12-year-
ol d-boy. The chi l d had recovered from an epi sode of cl i ni cal MH during anesthesi a several months
pri or to the episode. Fol lowi ng soccer practi ce on a day that was not overl y hot and humid, he
compl ai ned of muscl e discomfort and rapi dl y devel oped ventri cul ar fibri ll ati on. His CK rose to
9,000 IU. Geneti c i nvestigation revealed the presence of a ryanodi ne receptor mutation known to
be causal for MH. Other fami l y members al so harbor the mutation.
A few other cases of apparent awake epi sodes of fatal MH have been reported from other
countries.
Neur ol ept i c Mal i gnant Syndr ome and Ot her Dr ug- I nduced
P.533
Hyper t her mi c React i ons
The symptoms and si gns of the NMS i ncl ude fever, rhabdomyol ysis, tachycardi a, hypertension,
agi tation, muscl e ri gi dity, and aci dosi s.
46
The mortal ity rate is unknown, but is si gni fi cant.
Dantrol ene is an effecti ve therapeuti c modal i ty i n many cases of NMS. Therefore, it i s not unusual
for an anesthesiol ogi st to be consulted i n the management of pati ents wi th thi s disorder.
Although the resemblance of NMS to MH i s striking, there are si gnifi cant differences between the
two. MH is acute, whereas NMS often occurs after l onger term drug exposure. Phenothi azi nes and
haloperi dol or any of the newer potent anti psychoti c agents alone or i n combi nati on are usual ly
tri ggeri ng agents for NMS. Sudden wi thdrawal of drugs used to treat Parkinson' s di sease may al so
trigger NMS. El ectroconvul si ve therapy (ECT) wi th succi nyl choli ne does not appear to tri gger the
syndrome.
47
Al so, NMS does not seem to be inherited, and there are no case reports of i t i n fami l y
members who have had an epi sode of MH.
Many bel ieve that the changes i n NMS are a reflecti on of dopami ne depletion in the central
nervous system by psychoactive agents. In support of thi s theory, therapy wi th bromocri ptine, a
dopami ne agoni st, i s often useful in treatment of NMS. Therefore, al though there appear to be
si mi l ariti es between MH and NMS,
46
a common pathophysiol ogy is not readil y apparent. From an
anesthesiol ogi st' s vi ewpoint, it i s best to moni tor pati ents wi th NMS as though they were
suscepti bl e to MH. However, drugs such as succi nylchol ine have been used for ECT without
probl ems i n MH pati ents.
A si mil ar set of signs may be observed i n some patients taki ng serotoni n uptake inhi bitors. Much
less is known regardi ng this syndrome.
Other drugs known to i nduce a hypermetabol i c syndrome and rhabdomyol ysi s, probabl y through
mechani sms not rel ated to those of MH, are cocai ne, amphetamines, and MDMA. Dantrol ene has
been used sporadicall y as an adjunct to treatment of marked hyperthermi a wi th promi si ng resul ts.
Treatment, however, i s usuall y symptomati c.
Dr ugs That Tr i gger Mal i gnant Hyper t her mi a
It i s cl earl y establ ished that the potent inhal ati on agents, i ncl udi ng sevofl urane, desfl urane,
isoflurane, halothane, methoxyflurane, cycl opropane, and ether, may trigger MH.
Succi nylchol i ne and decamethoni um are al so tri ggers. Other anestheti c drugs and adjuvants are
not MH tri ggers. Tabl e 20-1 indi cates the drugs bel i eved to be safe and those that are unsafe.
TABLE 20-1 Safe Versus Unsafe Drugs in Malignant Hyperthermia
SAFE DRUGS UNSAFE DRUGS
Antibi oti cs
Antithi stami nes
Barbiturates
Benzodiazepines
Droperidol
Ketamine
Local anestheti cs
Ni trous oxi de
Nondepolari zing neuromuscul ar blockers
Opi oi ds
Propofol
Propranolol
Vasoacti ve drugs
All i nhal ati on agents (except ni trous oxide)
Succi nylchol i ne
Local Anesthetics
All l ocal anestheti cs are safe for MH-suscepti bl e pati ents.
48
Prel i mi nary studies of l ocal anesthetics
duri ng an MH cri sis (e.g., for dysrhythmia control) do not show an exacerbati on of MH by ami de
local anestheti cs.
Catecholamines
Although pl asma catecholami nes i ncrease duri ng an MH cri sis, such an el evati on i s usual ly
secondary to metabol ic and cardi ovascul ar changes. Vasopressors and other catecholami nes are
not i nvol ved i n tri ggeri ng MH.
49
Therefore, these drugs shoul d be used as necessary but onl y with
si multaneous treatment of the MH crisi s.
Nondepolarizing Relaxants and Anticholinesterases
Vecuroni um, rocuronium, atracurium, pancuroni um, and al l other nondepolari zi ng drugs are
consi dered safe to use i n pati ents wi th MH. Cli nical studi es have shown that anti choli nesterase
anti choli nergic combi nati ons are safe for reversal of nondepolarizing rel axants in MH-suscepti bl e
patients.
50

Phenothiazines and Drugs Used to Treat Psychoses
Phenothi azines i ncrease i ntracell ul ar calci um i on concentrati on and may cause contractures i n
vitro i n muscl e from MH-suscepti bl e pati ents.
51
Phenothi azines al so induce the related neurol eptic
mali gnant syndrome. Therefore, although there have been several reports that phenothi azines are
effecti ve i n managing temperature fl uctuati ons during recovery from MH,

these compounds shoul d be used cauti ousl y in MH-suscepti bl e pati ents. Medicati ons used i n the
treatment of psychiatri c condi tions such as hal operi dol , atypi cal anti psychoti cs may i nduce NMS.
Since NMS and MH are dissimi lar, there i s no evi dence that these agents are preci pitants of MH.
Other Drugs
Digoxi n, qui ni di ne, and calci um sal ts do not i nduce MH i n the swine.
52
Therefore, i t is reasonable
to assume that they are safe to use in clinical si tuati ons. Nei ther ketamine nor propofol are MH
triggers.
53

I nci dence and Epi demi ol ogy
Al though the i nci dence of reported epi sodes of MH has i ncreased, the mortali ty rate from MH has
decl ined. In part, these two trends refl ect a greater awareness of the syndrome, earl i er di agnosi s,
and better therapy. The incidence of MH vari es from country to country, based on differences i n
gene pool s. In the upper mi dwest of the Uni ted States, for exampl e, there are many fami li es
contai ning l arge numbers of MH-suscepti bl e peopl e. In contrast, other areas of the country and
parts of the worl d have rarel y reported MH. For exampl e, Bachand and coll eagues exami ned the
inci dence of MH in the province of Quebec, Canada, where many fami li es had been biopsied. They
traced the pedi grees of the pati ents to the origi nal i mmigrants from France and found an i nci dence
of MH suscepti bi li ty of 0.2% i n this province. However, that represented only five extended
famil i es.
54
A study i n Great Bri tai n reveal ed 3 cases of MH i n 100,000 admi ni stered anestheti cs.
55

The best epi demi ologic study of MH was done i n the mi d 1980s by Ordi ng.
20
Based on information
suppl i ed to the Dani sh Mal i gnant Hyperthermi a Regi stry comprisi ng the reported incidence of MH
in Denmark (popul ati on approxi matel y 5 mi ll i on), this study reveal ed ful minant MH i n
approxi mately 1 i n 250,000 admi ni stered anestheti cs. However, if the defi ni tion of MH i s expanded
to i nclude aborti ve cases of MH and is further refi ned to include onl y cases i n whi ch i nhal ati on
anesthetics and succi nylchol ine were used, the i nci dence was as high as 1 i n 4,000 anestheti c
administrati ons!
20

A better understandi ng of the preval ence of MH is l i kely to emerge from the wi despread use of
P.534
mol ecul ar geneti cs for the di agnosi s of MH susceptibi l ity. For exampl e, Monni er and col l eagues
estimate that one i n 2,000 to 3,000 persons i n France harbor one of the known MH causati ve
mutations.
56
Currentl y, the consensus is that mortali ty from MH is under 5% i n Western countri es.
However, the epidemiol ogi c characteri sti cs of MH are very diffi cult to defi ne for the fol l owi ng
reasons:
1. Wi despread di agnosti c testi ng for MH i s di ffi cul t to appl y.
2. The cli nical di agnosi s of MH is often questi onabl e.
3. Tri ggeri ng of MH even i n suscepti bl e pati ents may not occur on each anestheti c exposure. In
some cases, suscepti ble pati ents have recei ved tri ggeri ng agents for up to 13 anestheti cs
without any probl ems, onl y to have MH tri ggered on the subsequent anesthetic. Investi gation
of the Dani sh Mal i gnant Hyperthermi a Regi stry found the MH genotype to be expressed i n
only 34 to 54% of anesthetic exposures.
57

4. Regi stries of MH cases do not capture al l data. There is a pauci ty of data concerning the
frequency of use of anesthesi a i n the general popul ati on.
Inheritance of Malignant Hyperthermia
Many of the di fficul ties that li mit an understandi ng of the epidemiol ogi c characteri sti cs of MH also
li mi t accurate assessment of i ts inheritance. The animal model does not cl ari fy the issue of
inheri tance in humans. MH in most pig breeds is i nheri ted in an autosomal recessi ve fashion.
58

Variabi li ty i n cl i ni cal presentati on and the fact that MH is not regul arl y apparent on exposure to
triggering agents, even in those who are suscepti bl e, resul t i n great di ffi cul ty i n assessing the
inheri tance of MH i n affected fami l ies. Nevertheless, i t i s general l y accepted that MH in humans i s
inheri ted as an autosomal domi nant trai t wi th vari able penetrance.
59
Thi s impl ies that chil dren of
MHS pati ents have a 50% chance of bei ng MHS themsel ves.
Di agnost i c Test s f or Mal i gnant Hyper t her mi a
Development of the In Vitro Contracture Test
In 1970, Kal ow et al demonstrated that i sol ated muscl e from MH-suscepti bl e pati ents was
unusuall y sensi ti ve to caffeine when exposed i n vi tro.
4
Shortl y thereafter, El l is and co-
investi gators demonstrated that muscl e from MH-suscepti bl e pati ents al so had a more sensi ti ve
than normal contracture response to halothane. The European MH Group (EMHG)
60, 61
and North
Ameri can MH Group (NAMHG)
62, 63, 64
separately have standardized protocol s for contracture
testi ng. Treatment of muscl e biopsy speci mens i n a tissue bath with ei ther hal othane or caffeine
has come to be the standard test for diagnosing MH susceptibi l ity.
Other tests have been proposed to di fferenti ate pati ents with MH from those who are normal. None
of these tests di sti ngui shed MHS pati ents from normal s wi th accuracy. However, several newer
approaches suggest that nonmuscle biopsy tests mi ght be val uabl e as an i ni ti al estimati on of
li kel ihood of MH susceptibi l ity and are di scussed l ater in the chapter.
HalothaneCaffeine Contracture Test
Al though some procedures and interpretati ons differ between the EMHG and NAMHG
protocol s, the foll owi ng steps are si mil ar. Skeletal muscl e (1 to 3 g) i s usual ly biopsied from
the vastus l ateral i s muscle. Strips of muscl e wei ghi ng 100 to 200 mg and measuri ng 15 to 30 mm
(25 mm preferred) i n length by 2 to 3 mm i n wi dth by 2 to 3 mm i n thi ckness are careful l y
isol ated and mounted in a standard muscl e bath apparatus (Fi g. 20-1). The tissue bath contai ns a
modi fi ed Krebs sol uti on at 37C bubbl ed wi th O
2
and CO
2
(95%/5%), and the resti ng tensi on is
adjusted to the opti mum l ength for maxi mal twi tch tensi on (usual l y about 2 g). The bundl es are
stimul ated supramaxi mall y wi th pul ses of frequency 0.1 to 0.2 Hz wi th 2 msec pulses to veri fy
viabi li ty. After a 15- to 60-mi nute equil i brati on in whi ch the preparati on i s oxygenated with
O
2
/CO
2
(95/5%), halothane i s added to the gas phase, either as a bol us dose or in incremental ly
increasi ng concentrati ons (Fi g. 20-2). The concentrati on of hal othane i s verified by gas
chromatography. A second set of muscl e strips i s equi l ibrated and subsequentl y exposed to
incrementall y increasi ng concentrati ons of caffei ne-free base (see Fi g. 20-2). It i s recommended
that the caffei ne stri ps be tested early i n the procedure because they tend to be more sensi ti ve to
instabil i ty over ti me. Testi ng i s usual ly completed wi thi n about 5 hours of bi opsy to ensure
adequate vi abi l ity of the muscl e preparations. Owi ng to time constrai nts, i t i s essenti al that the
bi opsy be performed at or wi thi n about 1 hour of the testing laboratory. Usual l y, a histol ogi c
eval uation accompanies the contracture test to exami ne whether the subject has a muscle di sorder
other than MH.
FIGURE 20-1. Di agram of the muscl e bath apparatus used for contracture testing for
di agnosi ng MH susceptibi l ity.
Interpretation of the HalothaneCaffeine Contracture Test. Two protocol s have been adopted
for use over the past decade. These protocols were i ni tiated to standardize procedures so that the
resul ts from groups of l aboratori es coul d be pool ed for anal ysis. A uniform approach was
necessary to standardi ze the phenotype deri ved from the contracture test for use in geneti c
FIGURE 20-2. Muscl e stri ps wei ghi ng approximatel y 150 mg and sti mul ated supramaximal l y
are exposed to 3% hal othane or incremental doses of caffeine. A. A 3-g contracture is
recorded from thi s stri p from an MHS pati ent after exposure of the muscle to 3% hal othane
(top); a normal response to 3% halothane (bottom). B. Contractures noted after exposure to
0.5, 1, and 2 mM caffeine in MHS muscle (top); no contracture response to the same caffei ne
concentrations. Twitch height augmentati on i s normal fol l owi ng caffei ne addi tion (bottom).
anal ysi s.

In the EMHG protocol , al so known as the IVCT for In Vi tro Contracture Test,
60, 61
hal othane i s
added i ncremental l y (0.5, 1.0, 2.0%) wi th the preparati on exposed to each concentrati on for 3
mi nutes. A response indi cati ve of MH suscepti bil i ty i s based on a contracture threshol d (>0.2 g) at
a hal othane concentrati on 2% in ei ther of the two muscle stri ps tested. Caffei ne i s al so added
incrementall y in concentrati ons of 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, and 4.0 mM. Each caffeine
concentration is maintai ned unti l the contracture plateau is reached, or for 3 mi nutes, whi chever
is sooner. A positi ve response i s a contracture threshold (>0.2 g) at a concentrati on of caffeine of
2 mM or l ess i n either of two stri ps tested.
In the NAMHG protocol,
62
al so known as the Caffei ne Hal othane Contracture Test (CHCT), a bol us
dose of hal othane 3% i s added to the gas phase for each of three muscle stri ps and the maximum
contracture withi n 10 mi nutes i s recorded. A posi ti ve response i s a contracture >0.7 g tensi on to
halothane 3% and a negati ve response i s <0.5 g. An equi vocal response to hal othane (MH-
equivocal, or MHE) i s between 0.5 and 0.7 g.
63
As in the EMHG protocol , caffei ne i s added
incrementall y, but the concentrati ons are 0.5, 1.0, 2.0, 4.0, 8.0, and 32 mM. A posi tive response
is a contracture >0.3 g (determined by the speci fi c laboratory) to 2 mM caffeine. The
interpretati ons of the outcomes of the hal othane and caffei ne tests di ffer between the EMHG and
NAMHG protocol s. The EMHG protocol requi res a posi ti ve response to hal othane and a positi ve
response to caffeine for a diagnosis of MH-suscepti bl e (MHS). If the outcomes of both tests are
negati ve, then the subject i s di agnosed as MH-normal (MHN). If only the caffei ne test i s abnormal ,
the pati ent i s consi dered MHE to caffei ne (MHEc). If onl y the hal othane test i s abnormal , the
patient is considered MHE to hal othane (MHEh). The NAMHG protocol di ffers i n that the subject i s
consi dered MH positi ve (MH+ or MHS) i f ei ther the response to hal othane or the response to
caffei ne i s abnormal . The patient is di agnosed as normal (MH- or MHN) if nei ther test is posi ti ve.
As i n the EMHG protocol , MHE subjects are treated cl inicall y as MH susceptibl e.
Sensitivity and Specificity of the HalothaneCaffeine Contracture Test. The sensi ti vi ty of
the NAMHG protocol (CHCT) i s 100% wi th speci fi city 78% (fal se-negati ves are to be avoi ded).
64

The EMHG test (IVCT) has sensi tivity of 98% wi th speci fi ci ty of 93%. It i s diffi cult to be certai n of
the sensi tivity and speci fi ci ty of the contracture test because although one can be fairl y certai n of
the cl i ni cal phenotype of MHS based on anestheti c exposures, it i s almost impossibl e to be assured
that control subjects do not harbor a causati ve mutati on. Determinati on of the sensi ti vi ty and
specifici ty i s based on contracture studi es of pati ents wi th no known MH history undergoi ng
routine surgery (control s) compared to contracture studies from pati ents who experi enced a
cl i ni cal episode of MH. When the geneti c characterizati on of MH i s more compl ete, the sensiti vi ty
and speci fi ci ty of the contracture test may be cl ari fi ed.
Other Contracture Tests
In an attempt to further improve the specifici ty and sensi ti vi ty of the contracture test, other
agents have been tested for thei r effect on skel etal muscl e.
Ryanodine. An addi ti onal contracture test usi ng the pl ant alkal oid ryanodi ne was proposed for
incl usi on i n the EMHG protocol . Ryanodi ne bi nds to and acti vates the calci um rel ease channel of
the sarcoplasmi c reti culum. It was reasoned that thi s test woul d afford maxi mum speci fi ci ty for
MH, and earl y studi es supported thi s concept.
65, 66, 67, 68

The basi c testing conditi ons for ryanodine are si mi l ar to those described for hal othane and
caffei ne testi ng. Hi gh-puri ty ryanodine i s empl oyed. A bolus of ryanodi ne (1 M) i s added to the
bath and the time to onset of contracture, ti me to 0.2-g contracture, ti me to 1-g contracture, and
the time and amplitude of maximum contracture are recorded. Di scri minati on was improved by
using the ti me to initi al contracture and ti me to development of a 10-mN (1 g) contracture.
69

4-Chloro-m-cresol. 4-Chl oro-m-cresol (4-CmC) i s a potent acti vator of ryanodi ne receptor
medi ated Ca
2+
rel ease. Cumul ative admi ni stration of 25, 50, 75, 100, 150, and 200 mol/L 4-CmC
produced concentrati on-dependent contractures. Contractures devel oped earl i er and to a greater
P.535
magni tude i n muscl e from pati ents identi fi ed as MHS by the EMHG protocol than i n normal
muscle.
70
The addi ti on of testi ng wi th thi s compound has been approved by the EMHG.

Pitfalls in the Contracture Test
Ideall y, each laboratory shoul d deri ve specimens from pati ents who are clearl y and unequi vocal ly
normal and those who are cl earl y and unequivocall y MH suscepti bl e to veri fy that cutpoi nts for MH
suscepti bi l ity are diagnosti c wi thin the l aboratory. Unfortunately, because of the vari ati on i n
presentation of MH and the confusi on wi th signs associ ated wi th non-MH causes, i t i s not al ways
possi bl e to have compl ete agreement on the MH status of a pati ent based on a cli ni cal history,
even among experts in the fiel d. This probl em has made esti mates of sensi ti vi ty and specifi ci ty
di fficul t.
A cl i ni cal gradi ng scale has been devel oped to address concerns for objectively evaluati ng the
cl i ni cal episode.
71
Thi s scale lacks sensi tivity, because i ncompl ete recordi ng of necessary data or
early termi nation of the cri si s woul d not yi el d scores i ndi cati ve of MH, even i f an epi sode had
occurred. The scori ng system al so i s desi gned to avoi d overwei ghti ng dupli cati ve i ndi cators
representi ng the same processes. The value of the gradi ng scale i s mai nl y i n identi fying those
subjects wi th the most convincing episodes of MH for subsequent eval uati on of the sensi ti vi ty and
specifici ty of the di agnostic tests. The cl i ni cal gradi ng scale (Tabl e 20-2) i s useful in eval uati ng
cl i ni cal episodes i n those cases in which the subject i s rated a D6 (Di agnostic rank 6, al most
certai nl y MH), but l ower scores shoul d not be consi dered for actual di agnosi s. We woul d even
encourage the practi ce of sendi ng patients rated D6 for di agnostic muscl e contracture testi ng,
because these individual s are rare

and essenti al for the conti nui ng eval uati on of the sensiti vi ty and speci fi city of the contracture test
and for study of the genetics of MH.
P.536
P.537
TABLE 20-2 Criteria Used in the MH Clinical Grading Scale
Process I: Muscl e Rigi di ty
General i zed Ri gi di ty 15
Masseter Ri gi dity 15
Process II: Myonecrosis
Elevated CK>20,000 (+Succ.) 15
Elevated CK>10,000 (No Succ.) 15
Col a Col ored Uri ne 10
Myoglobin in urine >60 ug/L 5
Bl ood/pl asma/serum K>6 mEg/L 3
There have been a few reports descri bi ng pati ents who were di agnosed as nonsuscepti bl e by
contracture testi ng subsequently experi enci ng cl i ni cal epi sodes hi ghl y suggesti ve of MH; and i n
one case, the esti mated false-negati ve rate was 4 out of 171 subjects (2%).
72, 73
MH experts are
not convi nced that these are val id cases of MH. A mimic of MH such as sepsis may expl ai n the
cl i ni cal probl em.
73
In contrast, studi es have reported 16 MHN patients recei vi ng tri ggeri ng agents
on 23 occasi ons
74
and 13 MHN pati ents recei vi ng tri ggeri ng agents on 26 occasi ons,
75
al l wi thout
compl i cati ons. Unfortunatel y, studi es l i ke these are di fficul t to conduct because they requi re large
pati ent popul ati ons and tracki ng of subjects di agnosed several years before the actual study. Unti l
more data are gathered, it i s di ffi cul t to put the occasi onal fal se-negati ve di agnosi s i nto proper
perspective.
Variabi li ty seems to exist between fami l ies i n the magni tude of contracture.
76
Thi s may be because
of the inheritance of di fferent genetic defects. Unti l such time as al l the basi c biochemi cal defects
of MH are uncovered, the contracture test wi ll be subject to some differences i n i nterpretati on.
However, the halothanecaffei ne contracture test i s currently the onl y method of MH di agnosi s
Process III: Respi ratory Aci dosis
PetCO
2
>55 wi th CV
15
PaCO
2
>60 wi th CV
15
PetCO
2
>60 wi th SV
15
Inappropriate hypercarbia 15
Inappropri ate tachypnea 10
Process IV: Temperature Increase
Rapi d i ncrease i n temperature 15
Inappropriate temperature >38.8 in perioperati ve peri od 10
Process V: Cardi ac Invol vement
Inappropriate tachycardria 3
V. tach or V. fib 3
See Larach et al
71
for ful l detai ls of thi s scori ng system. Briefl y, a case may recei ve 15
poi nts for the worst presentati on i n five of the fi rst six categori es. A sum of more than
50 poi nts is termed D6, al most certainl y a case of MH. A sum of 35 to 49 points i s
D5, very likely to be a case of MH.
that has been standardi zed and has had sensiti vi ty and speci fi city confirmed i n any manner by
mul tipl e centers throughout the worl d. When a pati ent i s di agnosed as MHS by the contracture
test, then MH tri gger agents are to be avoi ded. IF the pati ent i s MHN, then volatil e agents may be
used.
Tests with More Limited Usefulness in Malignant Hyperthermia
Diagnosis
Alternati ve tests that have not gai ned acceptance wi thi n the EMHG or NAMHG have been revi ewed
el sewhere.
77, 78
These tests incl ude lymphocyte tests, platel et aggregati on, ski nned fi ber tests,
adenosine tri phosphate depl eti on, erythrocyte osmoti c fragi l i ty, and others. The tests di scussed
later have at l east some useful ness i n some cases of MH.
El evated resti ng CK val ues are associated wi th MH suscepti bi li ty i n a few famil i es. However, many
subjects suscepti ble to MH do not have el evated CK val ues, maki ng thi s method of di agnosi s
rel ati vely i nsensiti ve.
78
Al so, several muscl e di sorders are associ ated with elevated resting CK
val ues, making thi s test nonspecific.
78
We cauti on that this method of diagnosis i s only tentative
and shoul d be confi rmed by contracture testi ng. Elevated CK val ues al so may be useful i n
prel iminari ly i dentifying key fami l y members to be referred for contracture testi ng and in
identi fyi ng MH i n chil dren too young to undergo contracture testing.
The use of resti ng CK val ues for general screeni ng for MH is nei ther sensi tive nor specific, but
there i s a rel ati onship between hi gh postoperati ve CK val ues associ ated wi th masseter muscl e
ri gi di ty (MMR) and the probabi l ity for di agnosi s as MH susceptibl e by the contracture test.
15, 22

Although i t is not a perfect i ndi cator of MH susceptibi l ity,
79
the chances are about 80% that a CK
val ue >20,000 after MMR wi l l yi el d a positive di agnosis by contracture testing.
15, 22
A rel ati vel y
normal CK postoperati vel y does not rule out the possibi l ity of an acute MH reacti on duri ng that
anesthetic.
80

A vari ety of minimal l y i nvasi ve di agnostic tests are i n development at present. One uti li zes
nucl ear magneti c resonance spectroscopy to eval uate ATP depl eti on duri ng graded exerci se i n
vi vo. MH pati ents have a greater breakdown of ATP and creati ne phosphate as wel l as an increase
in aci d content compared to normal s.
81
Util i zi ng cultured muscl e cell s
82
or B lymphocytes,
83
it has
been shown that agents such as caffei ne and chl orocresol wil l rai se intracel l ul ar cal cium ion
concentrations to a greater extent in tissue derived from MHS i ndi vi dual s than normal s. Injecti on
of a smal l amount of caffei ne through a microdi alysi s catheter i nserted i nto muscl e wi l l eli cit an
enhanced release of carbon dioxi de l ocall y. Metabol i c changes are measured through the
catheter.
84, 85
Repeti ti ve nerve sti mulati on produces a di fferent pattern of contracti on and
rel axation in MHS muscl e than i n normal muscl e.
86, 87
Al l of these tests are sti ll i n the
developmental stage.
Molecular Genetic Testing for MH Susceptibility
The di scovery of mul ti pl e MH causi ng mutations i n the RYR1 gene
31, 59
has led to the i ntroducti on
of geneti c testi ng of MH suscepti bi li ty on a l i mi ted basis i n Europe and the US. The gui deli nes
publ i shed by the European Mal i gnant Hyperthermia Group suggest that for cl ini cal diagnosis a
panel of 23 of the more common RYR1 mutati ons shoul d be exami ned. <http://www.emhg.org> A
li mi tati on of genetic testi ng in the Uni ted States i s the sensiti vi ty of about 23% when testi ng for
21 mutati ons.
87a
Screeni ng of the enti re coding regi on of the RYR1 i denti fies sequence vari ants i n
more than 50% of pati ents.
87b
Therefore sensiti vi ty of genetic tests wi l l improve as more
mutati ons are i dentified as causative of MH.
Patients shoul d consider geneti c testi ng if:
1. They have had a posi tive contracture test.
2. A fami ly member has had a positi ve contracture test.
3. They have suffered a very l i kel y MH epi sode but have not had a contracture test.
4. A family member has been found to have a causal mutation.
When a mutati on known to be causati ve for MH is i denti fi ed i n a fami l y member who has had an
abnormal contracture response to hal othane or caffeine, it is possi ble to determi ne MH
suscepti bi l i ty i n other members of that fami l y by examinati on of thei r RYR1 DNA for that mutati on.
Those with the mutation are MH suscepti bl e (with hi gh specifici ty) but those

without the mutati on cannot be consi dered MH negati ve as they may harbor another mutati on. The
patient cannot be presumed to be MH-negati ve wi thout negative resul ts on muscl e contracture
testi ng.
88
The deci si on to undergo genetic testi ng i s compl ex. The pros and cons of testi ng shoul d
be discussed wi th either an MH expert or a geneti c counselor.
Tr eat ment of Mal i gnant Hyper t her mi a
Mal ignant hyperthermi a i s a treatable disorder. Al l insti tutions i n whi ch anesthetic agents are
administered shoul d have dantrolene avai l abl e (36 ampul es [720 mg] is recommended) and a
management pl an.
The Acute Episode
The fol lowi ng steps should be taken i mmedi atel y when MH i s di agnosed:
1. Admi ni strati on of all i nhal ati on agents and succi nyl chol i ne shoul d be di scontinued and
assi stance shoul d be secured. (It i s hel pful to have a dedi cated cart avail able contai ning the
agents for treatment of MH.)
2. Hyperventil ati on with 100% oxygen shoul d be i nstituted at >10 L/mi n. Oxygen fl ow shoul d
be 10 L/min to hasten purgi ng of resi dual anestheti c gases. Ti me shoul d not be wasted in
securing another anesthetic machi ne, but an ambu bag and E-cyl i nder of oxygen can be
used.
3. Assi stance shoul d be obtained i n mixing dantrol ene. The present preparation of dantrol ene i s
poorl y soluble. Each vi al contai ning 20 mg shoul d be mi xed wi th 50 mL of bacteri ostatic
steri l e distil l ed water (not sal ine sol ution). It i s important to store steri le water i n cl early
l abel ed contai ners of a di fferent size from that used for routine intravenous sol utions. It may
be hel pful to keep a mi xi ng system adjacent. Dantrolene wi l l dissol ve faster as temperature
of the dil uent i ncreases from 20 to 40C.
89
Intravenous therapy shoul d be started with 2.5
mg/kg wi th repeat doses as needed. More than 10 mg/kg of dantrol ene may be gi ven as
di ctated by cl ini cal ci rcumstances, however many acute episodes are control l ed wi th 2 to 3
mg/kg. There i s 300 mg manni tol wi th each 20 mg dantrolene. Therefore a bl adder catheter
should be inserted to facil i tate moni toring uri ne output.
4. Ti tration of dantrol ene and bicarbonate to heart rate, body temperature, and PaCO
2
is the
best cli ni cal guidel i ne of therapy.
5. In fulminant cases in which si gnifi cant metabol ic aci dosi s i s present, 2 to 4 mEq/kg
bi carbonate shoul d be given. Large vol umes of fl ui d may be needed to repl ace l oss i nto
edematous ti ssues and i nto the uri ne.
6. If it i s not al ready avai l abl e, a capnometer shoul d be obtained so that CO
2
excretion can be
documented.
7. Dysrhythmi a control usual l y fol l ows hyperventil ati on, dantrol ene therapy, and correcti on of
acidosis. Cal cium channel bl ockers should not be used i n the acute treatment of MH.
Verapamil can i nteract wi th dantrolene to produce hyperkal emi a and myocardi al
depressi on.
90, 91
Li docai ne can be gi ven safely duri ng an MH cri sis.

P.538
8. Body temperature elevation shoul d be managed by pl aci ng i ce packs on the groi n and i n the
axi l lae and by use of gastri c, wound, and rectal l avage. Gastri c l avage i s the quickest, most
practi cal means for rapi d temperature control . Some have recommended peri toneal di al ysi s
and others, cardi opul monary bypass. Cool i ng shoul d be stopped when core temperature
reaches 38C to avoi d hypothermi a.
9. Although arteri al bl ood is useful for assessing aci dosi s, central mi xed venous bl ood gas
determi nati ons (or, i f not avail able, femoral venous blood gas readi ngs) serve as a better
gui del i ne for therapy.
10. Hyperkal emi a shoul d be managed i n the usual fashi on wi th gl ucose, insul in, bi carbonate, and
hyperventi lation. If hyperkalemia i s associ ated wi th si gnifi cant cardiac effects, calci um
chl ori de, one gram or 10 mg/kg, shoul d be given. Duri ng therapy of MH, hypokal emi a
frequently resul ts. However, potassi um repl acement should be undertaken very cauti ousl y, if
at al l , because potassi um may retri gger an MH epi sode.
11. Basel ine l aboratory tests shoul d i ncl ude creati nine, coagul ati on profi le, and creati ne ki nase
(CK). CK elevations may not occur for 6 to 12 hours after an MH epi sode and shoul d be
fol l owed as a rough gui de to therapy. These tests wi ll serve as a basel i ne for management of
subsequent compl i cations.
Management After the Acute Episode
After the acute episode, the cli nici an shoul d be concerned about three compl icati ons of MH:
1. Recrudescence of MH. As many as 25% of patients may experi ence acute recrudescence, a
rel apse, wi thi n hours of the fi rst episode.
92, 93, 94, 95

2. Dissemi nated i ntravascul ar coagul ati on (DIC).
94
DIC has often been descri bed i n cases of
MH, probabl y resul ting from rel ease of thromboplasti ns secondary to shock and core
temperature >41C
95
and/or rel ease of cel l ul ar contents on membrane destruction. The
usual regi men for treatment of DIC shoul d be fol l owed.
3. Myogl obinuric renal fail ure. Myogl obi nuri a may occur wi thin hours after the epi sode begi ns.
If anal ysi s shows that there is bl ood i n the uri ne, urine shoul d be sent to measure RBCs and
myoglobi n. If there are no RBCs, myogl obi nuri a i s presumed present. If the uri ne is acid,
bi carbonate shoul d be given to decrease the chance that myogl obi n wi ll i njure renal tubul es.
The gui del ines for the dose and durati on of dantrol ene therapy after resoluti on of acute MH are
empi ri cal . It woul d seem prudent to conti nue dantrolene, 1 mg/kg every 6 hours intravenousl y
(i v), for at l east 24 to 36 hours but more may be gi ven i f si gns of MH reappear. Some recommend
conversion of dantrolene therapy from i v to oral form (4 mg/kg per day or more) wi th conti nuati on
for several days.
Significant muscl e weakness and pai n may foll ow MH, resul ting from muscl e destructi on al ong wi th
dantrol ene admi nistrati on; thi s should be managed symptomati cal ly. Recovery of strength may
requi re weeks to months.
A vari ety of other el ectrol yte changes may occur, such as hypocal cemi a and hyperphosphatemia.
Sodi um and chl ori de changes may occur secondary to fl uid shifts duri ng the acute epi sode. Al l
these changes usual l y respond to control of the acute episode.
Dantrolene
Dantrol ene sodium is a hydantoi n deri vati ve (1-[[[5-(4-ni trophenyl )-2-furanyl ]methyl ene]imino]-
2,4-imidazoli di nedi one). In 1979, iv dantrolene was approved for treatment of MH. Unti l that ti me,
the pri mary use of dantrol ene was i n the management of spasti ci ty. Dantrol ene i s a unique muscl e
rel axant. Unl i ke neuromuscular blocki ng agents (whose si te of action is at the ni coti ni c receptor of
the neuromuscul ar junction) or the nonspeci fi c rel axants (whi ch modul ate spi nal cord synaptic
refl exes), dantrol ene acts wi thin the muscl e cel l i tsel f by reducing cal cium rel ease by the
sarcoplasmi c reticul um. [
3
H]azi dodantrol ene, a pharmacol ogicall y active, photoaffi ni ty anal og of
dantrol ene, specificall y binds to a si te on the ryandodi ne receptor.
96, 97
Duri ng an MH epi sode,

dantrol ene reduces intracel l ul ar cal cium level s. Therefore, dantrol ene i s a speci fi c and effective
agent i n the treatment of MH. In the usual cli nical doses, dantrol ene has li ttl e effect on
myocardial contractil i ty.
98

Studies have al so i ndicated that doses of neuromuscul ar blocking agents need not be changed
si gni fi cantl y after dantrol ene administration. However, the drug shoul d be used cauti ousl y in
patients with neuromuscul ar disease.
99

The serum l evel of dantrolene required for prophylaxi s agai nst MH is about 2.5 g/mL. The half-
l i fe of i v dantrol ene, the onl y form recommended, i s approxi matel y 12 hours. However, the
therapeutic level of dantrol ene usuall y persists for 4 to 6 hours after a usual i v dose of 2.5
mg/kg.
100
Therefore, dantrol ene shoul d be suppl emented at l east every 6 hours after a cl ini cal
epi sode. Muscl e weakness may persi st for 24 hours after dantrol ene therapy i s disconti nued.
Nausea and phl ebi ti s are other compl icati ons of acute dantrol ene admi ni strati on. Hepatotoxi city
has been demonstrated onl y wi th l ong-term use of oral dantrol ene. Prophylaxi s for MH shoul d be
carri ed out wi th i v or oral dantrol ene (5 mg/kg per 24 hours) i n those rare si tuati ons where
prophyl axi s is desi red.
101

Management of the Patient Susceptible to Malignant Hyperthermia
Because of an increasi ng awareness of MH and more wi despread use of diagnosti c tests, it i s not
unusual for an anesthesiol ogi st to be confronted wi th a MH-suscepti bl e pati ent or a pati ent who
has a famil y hi story of MH. The management of such pati ents shoul d be careful l y pl anned.
In the preoperative intervi ew, the anesthesi ol ogi st should try to obtain suffici ent i nformati on
regardi ng previ ous episodes of MH and thei r documentati on. If the famil y has parti ci pated i n the
North American Mali gnant Hyperthermia Regi stry, the Regi stry may be abl e to gi ve detai l s to the
anesthesia provider. The anesthesi ol ogi st should al l ow adequate time to reassure pati ents and
thei r fami l ies that he or she i s famil i ar with MH and i ts impl icati ons and that appropri ate
moni tori ng and therapy wi ll be i nsti tuted as necessary. It may be worth menti oni ng that there
have been no deaths from MH i n previ ousl y di agnosed MH-suscepti bl e pati ents when the
anesthesia team was aware of the probl em. Anesthesi a and premedi cati on shoul d be desi gned to
produce a low normal heart rate. Standard premedi cant drugs such as opi oids, benzodi azepi nes,
ataractics, barbi turates, anti histamines, and antichol inergi cs do not cause probl ems in MH-
suscepti bl e pati ents when admi ni stered in appropri ate doses; however, phenothi azi nes are not
recommended. Dantrol ene need not be gi ven preoperati vel y i f nontri ggeri ng agents are used and
end-ti dal CO
2
and core temperature are moni tored. Dantrolene must be i mmediately avai l abl e i n
the operati ng room, and equi pment for rapi d measurement of blood gases and electrolytes shoul d
be avai l abl e.
The anesthesi a machi ne i s prepared by drai ni ng, removi ng, or di sabl i ng anestheti c vaporizers, and
changi ng tubi ng and CO
2
absorbent and fl owi ng oxygen at 10 L/mi n for 20 minutes.
102
The modern
anesthesia workstation i s l arger than ol der anesthesi a machines and requires 30 mi nutes to fl ush
out with 10 L/mi n at 1 L ti dal vol ume, if new breathi ng hoses, bag, and soda l i me cartri dge have
been placed.
103
Obviousl y, i ced sol utions and adequate suppl ies of dantrol ene must be avai l abl e i n
the vi ci nity of the operati ng room when MH-suscepti bl e pati ents are anestheti zed.
Exhal ed CO
2
shoul d be moni tored because the earl i est si gn of MH i s an i ncrease i n CO
2
production
and excretion.
104
Arteri al and central venous monitori ng i s recommended for MH-suscepti bl e
patients, as di ctated by the surgical procedure. Body core temperature shoul d be moni tored by
nasopharyngeal, rectal , or esophageal routes i n al l pati ents for al l surgi cal procedures. Ski n
temperature, al though acceptabl e, is not as desi rabl e because i t may not refl ect core
temperature.
105

P.539
If possibl e, a regi onal, local , or major conduction anestheti c shoul d be used wi th ei ther ami de or
ester l ocal anestheti cs. If not possi bl e, i v induction of anesthesi a fol l owed by nitrous oxi de,
oxygen, and a nondepol ari zi ng rel axant wi th opioi d suppl ementati on i s recommended. Inducti on
agents that have not been i mpl i cated in MH are mi dazol am, di azepam, droperidol , and propofol .
Neuromuscul ar bl ocking agents such as pancuroni um, vecuroni um, atracurium, ci satracurium,
rocuroni um, and mi vacuri um are safe. Routi ne reversal of nondepolarizing rel axants wi th
anti choli nesterase and anti choli nergi c agents is recommended.
Many thousands of safe anesthetics have been admi ni stered wi th ni trous oxi de in MH-suscepti bl e
patients. Two cases have been reported i n which early signs of MH have been documented despi te
the use of a safe anesthetic techni que.
106
Therefore, even under the most control l ed
ci rcumstances, the anesthesi ologi st shoul d be al ert to the early si gns of MH.
Admi ni strati on of dantrolene after surgery is not recommended i f there are no signs of MH.
However, the pati ent must be observed cl osel y for 4 to 6 hours. If there is no si gn of MH i n the
first hour postoperati vely after safe anestheti c techniques were used, it is very unlikely that MH
wil l occur l ater. The patient may be di scharged on the same day as surgery.
107, 108
Compl ete
rehydrati on with iv fl ui d and adequate oral i ntake decreases the chance that fever wil l occur
postdi scharge as a resul t of dehydrati on.
The same precautions shoul d be taken for the obstetri c pati ent as for the routine surgical pati ent.
Evi dence that the stress of l abor may preci pitate MH is not convi nci ng, and wel l-conducted
epi dural anesthesi a for labor and del i very wi thout dantrol ene pretreatment but wi th careful
moni tori ng of vi tal signs is recommended. If an emergency cesarean section with general
anesthesia i s necessary, alternati ves to succinyl chol i ne should be used. The maternal :fetal
parti tion rati o for dantrol ene i s probably 0.4.
109
Dantrolene has not been reported to produce
si gni fi cant problems for the fetus or newborn, but exi sti ng data are very scanty.
Mal i gnant Hyper t her mi a i n Speci es Ot her Than P i gs and
P eopl e
Mal ignant hyperthermi a has been reported sporadi cal l y i n many speci es. Cl inical epi sodes have
been documented i n cats, dogs, and horses.
110
Capture myopathy i s a syndrome characteri zed by
temperature el evati on, rhabdomyolysi s, aci dosi s, and death i n wil d ani mal s (e.g., zebra, el k).
111

Thi s al so has been suggested to be an MH vari ant.
Medi col egal Aspect s
In thi s era of mal practi ce actions, i t is not surpri si ng that MH cases have been the subject of
malpractice sui ts. Because MH may be consi dered an i nborn geneti c problem wi th a rel ati vel y fixed
associated mortali ty that may go unrecognized before a pati ent' s exposure to triggering agents, it
may be used as a cover for other problems.
Fever, opisthotoni c posturi ng, and neurol ogic abnormal i ti es may accompany hypoxi c brain i njury,
and because of thei r si mil ari ty to MH, MH may be incorrectl y impli cated i n the differenti al
di agnosi s. Furthermore, after cardi ac arrest from any cause, CK and potassi um l evel s may be
si gni fi cantl y el evated. The i nci dence of l iti gati on after the occurrence of MH i s unknown.

Some have stated that, with the advent of dantrol ene, there shoul d be no deaths from MH. Thi s i s
unreal i sti c because the syndrome may be truly expl osi ve i n some cases and i mpossi bl e to control
with current therapy. Al so, al l the factors that l ead to MH are not known. The dose of dantrolene
needed to prevent recrudescence cannot be determi ned with certai nty. Nevertheless, certai n
common themes underl i e the basi s for li tigati on i n MH:
1. Fai lure to obtain a thorough personal history i n regard to anestheti c probl ems and a
famil y hi story of any unexplai ned peri operati ve probl ems.
P.540
2. Fai lure to moni tor core temperature conti nuousl y with an electroni c temperature monitori ng
device. Several jury tri al cases have been lost by the defense because the pati ent' s
temperature was not moni tored. Intraoperati ve temperature moni toring i s now consi dered a
standard of care in the Uni ted States by the legal professi on, despi te the fail ure of the
Ameri can Soci ety of Anesthesi ol ogi sts to recommend routi ne temperature moni toring duri ng
administrati on of al l general anestheti cs.
3. Fai lure to have adequate suppli es of dantrolene on hand wi th a plan of management of MH.
4. Fai lure to investi gate unexplained i ncreases i n body temperature and i ncreased skeletal
muscle tone (especi al l y after succi nyl choli ne admini stration) when associated wi th i ncreased
heart rate and dysrhythmi as.
Several exampl es of medicolegal cases involvi ng these pri nci pl es are descri bed bel ow:
1. A young femal e pati ent had shoul der surgery with isofl uraneni trous oxideoxygen.
Temperature was not monitored continuously. At the end of the procedure, premature
ventri cul ar beats and increasi ng end-ti dal carbon di oxi de were noted. The pati ent had a
cardi ac arrest as the dysrhythmi a was being treated. As the drapes were bei ng removed, the
patient fel t warm. A temperature probe reveal ed a reading of nearly 42C. The pati ent was
di agnosed as havi ng an acute episode of MH. Dantrol ene was admi ni stered an hour l ater. The
pati ent devel oped DIC over the next day and di ed. The case was settled out of court.
2. A 26-year-ol d woman was undergoi ng a breast augmentation in a plasti c surgeon' s offi ce
using general anesthesia wi th i soflurane. Toward the end of the procedure, her heart rate
i ncreased as di d end-ti dal carbon di oxi de and ski n temperature. Dantrol ene was not
avai l abl e and the pati ent was sent to a nearby emergency room. By the ti me dantrol ene was
gi ven, her temperature was about 43C. She devel oped DIC and di ed. The case was settl ed
without jury tri al . The company provi di ng i nsurance for the physi cian now mandates that
dantrol ene be i mmedi atel y avail abl e wherever general anesthesi a i s admini stered.
3. Symptoms of bowel obstruction devel oped i n a mi ddl e-aged man. He was taken to a l ocal
hospi tal , and anesthesia was admi ni stered wi th ni trous oxideoxygenhal othane and
succi nyl choli ne. Hi s temperature was not monitored, but an unexpl ained tachycardi a (140 to
160 beats/mi n) was present throughout the 2-hour procedure. On arrival i n the intensi ve
care uni t after the operati on, the pati ent was sl ightl y hypotensi ve. Invasi ve moni tori ng was
started. Despi te marked metabol ic and respiratory aci dosi s, a Pa
CO
2
of 100 mm Hg, and a
recorded temperature of nearl y 42C, MH was not di agnosed. A cooli ng blanket and
anti bi otics fai led to arrest the decrease i n the pati ent' s bl ood pressure, whi ch eventuall y l ed
to cardiac arrest. A judgment against the physi ci ans and hospi tal of $4.5 mi l li on was
reached.
There have been several mal practi ce cases fi led against anesthesi ol ogi sts i n which cardi ac arrest
and death occurred after succi nylchol ine was used i n patients with an undiagnosed myopathy. The
usual outcome i s an out-of-court settl ement.
The message i s clear. Al l faci li ties where general anesthesi a is admini stered (i ncl udi ng hospi tal s,
outpati ent surgery centers, physi cian offi ces, and dental offi ces) shoul d have a full supply of
dantrol ene avai labl e. Al l patients undergoi ng general anesthesi a should have standard moni toring,
i ncl udi ng end-ti dal carbon di oxi de and, except for bri ef cases, body temperature.
P at i ent Suppor t Ser vi ces
To answer the needs of patients and famil i es who wi shed to l earn more about MH and of those
famil i es whose rel ati ves have di ed from MH, support groups were founded i n several countri es
(e.g., the Mal i gnant Hyperthermi a Associ ati on [of Canada] and the Mali gnant Hyperthermi a
Associ ati on of the Uni ted States [MHAUS]). Both groups serve as a repository of informati on about
MH, provi de names of physici ans knowl edgeabl e about MH and the location of MH diagnosti c
centers, and simply l end an ear to those wi th MH who have questi ons. Both organi zati ons have an
advi sory commi ttee of physi ci ans. The Mal i gnant Hyperthermia Associ ation of the United States
publ i shes a quarterl y newsl etter, The Communicator, wi th excerpts from the medical li terature,
explanatory arti cl es, questions and answers, and rel ated i nformati on. In addi ti on MHAUS
organi zed two hotl i nes so that a health care provi der with an urgent questi on about MH or NMS
can be placed in contact wi th a knowl edgeabl e vol unteer speci al i st. Approximatel y 30 to 40 cal ls a
month are handl ed by the MH Hotli ne, 1-800-644-9737, and a smal l er number by the Neurol ept
Mal ignant Syndrome Informati on Servi ce (NMSIS).
The address of the Mal i gnant Hyperthermi a Associ ati on of the Uni ted States is 11E State Street,
Box 1069, Sherburne, New York, 13460-1069, FAX 607-674-7910. The phone number i s 1-800-
98MHAUS. The hotl i ne number i s 1-800-MHHyper. The Web si te address i s http://www.mhaus.org.
In 1989, the North Ameri can MH Regi stry was formed. Now based i n Pittsburgh, Pennsyl vani a
(Chi ldren' s Hospi tal of Pi ttsburgh, 412-692-5464), the Regi stry is the reposi tory for patient and
famil y speci fi c i nformation for MH-suscepti bl e pati ents. MH suscepti bl e pati ents are i nvi ted to
contact the Regi stry. If an MHS individual wishes to joi n the Registry, he or she must compl ete a
questi onnai re and si gn a consent form. The Regi stry was merged with MHAUS in 1995. A
descri ption of the Regi stry is avail able at http://www.anesth.upmc.edu. The forms used i n the
Regi stry can be reviewed at http://www.mhreg.org.
P at hogenesi s and Et i ol ogy
Several major devel opments have contri buted to the present understandi ng of the compl ex
pathophysi ol ogy of MH. The first was the recogni ti on that the syndrome i s geneti cal l y
transmi tted.
2
Thi s fi ndi ng is si gni fi cant because it suggests that a rigorous appl i cati on of modern
mol ecul ar geneti cs wil l l ead to the identi fi cati on of mutations i n speci fi c protei ns causing the
di sorder. A second fi ndi ng was a greater sensi tivi ty of bi opsi ed skel etal muscl e from MH-
suscepti bl e pati ents to hal othane or caffei ne. This was the basis for an i n vi tro diagnosti c test and
studi es of the mechanisms underlyi ng MH. The thi rd was the recogni ti on of si mi l ariti es between
human MH and porcine stress syndrome. Thi s ani mal model was used to elucidate the rol e of
al tered Ca
2+
regulation i n MH and led to the fi ndi ng that a mutati on i n the ryanodi ne receptor may
be a causati ve factor in many famil i es with MH.
112
Fourth, MH has

been i dentified as a heterogeneous disorder.
31, 59
Heterogeneity may account for some vari abil i ty
in presentati on and forces i nvestigators to consider the rol e of a fi nal common pathway resul ting
from a mutati on i n any one of several di fferent proteins. Fifth, the findi ng that pi gs or human
subjects wi th MH do not al ways tri gger i n response to adequate tri ggeri ng agents, has suggested
that modul ators i nfl uence the expressi on of the syndrome.
113, 114

Experimental Models for Malignant Hyperthermia
Al though MH i s rare i n humans, breedi ng pi gs for l eaner meat and better muscul ature has resulted
i n the appearance of the MH gene in a rel ati vel y hi gh frequency i n a number of herds (e.g.,
Pol and, Chi na, Landrace, Pi etrai n). A syndrome i n pi gs undergoing anesthesi a is si mi l ar to the MH
syndrome in humans. However, the porcine syndrome can also be el ici ted i n the absence of
anesthetics, by factors such as heat and stress. Al though pi gs administered MH-triggering
anesthetics have provi ded a model for human MH, there is l i ttl e evi dence that a human stress
syndrome anal ogous to PSS exi sts i n the majori ty of pati ents. However, there i s a weak
association between exerti onal heat stroke and MH.
115, 116, 117
A si ngl e geneti c defect i n the
ryanodi ne receptor has been associated wi th porci ne MH, and this speci fi c mutation is found i n
some humans wi th MH. The mode of inheritance i n swi ne (autosomal recessi ve) is di fferent from
that i n humans (autosomal domi nant). The porci ne model has been extensi vel y exploited i n
studi es of MH. Reports of MH exi st, but are rare, i n horses, dogs, and cats. Of these, only the dog
has been proposed as a model of human MH.
118
The pattern of i nheri tance i n the dog appears to
be autosomal domi nant, yet there are some di fferences between the anesthesi a-el i ci ted canine and
P.541
human MH syndromes.
Understanding the Malignant Hyperthermia Defect: Necessary
Concepts
A hypothesis explaini ng MH must account for the puzzl i ng cl i ni cal observati ons surroundi ng this
di sorder. Most importantl y, the l arge majori ty of these patients function normal l y i n the absence
of anesthetics. Therefore, the defect shoul d not si gni fi cantl y i nterfere with normal muscl e
physi ol ogy. The defect, at l east in humans, appears to be expressed si gni fi cantl y only i n skeletal
muscle. The expressi on of the syndrome shows a l arge variabi l i ty among i ndi vi dual s. For exampl e,
30% of pati ents have had up to three uneventful anestheti cs.
57, 119
A spectrum of presentati ons
can occur, rangi ng from rel ati vel y minor i ntraoperati ve compl icati ons to rapid temperature rise,
muscl e ri gi di ty, aci dosi s, dysrhythmi as, and death. Some cases have a greater l atency to onset
and are not made manifest until several hours postoperati vel y. MH does not al ways occur i n
response to tri ggeri ng agents. Thi s i s a wel l -establ i shed observati on i n human MH and si mil ar
observations have been reported i n swi ne. Also, whil e most i nvesti gators would agree that PSS is
a more consi stentl y tri ggered syndrome than the human MH syndrome, even adul t swi ne
occasional ly do not respond to adequate tri ggeri ng agents in either a barnyard chal l enge with
halothane alone
120
or prol onged hal othane,
121
or hal othane and succi nyl chol i ne chal l enge.
11
The
term MH may, i n fact, be a mi snomer, as someti mes patients show no si gns of temperature
el evati on. Fi nal ly, many cases do not exhi bit rigi di ty. The l arge vari abi l ity among i ndi vi dual s may
be expl ai ned by di fferent genes causi ng MH i n di fferent famil i es or by other predi sposing factors
bei ng expressed di fferentl y i n di fferent pati ents or fami l i es.
76
The function of many different
protei ns has been reported to be al tered i n MH skeletal muscle. Thus, i t i s reasonabl e to assume
that systems other than those directl y i nvol ved i n Ca
2+
regulation are secondari l y altered in MH
and these may pl ay a cruci al rol e i n modifyi ng the response to tri ggeri ng agents. The involvement
of secondary systems woul d explai n the hi gh variabi li ty i n the phenotype.
Skeletal Muscle: Site of the Malignant Hyperthermia Defect
The MH and PSS defects are expressed in skel etal muscl e, as evi denced by the i n vi tro contracture
test for MH susceptibi l ity. Resul ts regardi ng other tissues are more controversial , especi al l y i n
humans, and are not consi dered i n detail i n thi s chapter. The defects are expressed i n type I and
type II fi bers.
122
Whi le the distri buti ons and amounts of protein i n whol e skeletal muscle and in
isol ated sarcoplasmi c reticulum appear to be normal by electrophoreti c anal ysi s, downregulation of
specific protei ns, i ncl udi ng the ryanodi ne receptor
123
and di hydropyri di ne receptor,
124
has been
reported. Addi ti onal l y, the expression of subtypes of the sodi um channel i s altered in MH
muscle.
125, 126, 127

Altered Calcium Regulation: The Common Final Pathway
Ul ti matel y, the mai n probl em in skel etal muscl e is a l ack of control of myopl asmi c Ca
2+

concentration during anesthesi a,
6, 128
whi ch may be manifest cli nicall y as muscl e rigi di ty. Ca
2+

level s are control l ed by a complex i nteracti on of Ca
2+
rel ease from the termi nal ci sternae, the
adenosine tri phosphatedri ven Ca
2+
pumps at the sarcoplasmi c reti culum and sarcol emma,
Na
+
/Ca
2+
exchange, several Ca
2+
bufferi ng protei ns (cal sequestri n, parval bumi n), and
mitochondrial Ca
2+
regulation (Fi g. 20-3). Al though several of these systems may become involved
as the MH syndrome progresses, the diffi culty in Ca
2+
regulation appears to origi nate in the Ca
2+

rel ease mechani sm i n the terminal ci sternae. The Ca
2+
rel ease mechanism coul d be made sensi ti ve
to anestheti cs by any of several possibi l iti es, incl udi ng a mutati on i n the skel etal muscle cal ci um
rel ease channel , termed the ryanodine receptor (RYR1); a protei n di rectl y coupl ed to RYR1 (e.g.,
di hydropyridi ne receptor); or an al tered modul ator of RYR1 functi on (e.g., fatty aci ds).
Succi nylchol i ne opens the acetyl chol i ne receptor and depol arizes the muscl e membrane by opening
the vol tage dependent sodi um channels, whi ch may have altered functi on i n MH. Depol ari zati on
leads to Ca
2+
rel ease from the sarcopl asmi c reticul um. Dantrolene antagoni zes Ca
2+
rel ease from
the sarcoplasmi c reti culum, lowers elevated intracel l ul ar Ca
2+
level s, and reverses an epi sode of
MH.
6

Presence or Absence of a Malignant Hyperthermia-Associated
Defect Within Skeletal Muscle Organelles: Sarcolemma
The sarcol emma (see Fi g. 20-3) mai ntains the membrane potenti al of the muscl e cel l and acts as a
permeabil i ty barrier to ions, i ncl udi ng Na
+
, K
+
, Cl
-
, and Ca
2+
. Skel etal muscl e, i n most cases, does
not requi re extracel lul ar Ca
2+
for nerve or el ectri cal l y evoked contracti l ity. In contrast, hal othane-
induced contractures
128, 129
and, to a l esser extent (dependi ng on the speci es), caffei ne-induced
contractures
128
require extracel l ul ar Ca
2+
. A l oss of i ntegri ty i n the sarcol emma could cause a
large influx of Ca
2+
from the extracell ul ar medium. Also, openi ng speci fi c Ca
2+
channel s (e.g.,
di hydropyridi ne receptors) i n the sarcolemma woul d al l ow the entry of extracel lular Ca
2+
.

FIGURE 20-3. Exci tationcontracti on coupl i ng and MH. The action potenti al generated at the
endplate regi on of the neuromuscular juncti on i s propagated down the sarcol emma (muscle
plasma membrane) by the openi ng of vol tage-dependent Na
+
channel s (1). The acti on
potential conti nues down i nto the t-tubul es (2) to the di hydropyri dine receptors (3). The
di hydropyridi ne receptors i n skeletal muscle functi on as vol tage sensors and are coupl ed to
the Ca
2+
rel ease channels (4). Through thi s coupl ed si gnali ng process, the Ca
2+
rel ease
channel s are opened, some of the avail able termi nal cisternae Ca
2+
stores (5) are rel eased,
and the l evels of myoplasmi c Ca
2+
are el evated. The Ca
2+
then diffuses to the myofibri ls (6)
and interacts wi th the troponi n/tropomyosi n compl ex associ ated wi th acti n (thin l ines) and
al lows interacti on of actin wi th myosi n (thick li nes) for mechanical movement. The Ca
2+

diffuses away from the myofibrils and this Ca
2+
si gnal i s termi nated by an ATP-dri ven Ca
2+

pump (7), whi ch pumps Ca
2+
into the longi tudi nal sarcoplasmi c reticulum (8). The Ca
2+

di ffuses from the l ongitudi nal sarcoplasmi c reticulum to the terminal ci sternae, where i t is
concentrated for release by Ca
2+
bi ndi ng protei ns. Na
+
enteri ng during the acti on potenti al is
subsequently extruded from the cel l by the Na
+
/K
+
-ATPase (9) and possi bl y through Na
+
/Ca
2+

exchange (10). Thi s latter process woul d el evate i ntracell ular Ca
2+
and coul d resul t from
del ayed i nacti vati on of Na
+
currents. A major form of energy for suppl yi ng cel l ular ATP for
the ion pumps and numerous other energy consumi ng processes i s fatty aci ds (FA) deri ved
from the serum (dietary FA), or from intramuscul ar tri glyceride (TG) stores. Therefore, a
defect i n the intracel l ul ar Ca
2+
regul ati ng processes (i ncreased Ca
2+
rel ease or decreased
Ca
2+
uptake), or a defect i n the sarcol emma coul d account for an i ncrease in myopl asmic
Ca
2+
.

Terminal Cisternae: Ca
2+
Release. The terminal ci sternae of the sarcopl asmi c reti cul um are the
si tes of Ca
2+
sequestration. They are coupled to the t-tubul es through the ryanodi ne receptor and
the di hydropyri di ne receptor (Fi g. 20-4; see Fi g. 20-3). Several investi gators have reported a
hypersensi tive Ca
2+
-induced Ca
2+
rel ease i n termi nal ci sternae preparations from porci ne MH
muscle.
130, 131, 132
Al so observed for PSS

Ca
2+
-induced Ca
2+
rel ease are an enhanced rate of rel ease from ski nned fibers
133
and terminal
ci sternae preparations.
134, 135

The maximum amount of Ca
2+
rel eased i s normal for PSS vesicl es.
136
In the human MH popul ati on,
the Ca
2+
rel ease process appears to be less dramati cal l y affected than that i n PSS muscl e. For
example, the threshol d of Ca
2+
-induced Ca
2+
rel ease i n termi nal ci sternaecontai ning fractions i s
P.542
FIGURE 20-4. Schemati c i ll ustration of the homotetrameri c ryanodi ne receptor, the cal ci um
rel ease channel si tuated in the membrane of the sarcopl asmi c reti cul um (SR). The cytosol ic
part of the protei n compl ex, the so-call ed foot, bri dges the gap between the transverse
tubul ar system and the SR. Mutati ons have been descri bed for the skel etal muscl e ryanodine
receptor (RYR1), whi ch cause susceptibi l ity to mal ignant hyperthermi a (MHS) and central
core disease (CCD). (From Lehmann-Horn F, Lerche H, Jurkat-Rott K: Skel etal muscl e
channel opathi es: Myotonias, peri odi c paral yses and mal i gnant hyperthermi a. In Stahl berg E
(ed): Cli nical Neurophyi sol ogy of Di sorders of Muscl e and Neuromuscular Junction. Handbook
of Cl inical Neurophysi ol ogy, vol 2. El sevier BV, 2003:476.)
not al tered i n a human MH popul ati on.
131, 137
Although the alterations in Ca
2+
rel ease reported i n
swi ne cannot be observed in i sol ated heavy sarcopl asmi c reti cul um preparati ons from humans,
abnormali ties i n Ca
2+
rel ease are observed when preparations containi ng additi onal cel lular
components are examined, such as ski nned fi ber preparations (Fi g. 20-5). MH subjects have a
greater than normal rate and hypersensi tivity of Ca
2+
-induced Ca
2+
rel ease
138
and Ca
2+
rel ease i s
hypersensi tive to caffei ne usi ng the ski nned fi ber preparati on.
139

FIGURE 20-5. Methods to examine Ca
2+
regulation. (1) Termi nal cisternae. Skel etal muscl e
can be homogeni zed and resealed porti ons of the terminal ci sternae contai ning the Ca
2+

rel ease channel (RYR1) can be recovered by a series of centri fugati on steps. These vesi cles
can take up Ca
2+
from the bathing medi um by means of the ATP-dri ven Ca
2+
pump and can
subsequently rel ease Ca
2+
by openi ng of RYR1. Ca
2+
level s i n the extravesicul ar medium can
be moni tored spectrophotometri cal l y by a number of dyes (usuall y metal ochrome i ndi cators
such as arsenazo III or anti pyryl azo III). Alternati vel y,
45
Ca
2+
and fi l trati on of the vesi cl es
can be used. The amount of cal ci um released is usual l y determined by the decrease i n
radioactivity retai ned on the fi l ters that contai n the vesicl es. Both the spectrophotometri c
and radi oi sotopi c approaches al l ow monitori ng of Ca
2+
uptake and Ca
2+
rel ease, and these
processes can be di ssoci ated pharmacol ogi cal l y wi th the RYR1 blocker, rutheni um red. The
termi nal ci sternae method all ows the overall response of a l arge popul ati on of channels to be
examined and may best refl ect the overal l responsiveness of the muscl e. (2) Pl anar li pi d
bi l ayers. It i s possi bl e to incorporate RYR1 i nto arti fi ci al l i pi d bi l ayers (i .e., pl anar l i pi d
bi l ayer) and monitor the Ca
2+
current as electri cal charge movement through one to several
channel s at a time. Al though this method can provi de very useful , detai l ed informati on on the
openi ng and cl osi ng of i ndi vi dual RYR1s, i t does not provide an i ndi cation of the overal l
responsi veness of the muscle i n which both Ca
2+
uptake and Ca
2+
rel ease are parti cipati ng
and in which many modulating substances are present. (3) Ski nned fi bers. A thi rd approach
invol ves ski nned fi ber preparati ons i n whi ch the sarcol emma is either removed mechani cal l y
or made permeabl e chemi cal l y, and the function of the sarcopl asmi c reti cul um (Ca
2+
uptake
and rel ease) and myofi bril s (acti n and myosi n) moni tored by the contractil e response of the
fi ber. Thi s preparati on has an i nteresting advantage i n that type I and type II fi bers can be
di sti ngui shed. Al so, the t-tubul es seal compl etel y, al l owing the function of the
di hydropyri di ne receptors and Na
+
channels to be examined. Thi s method onl y examines one
muscle fiber at a time, which might be a slight di sadvantage i n MH or PSS skel etal muscl e,
because the defect is not uni formly expressed throughout the tissue. (4) Ca
2+
el ectrodes and
fluorescence dyes. The cytopl asmi c Ca
2+
level s can be monitored i n intact muscle either wi th
fl uorescence dyes or Ca
2+
electrodes. The former can moni tor a muscl e mass, whi l e the l atter
Wi th respect to anesthetic acti on, the rate of hal othane i nduced Ca
2+
rel ease i s abnormal ly hi gh in
PSS suscepti bl es.
132, 140
In contrast, i n human MH muscl e
141
and PSS muscl e,
142
the dose-response
curves for hal othane-i nduced Ca
2+
rel ease are normal when the amount of Ca
2+
rel ease i s
moni tored. Free cal ci um was determi ned (with fura-2) in vol tage-cl amped human muscl e fi bers.
143

The ki neti cs and vol tage dependence of cal ci um rel ease for MH muscle was normal ; however, the
maximal peak rate of Ca
2+
rel ease i ncreased about 3-fol d. Al though resting Ca
2+
concentrati ons
are normal , human skeletal muscle cel l cultures have a 2-fol d greater than normal sensi ti vi ty to
halothane.
144
There is no effect of temperature on the rate of halothane-induced Ca
2+

rel ease.
140, 145

In heavy sarcoplasmi c reticulum preparati ons (contai ni ng tri ads and sarcoplasmi c reti culum),
halothane at cl i ni cal ly rel evant concentrati ons cannot induce a sustai ned net Ca
2+
rel ease i f
physi ol ogi c l evels of adenosi ne tri phosphate and Mg
2+
are i ncl uded. This abil i ty to overcome the
effects of hal othane under approxi mate physi ol ogic condi ti ons is because of the enormous capacity
of the Ca
2+
pumpi ng system.
137
The addi ti on of fatty aci ds, even to vesi cl es isolated from normal
muscle, markedl y (~20- to 30-fol d) decreases the concentrati on of hal othane requi red for the
sustained opening of the Ca
2+
rel ease channel in the presence of adenosine tri phosphate and
Mg
2+
.
137
Under these conditi ons, fatty acids can cause a sustained Ca
2+
rel ease at cl i ni cal
concentrations of hal othane. Unli ke studi es of Ca
2+
rel ease i n the absence of fatty aci ds,
145
there
is an absol ute temperature dependence (occurs at 37C, not at 25C) of the fatty aci d
enhancement of halothane-induced Ca
2+
rel ease, whi ch i s consi stent wi th the temperature
dependence of hal othane-induced contractures of MH muscl e.
146

Mitochondria. Mitochondri a oxidi ze a vari ety of substrates to generate the form of energy
(adenosi ne triphosphate) most useful for dri vi ng cel lul ar reacti ons. Defects i n mi tochondrial
functi on do not appear to i ni ti ate the MH syndrome. The uncoupl i ng of Ca
2+
-stimul ated, but not
adenosi ne di phosphate-stimul ated, mi tochondrial succi nate

oxi dati on has been demonstrated i n muscl e from pi gs and humans
147
susceptibl e to MH.

Longitudinal Sarcoplasmic Reticulum: Ca
2+
Uptake. The l ongi tudinal sarcopl asmi c reticul um
(see Fi g. 20-3) i s primaril y involved i n removi ng Ca
2+
from the myopl asm through the adenosine
triphosphatedri ven Ca
2+
pump. Whi l e earl i er studi es had suggested a defect i n Ca
2+
uptake mi ght
cause the l oss of Ca
2+
regulation associ ated wi th MH, subsequent studi es have rul ed out a role for
the Ca
2+
pump i n causi ng MH.
140

Myofibrils. Rel ati vel y few studi es have been conducted on myofibril s i n MH. However, there is
apparentl y no defect i n the Ca
2+
sensi tivity of the fast or sl ow fi bers of the contractil e system
from MH skel etal muscle.
P r ot ei ns or Syst ems Repor t ed Al t er ed i n Mal i gnant
Hyper t her mi a Muscl e
Calcium Release Channel of Skeletal Muscle
The human skeletal muscl e calci um rel ease channel is encoded by a ryanodi ne receptor type 1
(RYR1) gene l ocated on chromosome 19q13.1.
148
There are other types of RYR that exi st i n cardiac
muscle (type 2) and brai n (type 3) ti ssues, respecti vel y. RYR1 is the pri mary condui t through
whi ch the sarcoplasmi c reticul um stores of Ca
2+
are rel eased to the sarcoplasm.
112
RYR1 is an
extremel y l arge homotetramer, havi ng subuni ts of about 560,000 MW each. RYR1 has bi ndi ng si tes
for the contracture-inducing plant al kaloi d ryanodi ne
149
and the preservative 4-chloro-m-cresol .
150

In about 50% of MH suscepti bl e famil i es, susceptibi l i ty to MH i s l i nked to chromosome 19 and a
exami nes i ndi vi dual fi bers. Both approaches can be used wi th muscl e fi bers or cel l cul ture
systems.
P.543
mutation in ryr1.
31, 59, 151
The hypothesi s that mutati on i n RYR1 causes MH susceptibi l ity is
supported by physi ol ogi c studi es showing subtle effects of hal othane on isolated RYR1 currents in
human MH muscl e.
152
Halothane can open a hypersensi ti ve RYR1, leadi ng to an uncontrol l ed
release of Ca
2+
into the myopl asm and the MH syndrome. However, the bufferi ng capaci ty of the
Ca
2+
pump i n the presence of adenosi ne tri phosphate is abl e to sustai n normal Ca
2+
regulation i n
the presence of hal othane i n termi nal cisternae preparati ons isolated from MH muscl e.
114
These
observations are consi stent wi th the observed interi ndi vi dual vari abi l i ty in human MH and the
occurrence of nonri gi d MH. When ATP i s l ow the syndrome occurs and the l ower the energy stores
are, the worse the MH sysndrome i s. Unl ike the hypersensiti ve Ca
2+
rel ease i n porcine muscl e,
130

Ca
2+
regulation in human MH heavy sarcopl asmi c reti cul um fracti ons appeared to be normal .
131

However, usi ng pl anar bi l ayer approaches capabl e of moni toring singl e RYR1 channel s, subtle
changes i n the functi on of RYR1 have been observed in human MH muscl e,
152, 153
si mil ar i n some
respects to those in PSS muscle in pl anar bi l ayers.
154
These di fferences relate pri maril y to an
i ncreased probabi l i ty of the MH RYR1 being i n an open state. Whi le di fferences between normal
and PSS suscepti bl es have been reported i n the absence of hal othane or caffeine,
154
human MH
muscle requi res the presence of caffei ne
153
or hal othane
152
to detect di fferences i n RYR1 functi on.
In human MH muscl e two populations of i on channel s appear to be present: one hal othane-
insensi tive and the other hal othane-sensi ti ve.
152
The hal othane-sensi ti ve channel s have an
increased probabil i ty of openi ng i n the presence of cl inicall y rel evant concentrati ons of hal othane.
The hal othane-sensi ti ve channel s do not occur i n muscle from al l MH pati ents, and both types (or
states) of channel s can coexi st i n the same muscl e bi opsy. Whether these subtl e di fferences i n
RYR1 function in planar bilayers, or the di fferences i n K
d
of ryanodi ne binding,
149
in human muscl e
refl ect a di fferent acylation or phosphoryl ati on state of RYR1 is not known. Consi stent wi th the
al tered functi on of the PSS RYR1, there has been a speci fi c mutation identi fi ed (Arg
615
to Cys
615
)
in RYR1 i n PSS.
155
The mutation i s on the cytoplasmi c surface of RYR1.
156
Thi s mutation accounts
for the al tered functi onal states of RYR1 and ryanodi ne bi ndi ng i n PSS swi ne. However, the
porci ne mutati on does not appear to account di rectly for the caffei ne sensi tivity of PSS muscl e.
157

In between 2 and 11% of MH fami l ies the human equi val ent (Arg
614
to Cys
614
) to the PSS RYR1
mutati on has been identi fi ed. However, there may be discordance between the presence of thi s
mutati on and the outcome of the di agnosti c contracture test.
158, 159, 160
A major reason for the
attenuated effects of the RYR1 mutation in human muscle is l i kely the domi nant mode of
i nheri tance wi th reduced penetrance and geneti c heterogenei ty of MH versus recessi ve mutati on i n
the pig. Thus, normal copi es of RYR1 are expressed i n human MH muscl e, but not PSS muscle. The
number of sequence variants in RYR1 reported at scienti fi c meetings to date i s more than 200,
incl udi ng Arg614Cys, and thi s number is constantl y risi ng. The majori ty of these are usual ly found
in onl y one or two famil i es.
There i s a 2-fol d greater than normal sensi ti vi ty to hal othane i n cel l cul tures from MH muscl e.
144

However, a 2-fol d i ncrease i n sensi ti vi ty to triggeri ng agents in cell cul ture does not equate to the
much greater sensiti vi ty of MH muscle to hal othane observed in vi vo. Transfection of human MH
skel etal

muscle cel l cul tures wi th normal (wil d-type) RYR1 does not resul t i n the MH-negati ve phenotype
(judged by sensi ti vi ty of Ca
2+
transients to halothane), whereas expression of a mutated ryr1
(Arg
163
to Cys
163
) i n normal muscle cel ls causes hypersensi tivity to hal othane.
144
Transfecti on of
nonmuscl e cell l i nes wi th any one of 19 RYR1 mutati ons i ncreased the sensiti vi ty of the cel l s to
rel ati vely hi gh concentrati ons of halothane and caffei ne.
161, 162
Therefore, cell cul tures can be
useful model s for el uci dati ng the mechani sms by whi ch MH mutations enhance the sensi ti vi ty of
muscle to tri ggeri ng agents.
In summary, there are physi ol ogi c, bi ochemi cal , pharmacol ogi c, and mol ecul ar geneti c data
supporting a mutation in RYR1 as an important factor, and perhaps an i ni ti ati ng factor, i n about
50% of the fami li es wi th MH. The effects of the altered RYR1 function on Ca
2+
regulation
determi ned i n vitro are not as pronounced in humans as i n swi ne, possibl y owi ng to the domi nant
mode of i nheri tance and geneti c heterogenei ty of MH in humans. It i s hi ghl y probabl e that other
systems come into pl ay as modul ators of the MH response. Thi s may better expl ai n the extreme
intra- and i nteri ndi vi dual vari abil i ty i n the human MH syndrome, which is i n contrast to the more
P.544
consi stent response i n MH swine.
Sodium Channel
Skeletal and cardiac muscl e sodi um channel s are composed of two subunits (, 220,000 MW; ,
40,000 MW). The subuni t forms the ion pore, all owing Na
+
to enter the cell , and the small er
subuni t can modi fy the ki netics of the i on fl ux.
163, 164
Sodi um channels i n skeletal muscle are of
two, and possi bl y three,
127
subtypes. These subtypes can be di fferenti ated by thei r sensi ti vi ty to
tetrodotoxin (TTX), a toxi n from the puffer fi sh that bl ocks the channel pore. The adul t sodi um
channel (SKM1) i s 90% blocked by a 100 nM concentrati on of TTX. The embryoni c sodi um
channel (SKM2) i n skel etal muscl e i s i denti cal to the cardiac sodi um channel , and is bl ocked by a
10-M concentrati on of TTX i n cel l cul ture. A thi rd channel i s expressed fol l owing denervati on,

and thi s subtype is not antagoni zed by TTX, even at a 100-M concentration. The adul t sodi um
channel subuni t, encoded on chromosome
17, 163, 164
was formerly bel ieved to be the onl y subtype
expressed i n normal, mature skeletal muscle. The embryoni c sodi um channel subuni t appears
early in muscl e differenti ati on and is encoded on chromosome 3. Each of the subuni ts interacts
with the same subuni t (
1
), encoded on chromosome 19.
165
The sodium channel s of normal
human skel etal muscl e (vastus l ateral is) are composed of approxi mately 50% SkM1 and 50%
SkM2.
127
Speci fi c mutations i n the subuni t of SkM1 have been i mpl i cated as the cause of other
di sorders of skel etal muscl e, including the myotoni c form of hyperkal emi c peri odi c paralysi s,
164, 166

paramyotoni a congenita,
167
and myotonia fluctuans.
168
These di sorders are wel l known to exhi bi t
masseter muscl e rigi di ty and whol e body ri gi di ty to agents associ ated wi th the MH syndrome,
169

al though they l ack the si gns of aci dosis characteri sti c of MH.
Al tered sodi um channel functi on may pl ay a role in the expression of MH. The function of the
sodium channel i s abnormal in primary cultures of human MH skeletal muscle.
170
There are two
popul ati ons of sodi um currents separated by their kineti cs of inactivati on (i .e., cl osi ng of the
channel ). These are the normal ly inacti vati ng and delayed inactivati ng fast sodi um currents. There
is a greater proporti on of the sl ow inactivati on of the Na
+
current i n cultured human MH muscl e
125

that woul d keep the sodi um current acti ve for a longer time (del ayed i nacti vati on). The
consequence of thi s prol onged sodi um current i n MH muscl e i s a longer membrane depolarizati on
and i ncreased peri od of Ca
2+
rel ease from the termi nal ci sternae. A toxin from the sea anemone
(ATX II) causi ng del ayed i nacti vation of the sodi um current, as found i n human MH muscl e
cultures, enhances the response of normal muscle to halothane, caffeine, and ryanodine.
171
Thi s
findi ng supports a rol e for altered Na
+
channel currents i n the response of MH muscl e to tri ggeri ng
agents. Veratri di ne, al so a sodi um channel inhi bitor, enhances the response of MH muscl e to
halothane.
173
Therefore, altered Na
+
currents may be important for at least some of the si gns
associated wi th MH. Those patients expressing sodi um channel abnormali ties may be more li kel y
to exhibi t certai n si gns, such as muscl e ri gi dity.
The expressi on of sodi um channel subtypes i s also al tered i n MH skeletal muscle. SkM2 (embryonic
form) appears to be downregul ated i n MH, i n cel l cul ture systems, or i n bi opsies of vastus l ateral is
muscle.
126
Thi s woul d l ead to a predomi nance of SkM1 in MH muscl e. SkM1 i s more sensi tive to
halothane than SkM2.
173
There al so is evi dence for li nkage of MH to chromosome 17
174, 175
at or
near the l ocus encodi ng the Na
+
channel subuni t.
176
In one famil y, a Gly1306Al a mutati on i n the
sodium channel known to cause myotoni a fl uctuans cosegregated with MH suscepti bil i ty, as
determi ned by contracture testi ng.
34
Two of these pati ents had whol e body ri gi di ty and/or
masseter muscl e rigi di ty to succinyl choli ne, al though wi thout metaboli c aci dosi s. As wi th RYR1, it
is not clear in most cases if the altered functi on reflects a pri mary defect i n the Na
+
channel
protei n, or i f the functi on is al tered i ndi rectl y by processes such as phosphoryl ati on or
acyl ati on.
177

In summary, changes in sodi um channel expressi on or function could be the result of mutations
within a sodi um channel subtype, or a secondary effect of a pri mary mutation in another protei n
(e.g., RYR1). Al so, second-messenger systems, such as fatty acids, may pl ay a rol e i n al tered
sodium channel functi on and expression. These changes in sodi um channel functi on may be
essential for the phenotypi c expression of certai n aspects of the MH syndrome, such as muscl e
P.545
ri gi di ty.
Elevated Fatty Acid Production
Lipi ds are an i mportant component of a cell , as they provide energy and structure (e.g.,
membranes) and participate in function. Several l i pi d metabol i tes, i ncl uding fatty aci ds, serve
second-messenger functions.
178
Fatty aci ds are the major source of energy i n the resti ng state of
skel etal muscl e and can al so contri bute up to 65% of the energy during exerci se.
179
Fatty aci ds
provi de about 70% of the energy i n resti ng muscl e. Therefore, fatty aci d uti l izati on is l i kel y
upregul ated i n MH muscl e to compensate for the energy consumed by the adenosine
triphosphatases attempting to mai ntai n Na
+
and Ca
2+
homeostasi s.

In addi ti on to exi sti ng i n a free form, fatty aci ds are esteri fi ed to phosphol ipi ds, tri acyl gl yceri des,
di acylgl yceri des, monoacylgl yceri des, chol esterol esters, and many proteins. Free fatty aci ds are
maintai ned at very low level s i n a cell (since they are not onl y essential , but very toxi c) and most
of the free fatty aci ds actual ly are bound to fatty aci dbi ndi ng protei ns.
180

Fatty aci d production is el evated i n mi tochondrial fractions
147
and whol e muscl e homogenates from
PSS and MH susceptibl es. There i s an age-rel ated i ncrease in fatty aci d production in skeletal
muscle that paral lel s an age-rel ated i ncrease in suscepti bil i ty to the PSS.
181
When only stati c
level s of free fatty aci ds are exami ned, they are at normal l evel s in human MH and PSS muscl e.
However, the fl ux of fatty acids through -oxi dati on can sti ll be i ncreased to a l arge extent i n MH
muscle wi thout i ncreasi ng the level s of free fatty aci ds. The fatty aci d fl ux i s deri ved from
triacyl glycerides, and this l i kely accounts for the l ow level s of tri acyl gl yceri des (or total neutral
l i pi d) i n bi opsi ed MH or PSS skeletal muscl e.
138
The effects of fatty acids on Ca
2+
rel ease from
skel etal muscl e sarcopl asmic reti cul um are si gnifi cant, but not dramati c, in the absence of
anesthetics,
182, 183
and they are not medi ated through RYR1.
184
However, the fatty aci ds act in
synergy wi th hal othane and decrease the amount of halothane requi red for sustai ned Ca
2+
rel ease
by 20- to 30-fol d!
114, 131
Thi s fatty aci d enhancement of hal othane-induced Ca
2+
rel ease, i n
contrast with al l other studi es of Ca
2+
rel ease, exhi bits the same temperature dependence (i .e., i t
occurs only at 37C, not at 25C) as halothane-induced contractures of skel etal muscl e and i s
mediated through RYR1.
114
Whi le the concentrati on of fatty acid required for this effect exceeds
that of the normal unbound form, halothane can di spl ace fatty aci ds from fatty aci dbi nding
protei ns.
185
Therefore, i t is highly l ikely that suffi ci ent concentrati ons of fatty aci ds coul d be
achi eved at the site of hal othane acti on. If the production of free fatty aci ds i s sustained by
accel erated tri acyl gl yceri de breakdown and the fatty aci ds are shunted toward acyl ati on of RYR1
and the sodi um channel , then thi s coul d l ead to greatl y el evated myopl asmi c Ca
2+
level s. In the
case of RYR1, this would lead to a greater sensi tivity to hal othane.
Phospholipase C and Inositol 1,4,5-Trisphosphate
One speci fi c metaboli te of phosphol i pase C action, IP
3
, has been demonstrated to be el evated i n
human MH
186
and PSS
187
muscl e, but not i n MH human blood speci mens.
186
Thi s product of the
hydrol ysi s of the phospholi pi d, phosphati dyl i nosi tol 4,5-bi sphosphate, causes Ca
2+
rel ease from
intracel lular stores.
188
The el evati on of al l products of phosphati dyl inosi tol hydrolysi s i s
observed,
188
and thi s suggests that phosphol i pase C acti vi ty may be el evated i n MH. Acti vati on of
phosphol i pase C i n skeletal muscle al so el evates di acyl gl ycerol and i ndi rectly elevates free fatty
aci ds by deacyl ati on of the di acylgl ycerol . Di acyl gl ycerol and fatty acids have di verse cel l si gnal i ng
effects.
178, 189
In additi on to el evated IP
3
production, MH muscl e i s al so hypersensiti ve to IP
3
.
190

Therefore, secondary involvement of thi s system coul d have multi ple effects that together
increase the sensi ti vi ty of Ca
2+
rel ease.

Mol ecul ar Bi ol ogy of Mal i gnant Hyper t her mi a
The i dentificati on of the porci ne mutati on causing PSS and the locati on of the human RYR1 gene
on chromosome 19q13.1 has hel ped to establ ish a direct l i nk of thi s gene to MH.
148, 191
RYR1 was
proposed as a candi date gene for MH and the pi g mutati on Arg614Cys was identi fi ed i n an MH
P.546
family subsequently.
155
Further geneti c li nkage studi es and research on mutations i n RYR1 have
revealed that MH is characteri zed by geneti c heterogenei ty. About 50% of MH fami li es are li nked
to RYR1. RYR1 i s one of the l argest human genes. It contai ns 106 exons that are transcribed into
a 15,364 nucleoti de mRNA. Transcri pti on occurs practi cal l y onl y i n skeletal muscle l evel . More
than 200 different sequence vari ants have been i denti fi ed i n the RYR1 gene. The majori ty are
cl ustered i n three regions: the N-termi nal regi on between codons 34 and 614, the central regi on
between codons 2163 and 2458 and the C-termi nal regi on between codons 4136 and
4973.
31, 59, 192, 193
Thi s preferenti al l ocali zation raised speculations concerning the speci fi c rol e of
these regions. The central regi on i s cl ose to the regi on where the protei n woul d i nteract with the
regul atory protei n, FKBP12, and the di hydropyri di ne receptor, a voltage sensor of RYR1. The C-
termi nal regi on that corresponds to the transmembrane domai n of the protei n.
192
The pathogeni c
character of many RYR1 gene mutati ons has been studi ed by kineti c measures of i ntracell ular
calci um rel ease i n response to caffeine or hal othane wi th use of di fferent cell l i nes.
161, 162, 194, 195

Sei and col leagues have demonstrated the presence of cal ci um channel s simi lar to those found i n
skel etal muscl e i n the B l ymphocyte. Enhanced intracel l ul ar cal ci um l evel s are found i n
lymphocytes from cel l li nes wi th mutated ryanodine genes upon exposure to caffei ne or
chlorocresol .
196, 197

The phenotype and genotype correl ation studi es are very l i mi ted in MH because it i s diffi cult to
establ i sh correl ati on between the mutati on and contractil e data because of vari abl es among
di agnosti c laboratori es and because of the fact that cli nical epi sodes of MHS that ful fi ll all criteri a
are rare as a resul t of successful i ntervention during anestheti c compl i cations. Neverthel ess, the
most severe phenotype as a resul t of RYR1 mutation is central core disease (CCD), characteri zed
by marked hypotoni a and muscl e weakness. Interesti ngl y, the majori ty of RYR1 mutati ons causi ng
CCD are located i n the transmembrane region of the protei n, suggesti ng a criti cal rol e of thi s
region in Ca
+
regulation. In additi on, the mutati ons causi ng both MH and CCD (R163C, R2163H,
and R2435H) exhi bit more severe caffei ne and halothane responses than those associated wi th MH
al one.
198

Geneti c studies have identi fi ed l inkage of fi ve other chromosomal regi ons to MH, suggesti ng
geneti c heterogenei ty of the di sorder. However, onl y a si ngl e gene has been i denti fi ed to date.
The Arg1086Hi s mutation was identi fi ed in the CACNL1A3 gene of a l arge French MH fami l y.
CACNL1A3 codes for the skeletal muscle L-type cal ci um channel' s alpha1 subuni t.
199
Thi s vol tage-
dependant channel i s al so call ed the dihydropyri dine receptor (DHPR) and serves as a vol tage
sensor for RYR1. Mutati onal screeni ng studi es, however, i ndi cate that onl y 1% of MHS fami l i es
exhi bit mutati ons in the DHPR.
There have been several reports of di scordance between segregation of mutations i denti fied in
RYR1 and the outcome of the in vi tro contracture test for MH.
158, 159, 200
Thi s discordance is
rel ati vely rare and the reason for i t i s unknown. However, a study i n swi ne has demonstrated that
there i s an excell ent correlation between the contracture test outcome and the genetic
suscepti bi l ity for MH. In human fami li es, speci fi c ryanodi ne mutati ons usual ly correl ate extremely
well with the in vi tro contracture test result. Hence, in a particular fami ly the presence of the
famil i al MH mutation predi cts MH suscepti bi li ty.
201

The Fut ur e of Resear ch i n Mal i gnant Hyper t her mi a
Whil e mol ecul ar geneti cs has domi nated the research i n MH i n recent years, a deeper
understandi ng of the physi ol ogy and bi ochemi stry of the interpl ay among RYR1, the Na
+
channel ,
and fatty acid metaboli sm stil l i s needed. DNA-based l inkage anal yses are no l onger pursued to
the same extent as i n the early 1990s. Instead, the focus of recent molecul ar geneti c studies has
been on i denti fyi ng new mutati ons in RYR1. Further l i nkage studies are necessary to i dentify other
chromosomes l i nked to MH. Mol ecular geneti c approaches may be the onl y hope for a di agnosti c
bl ood test. However, at present molecul ar geneti c testing wi ll be most useful for the 50% of MH
suscepti bl e fami l ies i n whi ch a speci fi c proven causati ve mutati on i s known to exist.
Summar y
Mutations associated wi th skeletal muscle control of i ntracel l ul ar cal ci um concentrati on are causal
for most cases of cl assi c MH. Any one of at least si x di fferent genes may cause MH, although the
exact protei ns remai n to be identi fi ed i n some cases. Mutati ons have been i dentified i n RYR1 and
i n the di hydropyri di ne receptor gene. A vari ety of poorl y understood biochemi cal and/or gene
expressi on factors infl uence the cl i ni cal manifestati ons of MH. For example, mutati ons i n a sodi um
channel subunit may be associ ated with some si gns of MH, but thi s cl i ni cal MH requi res the
expressi on of other factors also. A di sturbance i n fatty acid metabolism, as a secondary effect,
al ters the functi on of several organel l es and can lead to a hypersensiti ve RYR1 response to
halothane and al tered Na
+
channel subuni t expression in skel etal muscl e. The MH syndrome i s the
resul t of a compl ex and poorl y understood i nteraction among several systems in skel etal muscl e.
OTHER INHERITED DISORDERS
Inheri ted di seases affect every bodi l y organ and every physi ol ogi c and bi ochemical process. Some
are mi l d and all ow a relati vel y normal l ife span, whereas others are incompatibl e wi th extrauteri ne
existence even for a few days. Adding to the compl exi ty i s a natural vari abil i ty of genetic
penetrance and expressivity even i n a si ngl e fami l y. All of these di sorders have as a common
feature an abnormali ty i n one or more genes that affects the function of one or more enzymes.
The metabol i c basis of i nheri ted di seases i s the subject of several well -known books,
202
which may
be consul ted for an i n-depth appreci ati on of our state of knowl edge of many of these disorders.
DISORDERS OF PLASMA CHOLINESTERASE
Pl asma choli nesterase, pseudochol inesterase, or nonspeci fi c chol inesterase i s an enzyme with a
mol ecul ar wei ght of 320,000 and a tetrahedral structure. It i s found i n pl asma and most ti ssue but
not i n red bl ood cel l s. Pseudocholi nesterase degrades acetyl chol i ne released at the neuromuscul ar
juncti on, as well as other choli ne and ali phatic esters.
203
The hal f-li fe of pseudochol inesterase has
been esti mated to be 8 to

16 hours. It i s very stabl e in serum sampl es and can be stored for l ong periods of time at 20C
with li ttl e or no activity loss. Chol inesterase i s synthesi zed in the l i ver. Therefore, decreased
pl asma chol i nesterase acti vi ty occurs i n advanced cases of hepatocell ul ar dysfuncti on.
Inheri ted vari ants of pseudochol inesterase are of i nterest to the anesthesi ol ogi st because the
duration of action of succi nylchol ine, mi vacurium, and (in some cases) ester-li nked local
anesthetics, as well as the toxici ty of cocai ne,
204
is a function of the acti vi ty of thi s enzyme
system. Prolonged apnea after succinyl choli ne, or mi vacurium, admini stration occurs i n pati ents
who have very l ow absol ute acti vi ty of pseudochol inesterase or have enzyme variants.
205, 206
These
patients otherwise have no symptoms.
Many physi ol ogi c, pharmacol ogic, and pathol ogi c factors can ei ther increase or decrease the
acti vi ty of thi s enzyme to a significant extent. However, it i s onl y when there i s a >75% decrease
in the l evel s of the normal pseudochol inesterase that there i s cl i ni cal ly evi dent prol ongati on of
succi nyl choli ne activity (see l ater). Tabl e 20-3 li sts some of the causes for vari ati on i n pl asma
P.547
TABLE 20-3 Some Causes of Changes in Cholinesterase Activity
INHERITED
Choli nesterase vari ants that may lead to decreased or i ncreased acti vi ty (e.g., si l ent
gene or C5 vari ant)
PHYSIOLOGIC
Decreases in l ast tri mester of pregnancy
Reduced acti vi ty of the newborn
Succi nyl chol i ne- Rel at ed Apnea
Succi nylchol i ne i s hydrolyzed by a two-step process, first to succi nylmonochol ine and then to
succi ni c aci d. It has been esti mated that onl y about 5% of the injected drug reaches the end-pl ate
regi on because of a combi nation of both hydrolysi s and di ffusi on from the plasma. Urinary
excreti on and protei n bi ndi ng pl ay uni mportant rol es in the di spositi on of the drug when plasma
chol i nesterase acti vi ty is normal . The rate of metaboli sm determines the durati on of acti on of
succi nyl choli ne.
A vari ety of assay procedures are avai l abl e for pseudochol inesterase activity. However, most
invol ve the reacti on of a thi ocholi ne (e.g., butyryl thiocholi ne) with serum or pl asma contai ni ng
chol i nesterase. The reacti on product i s coupl ed wi th 5,5 -di thi obi s(2-ni trobenzoic aci d) and forms
ACQUIRED DECREASES
Li ver di seases
Carcinoma
Debi l i tati ng diseases
Col l agen di seases
Uremia
Mal nutriti on
Myxedema
ACQUIRED INCREASES
Obesity
Alcohol i sm
Thyrotoxicosi s
Nephrosi s
Psori asi s
Electroshock therapy
DRUGS RELATED TO DISEASES
Neosti gmi ne
Pyri dosti gmi ne
Chl orpromazi ne
Echothi ophate i odi de
Cyclophosphami de
Monoami ne oxi dase inhi bi tors
Pancuroni um
Contracepti ves
Organophosphorus i nsecti ci des
Hexaflurenium
OTHER CAUSES OF DECREASED ACTIVITY
Pl asmapheresi s
Extracorporeal ci rculation
Tetanus
Radi ati on therapy
Burns
The signi ficance of these factors depends on the severi ty of di sease, drug dosage, and
i ndi vi dual vari ati on.
Adapted from Whittaker M: Pl asma chol i nesterase vari ants and the anestheti st.
Anaesthesia 35:174, 1980.
a colored product that can be foll owed spectrophotometrical l y. The use of benzoyl chol i ne, a
specific substrate for pl asma chol i nesterase, avoids contaminati on of the assay for pl asma
chol i nesterase by the esterase in red bl ood cel l s that i s rel eased when hemol ysis occurs.
Kalow and Genest were the first to show that quali tati ve as well as quanti tati ve differences i n the
pseudocholi nesterase enzyme determi ne the durati on of succi nyl chol i ne apnea.
207
Kal ow found
that i n certain persons di splayi ng succi nyl choli ne sensi tivity, the l ocal anestheti c dibucai ne
(Nupercai ne) i nhi bi ted the hydrolysi s of a benzylchol i ne substrate l ess than it i nhibi ted the
reacti on in those displ aying a normal response to succinyl chol i ne. Thus, thi s atypical phenotype
may be referred to as di bucai ne-resistant. The percentage i nhibi ti on of the reacti on was termed
the di bucai ne number. It was found to be constant for a person and di d not depend on the
concentration of the enzyme.
A di sconti nuous di stri buti on of di bucaine numbers suggested an inheritance pattern based on
al terati on at a si ngl e gene l ocus (Tabl e 20-4). Those wi th di bucai ne numbers i n the range of 80
woul d be homozygous normal wi th a normal response to succi nyl chol i ne, those wi th dibucai ne
numbers of 20 woul d be homozygous atypical wi th a marked prol ongation of succi nylchol ine
acti vi ty, and those wi th di bucaine numbers in the 60 range woul d be heterozygous and, i n general ,
have a normal response to succi nylchol ine.
Over the years, two other major allel ic vari ants were di scovered. In one case, the si l ent gene, the
enzyme i s not produced. In the other, there is a differenti al i nhi biti on of choli nesterase acti vi ty by
fl uori de.
208
In those wi th prol onged durati on of succi nylchol ine acti vi ty wi th thi s genotype, fl uori de
ion i nhi bits the i n vi tro hydrolysi s of substrate by the enzyme less than i t does i n normal s. Thus
TABLE 20-4 Biochemical Characteristics of Some Cholinesterase Variants
GENOTYPE ACTIVITY DIBUCAINE
#
FLUORIDE# CHLORIDE# SUCCINYLCHOLINE#
EuEu 677
1860
7886 5565 112 8998
EaEa 140525 1826 1632 4658 419
EuEa 285
1008
5170 3855 1534 5178
EuEf 579900 7480 4748 1430 8791
EfEa 475661 4959 2533 3136 5659
EfEs 351 63 26 25 81
Eu = normal enzyme gene; Ea = atypical enzyme gene; Ef = fl uori de-resistant gene; Es = si l ent
gene.
Reproduced with permission from Vi by-Mogensen J: Succi nyl chol ine neuromuscul ar bl ockade i n
subjects homozygous for atypi cal pl asma chol i nesterase. Anesthesi ol ogy 55:429, 1981.
the phenotype may be referred to as fl uori de resi stant. A fl uori de number, si mi l ar to a di bucai ne
number, is thereby created. Other vari ants exist, i ncludi ng the K variant, whi ch can be i denti fied
onl y by geneti c anal ysi s, not by the current tests of substrate degradati on.
When there i s a questi on of succinyl chol i ne sensi ti vi ty, the absolute acti vi ty of
pseudochol i nesterase shoul d be determi ned as wel l as the di bucai ne and fl uori de numbers. In
some cases, because of biol ogi c vari abi l i ty or unusual combinati ons of genotype (e.g., combi nati on
of atypi cal and fluoride genes), it i s hel pful to use other i nhi bitors of the chol inesterase reacti on
i n genotypi ng the pati ent. Bromi de, urea, sodi um chl ori de, and succinyl chol i ne have been used to
di sti ngui sh the various genotypes (see Tabl e 20-4).
Mol ecular genetic techni ques have been successfully appl i ed to pseudochol i nesterase vari ants. La
Du' s l aboratory

has i denti fi ed a poi nt mutati on i n the gene for human serum chol inesterase in whi ch a nucl eoti de
change leads to an al terati on of a si ngl e ami no aci d (adenine to guani ne) in the protei n.
209
Thi s
change apparentl y al ters the affi ni ty of atypi cal chol inesterase for chol ine esters. Other base pai r
al terati ons account for other atypi cal variants, i ncludi ng the K and J si l ent gene variants, which,
whi l e common, produce li ttl e to no cl i ni cal prol ongati on of succinyl chol i ne action (Tabl e 20-5).
210

The i dentificati on of causati ve mutations offers the prospect that more accurate and preci se
di agnosti c tests for atypical pseudocholi nesterase vari ants wil l exi st in the future.
The frequenci es of occurrence of the vari ous genes vary to some extent wi th ethni c background.
For example, South Afri can blacks
211
and Eski mo popul ati ons have the si l ent gene much more
frequently, pati ents wi th Huntington's chorea are more l i kely to have an Ef gene (fl uori de-
resistant) than are normal controls, and Israel i s have a hi gher chance of havi ng an atypi cal
genotype than Americans. In European studi es, the approxi mate percentages in the popul ati on of
the genotypes are as follows: EuEu (96%), EuEa (2.5%), EuEf or EuEs (0.3%), EaEf (0.005%),
EaEa (0.05%), and EfEf or EfEs (0.006%).
212

Patients homozygous for atypi cal , fl uori de, or si l ent genes as wel l as those wi th the combi nati on
P.548
TABLE 20-5 Structural Changes of BCHE Variants
Fl uori de-2 117 GLYFrame shi ft
Atypical 70ASPGLY
Silent 117 GLYFrame shi ft
Fl uori de-1 243 THRMET
Fl uori de-2 390 GLYVAL
K Vari ant 539 ALATHR
H Vari ant 142 VALMET
J Variant 497 GLUVAL
of atypi cal wi th fluori de, atypi cal wi th si lent genes, or fluori de wi th sil ent genes shoul d wear
safety i dentificati on bracel ets indi cati ng that succi nyl choli ne administration wil l l ead to prol onged
apnea. Rel ati ves shoul d be tested as wel l. There are onl y a few chol i nesterase research units that
investi gate fami l i es and interpret results: Whittaker' s i n Great Britain, Hanel and Viby-Mogensen' s
in Denmark, and La Du' s i n the Uni ted States (Uni versi ty of Mi chi gan, Department of
Anesthesi ol ogy).
Cl i ni cal I mpl i cat i ons of P seudochol i nest er ase Abnor mal i t i es
Important questi ons for the anesthesiol ogi st are: Which patients are at ri sk for development of an
abnormal response to succi nyl chol i ne? What are the cli ni cal characteri sti cs of thi s response? and
What are the treatment opti ons?
Significant prol ongati on of succi nyl chol i ne' s effects occurs i n the foll owing genotypes: EaEa, EfEf,
EaEs, EfEa, and EsEs. The more common situations in which homozygote normals and
heterozygotes are at ri sk are as foll ows: patients who have been receiving echothiophate eyedrops
(up to 2 weeks after therapy is di sconti nued), pati ents who are undergoing pl asmapheresi s
patients with severe l iver di sease, and patients (particul arl y heterozygotes) who have received
succi nyl choli ne after reversal of nondepol ari zi ng bl ockade wi th neosti gmi ne.
Vi by-Mogensen
205, 206
has studi ed the questi on of pl asma chol inesterase apnea in detai l. Hi s
chol i nesterase uni t found that 6.2% of pati ents who di spl ayed apnea for 50 to 250 mi nutes after a
usual dose of succi nyl chol i ne had an acqui red defici ency of pl asma chol i nesterase. He then
studi ed 70 pati ents who were genotypi cal ly normal for pseudochol i nesterase and admi ni stered 1.0
mg/kg of succinyl chol i ne duri ng a 50% ni trous oxideoxygen1% halothane anestheti c and
fol l owed the depressi on and return of thumb twitch. He found that there was i ndeed a relationshi p
between the durati on of apnea, the return of a ful l twi tch response, and pl asma chol inesterase
acti vi ty. However, onl y moderate prol ongati on of apnea was found when chol i nesterase was
depressed by as much as 70%. Apnea i s si gni fi cantl y prol onged only wi th extreme depression of
In a second study with a si mi l ar protocol, he found that heterozygotes having one normal gene
(e.g., EuEa, EuEf) had a normal response to succi nylchol ine, i ncl udi ng typi cal fasci cul ati ons and a
depol ari zi ng type of bl ock wi th trai n-of-four sti mul ati ons.
205
However, heterozygotes without the
usual gene (e.g., EaEf) had a prol onged response to succinyl chol i ne, with apnea lasti ng as l ong as
24 mi nutes. Most showed typical fasci culations. Fade wi th trai n-of-four sti mul ati ons was the rule.
It shoul d be noted that others have found that heterozygotes wi th one normal gene di spl ay a
prolonged response to succi nylchol ine under certai n condi tions. About 1 in 500 heterozygotes i s
prone to such a response.
Apnea lasts from 120 minutes to more than 300 minutes in homozygous atypi cal pati ents (EaEa)
when they are given succinyl chol i ne.
206
The other cl ass of patients who regul arl y displ ay
prolonged apnea after succi nyl choli ne administrati on comprises pati ents who are homozygous for
the si l ent gene.
Tr eat ment of Succi nyl chol i ne Apnea
The safest course of treatment after the patient fails to breathe within 10 to 15 mi nutes after
succi nyl choli ne admini stration is to conti nue mechani cal venti l ati on until adequate muscle tone
has returned. Two uni ts of blood may contai n adequate amounts of pseudochol i nesterase to
hydrol yze

the succi nylchol ine,
213
al though bl ood transfusi on i s not recommended for routi ne treatment of
succi nyl choli ne-induced apnea.
The use of chol inesterase i nhi bi tors in treati ng succi nyl chol ine apnea is controversi al . When gi ven
al ong wi th bl ood or pl asma, the i mprovement i s rapi d and l asti ng. If they are admini stered al one
before there i s evi dence of fade wi th trai n-of-four sti mul ati on, there may be a transient
improvement foll owed by i ntensi fi cation of the neuromuscular block. Remember that neosti gmi ne
P.549
i nhi bi ts the degradati on of succi nyl choli ne by pl asma chol i nesterase. The best chance for reversal
of succi nyl chol ine-rel ated apnea in these si tuati ons occurs when no more than 0.03 mg/kg of
neostigmine i s given 90 to 120 minutes after succi nylchol ine when a nondepol ari zi ng type of
bl ockade i s present.
C5 Var i ant
An i soenzyme of pseudochol inesterase has been demonstrated whereby the hydrolysi s of
succi nyl choli ne is i ncreased, and therefore the duration of apnea is decreased after succi nylchol ine
admi ni strati on. The gene does not appear to be an al l el e of the Eu and Ea gene and i s found
infrequently i n the population.
214

P l asma Chol i nest er ase Abnor mal i t i es and t he Met abol i sm of
Local Anest het i cs
Although the ester-li nked local anestheti cs (e.g., procai ne, tetracai ne, 2-chloroprocai ne) are
metabol i zed by pseudochol i nesterase, prol ongation of block and/or cl inical toxi city of these l ocal
anesthetics i n homozygous atypi cal pati ents has rarel y been documented.
215, 216
Jatl ow et al have
shown del ayed hydrolysi s of cocai ne in vi tro wi th pl asma from homozygote atypi cal s.
217
They
theorized that such persons may be at risk for toxi c reacti on from normal doses of cocai ne.
Mivacurium Disposition and Plasma Cholinesterase. The short duration of action of
mi vacuri um i s because of its degradati on by pseudochol inesterase. Al though i t i s theoreti cal l y
possi bl e to reverse neuromuscular block i n pati ents with atypi cal pseudochol i nesterase who
recei ve mi vacuri um, the few cases so far reported i ndi cate that anti chol inesterase agents may not
be effecti ve under such si tuati ons. These indi vi duals shoul d be managed in a manner si mi l ar to
patients with the atypi cal enzyme who received succi nylchol i ne.
218
When abnormal pl asma
chol i nesterase does not metabol i ze mivacuri um as rapi dl y as expected, the neuromuscul ar bl ocker
i s cl eared by the ki dneys as i s curare. The most rapi d adequate recovery from mi vacuri um-induced
bl ock wi l l be obtai ned when the pl asma concentrati on of mivacuri um has decreased to the l evel at
whi ch three to four responses to a trai n-of-four sti mul ati on to the ul nar nerve are pal pable. Then
neostigmine shoul d i nduce recovery as i t woul d from blocker that was expected to be long acti ng.
THE PORPHYRIAS
Al l the porphyri as resul t from a defect in heme synthesi s. The heme pigments are tetrapyrrol es
that are the essential el ements in hemogl obin, myogl obi n, and the cytochromes, that is,
compounds that are i nvol ved i n the transport of oxygen, acti vation of oxygen, and the el ectron
transport chai n. Cytochrome P-450 i s a hemoprotei n i nti matel y i nvol ved in the conversi on of li pi d-
solubl e nonpolar drugs to sol ubl e pol ar compounds that may be excreted i n the uri ne.
A compl ete defi ci ency of enzymes that are involved in heme synthesis i s i ncompati ble wi th l ife.
However, a parti al defici ency may lead to the accumul ati on of one or more of the molecul ar
intermedi ates in heme production. Such an accumul ati on of precursors i s responsi bl e for the
cl i ni cal mani festations of the porphyri as (in an as-yet unexplai ned manner).
The rate-li mi ting step i n heme synthesis i s the conjugation of succi nyl -CoA wi th gl ycine to form D-
aminol evuli ni c aci d (the enzyme is aminol evuli nic acid synthetase). In the porphyrias, there i s a
parti al defi ci ency of enzymes subsequent to this i ni tial step, whi ch results i n a sti mulation of this
reacti on to form ami nol evul i ni c aci d. The resul t is overproducti on of i ntermedi ate products before
the defi ci ent step (Fi gs. 20-6 and 20-7).
The porphyri as general ly mani fest after puberty. Inheri tance i s through an autosomal domi nant
pattern, but congeni tal erythropoi eti c porphyri a is i nheri ted as an autosomal recessi ve pattern.
A functi onal cl assi ficati on for the anesthesi ologi st i s based on a di vi si on of the porphyrias i nto
i nduci bl e and noni nduci bl e forms. The i nduci bl e porphyri as are those i n whi ch the acute symptoms
are preci pitated on drug exposure (Tabl e 20-6).
219
These forms are acute i ntermi ttent porphyri a,
vari egate porphyri a, and heredi tary coproporphyri a. These porphyri as cause an acute neurologi c
syndrome and are therefore of i nterest to the anesthesi ol ogi st. Cutaneous mani festations, wi th
parti cul ar sensi ti vi ty to ul traviol et l i ght exhibi ted by ski n fragi li ty and bleedi ng, are the chi ef
features of the other porphyrias. About 80% of pati ents wi th variegate porphyria are
photosensi tive. Some pati ents wi th heredi tary coproporphyri a also may have ski n l esi ons. The
porphyri as are very diffi cult to diagnose i n the l atent phase of the disorder. Di rect assay of the
intermedi ates themselves may be used i n the acute state to measure the elevated level s of the
heme i ntermedi ates. The i nduci bl e porphyri as are seen as a neurol ogi c syndrome wi th a vari ety of
presentations.
FIGURE 20-6. Bi osynthesi s of heme and sites of defects i n certai n porphyrias. (ALA =
aminol evuli ni c aci d; PBG = porphobil i nogen; URO = uroporphyri nogen; COPRO =
coproporphyri nogen; PROTO = protoporphyri nogen; PRO = protoporphyri n.) In i ntermi ttent
acute porphyri a, there i s a partial defi ci ency of the enzyme at si te 1. In heredi tary
coproporphyri a, there i s an enzyme defi ci ency at si te 2. In vari egate porphyri a, the enzyme
problem i s at site 3. In porphyri a cutanea tarda, there i s a defici ency at site 4. (Repri nted
with permission from Mees DL, Frederi ckson EL: Anesthesi a and the porphyri as. South Med J
68:29, 1975.)
FIGURE 20-7. The glycogengl ucoselactate pathway.
The central , peri pheral , and autonomi c nervous systems may be involved i n the porphyrias. A
frequent mani festati on

is col i cky abdomi nal pai n, often wi th nausea and vomi ting, whi ch may suggest the di agnosi s of
acute abdomen, l eadi ng to expl oratory laparotomy. Other symptoms are psychi atri c di sturbance,
quadri plegi a, hemipl egi a, al terati ons of consci ousness, and pain. Hyponatremi a and hypokal emi a
may resul t from vomiti ng duri ng the acute attack or may be rel ated to hypothal ami c di sturbance.
Death may result from paral ysis of the respi ratory muscl es. The cause of these changes is
unknown; they may be rel ated to metabol i tes of the i ntermedi ates or result from deficiency of the
heme pigment i n the nerve cell i tsel f.
Because the porphyri as are unusual di sorders, there i s l i mi ted experi ence wi th the cl i ni cal use of
many anesthetic drugs. In vi tro studi es suggest that certai n anesthetics or anesthetic adjuvants
may be contrai ndi cated, but suffici ent cli ni cal experi ence is l acking (see l ater).
220

Management of P at i ent s wi t h P or phyr i a
It i s important to recogni ze porphyri a i n pati ents who are schedul ed for surgery. It may become
apparent through a careful fami l y history and personal hi story rel ated to anesthesi a. A careful
hi story in the pati ent wi th porphyri a shoul d concentrate on neurol ogic background. Laboratory
work shoul d i nclude electrolyte and blood urea ni trogen l evels. Physi cal exami nati on includes
inspecti on of cutaneous l esi ons over the body.
In the anestheti c management of patients with porphyri a, the chi ef concern i s to avoid the
administrati on of drugs that can i nduce a cri sis; the drugs that i nduce cytochrome enzyme
producti on can tri gger the syndrome. Chi ef among those are the barbi turates; therefore, all
barbiturates are contrai ndi cated i n porphyria. Ethyl alcohol, nonbarbi turate sedatives, hydantoin
anti convul sants, and a vari ety of other drugs also can induce a cri sis (see Tabl e 20-5). Other
factors, such as fasting, i nfecti on, and estrogens, may al so preci pitate porphyri a. Diagnosis can be
especial ly diffi cult because attacks may occur at a variabl e ti me peri od after drug admini stration
TABLE 20-6 Drugs Known to Precipitate Porphyria
SEDATIVES
Barbiturates
Hypnotics such as chl ordi azepoxi de, gl utethi mi de, di azepam
ANALGESICS
Pentazocai ne, anti pyrine, aminopyri di ne
Li docai ne
ANTICONVULSANTS
Phenytoin, methsuximide
ANTIBIOTICS
Sul fonami des, chl orampheni col
STEROIDS
Estrogens, progesterones
HYPOGLYCEMIC SULFONYLUREAS
Tol butamide, chl orproprami de
TOXINS
Lead, ethanol
MISCELLANEOUS
Ergot preparati ons
Amphetami nes
Methyl dopa
P.550
or they may not occur at al l despi te admi ni strati on of i nduci ng drugs.
Propofol appears to be a safe inducti on agent.
221
Ni trous oxi de, muscl e relaxants, and opioi ds are
unequivocall y safe drugs. Experi ence wi th other inhalation agents and reversal agents has been
favorabl e, but in vi tro studies suggest that they mi ght exacerbate a cri si s.
Most experts have advi sed that regi onal techni ques be avoi ded to prevent confusion shoul d
neurol ogi c si gns devel op after operati on. However, reports of uneventful epi dural anesthesi a i n
the parturi ent with acute intermi ttent porphyri a may i ndi cate that this techni que can be safel y
performed in these pati ents.
222
Bl istered or fragi le skin areas shoul d be padded and gi ven speci al
attenti on. Gl ucose i nfusi on shoul d be started because starvati on may i nduce an attack.
The acute attack shoul d be treated wi th gl ucose i nfusi on, and correcti on of hyponatremi a,
hypokal emi a, and hypomagnesemi a. Pyri doxi ne and hemati n al so have been val uabl e i n some
cases. Supportive therapy for respi ratory i nsuffici ency and treatment of pai n is al so suggested.
GLYCOGEN STORAGE DISEASES
The metabol i c pathways i nvol vi ng gl ucose degradati on to l actate, glucose conversi on to gl ycogen,
and the breakdown of gl ycogen to gl ucose are important to the whol e body bi ochemi stry as wel l as
to cell ul ar physi ol ogy i n general . The enzymati c steps i nvol ved i n gl ucose metabol i sm have been
studi ed intensivel y si nce the earl i est days of modern bi ochemi stry. The glycogen storage diseases
are inherited and are characteri zed by dysfuncti on of one of the many enzymes i nvol ved i n gl ucose
metabol i sm. To date, several di fferent gl ycogen storage di sorders, each based on the defici ency of
an enzyme i nvol ved i n glucose metabol ism, have been identi fi ed. Some of the glycogen storage
di seases are incompatibl e with li fe past i nfancy, whereas others are not. Anesthetic experi ence
with these diseases i s li mi ted, but several particular problems have been i denti fied.
223

Hypogl ycemi a. Hypogl ycemia i s a constant ri sk i n these patients. It resul ts from fai l ure to
metabol i ze stored glycogen to gl ucose.
Aci dosi s. Thi s is rel ated to fat and protei n metabol i sm because gl ycogen stores are not
metaboli cal l y avai l abl e.
Cardi ac and Hepatic Dysfuncti on. Thi s is secondary to destructi on and di splacement of
normal tissue by the accumul ated gl ycogen.
Detai l ed descri pti ons of gl ucose metabol i sm are gi ven el sewhere. Fi gure 20-7 outl i nes the
gl ycogengl ucoselactate pathway. There are, of course, mul ti pl e enzymatic steps to reach each
of the end poi nts.
Def ect s i n Gl ucose Met abol i sm
Type I ( Von Gi er k e' s Di sease; Gl ucose- 6- phosphat e Def i ci ency) . Inheritance i s
autosomal recessi ve. The prognosis i s moderately good, wi th many patients surviving i nto
adulthood. Short stature and l i ver enl argement are characteri sti c. These pati ents tol erate
fasti ng very poorl y. Hypogl ycemi a, aci dosi s, and convul sions may be a probl em. Prol onged
bl eedi ng has been descri bed. Often, preoperati ve hyperal imentati on i s used to reduce l iver
gl ycogen stores. Portacaval shunt has been performed wi th l i mited success i n these patients.
Type I I ( P ompe' s Di seas e) . Inheritance of thi s disease i s consi dered to be autosomal
recessi ve. Thi s i s a devastati ng di sease wi th a very poor prognosi s. There is a defi ciency of
lysosomal aci d mal tase wi th an accumul ation of glycogen in the l ysosomes, especi al l y i n the
heart, l iver, muscle, and central nervous system. Cardi ac compromise resulti ng from outfl ow
obstruction of hypertrophi ed muscl e occurs, as does congestive heart fai lure secondary to
myocardial disruption by gl ycogen stores. A case report has been descri bed i n whi ch
halothane was used wi thout i nci dent.
224
In another case, halothane l ed to prompt
P.551
hypotensi on and intractabl e cardi ac fail ure.
225
A l ate-onset form wi th a better prognosis has
been descri bed as wel l .
Type I I I ( For bes' Di s ease; Debr anchi ng Enzyme Def i ci ency) . Inheritance of thi s disease
is autosomal recessive.
Type I V ( Ander sen' s Di seas e; Br anchi ng Enzyme Def i ci ency) . Thi s is a very rare
di sorder, characteri zed by a defect i n the synthesi s of normal gl ycogen. Ci rrhosi s of the l i ver
and death are characteristi c before a patient reaches age 2 years.
Type V ( McAr dl e' s Di s eas e; Mus cl e P hosphor yl as e Def i ci ency) . An autosomal recessi ve
i nheri tance pattern and crampi ng wi th exerci se are characteristic of thi s disorder. Skel etal
muscle is not able to mobi li ze gl ycogen stores, the usual fuel i n muscl e, for sustai ned
exercise. Myogl obi nuri a occurs wi th overexertion in these pati ents and may occur after
succi nyl choli ne admini stration as wel l . Muscl e atrophy occurs i n adul thood. Tourni quets
should not be used i n these pati ents, and frequent automated bl ood pressure readi ngs
shoul d be done wi th cauti on. Severe rhabdomyol ysi s has been observed after bypass for
cardi ac surgery.
226

Type VI ( Her s' Di sease; Reduced Hepat i c P hosphor yl ase) . A decreased abi l i ty to
mobi l i ze hepati c gl ycogen occurs in thi s disorder, wi th normal muscl e and cardiac
physi ol ogy.
Type VI I ( Muscl e P hos phof r uct ok i nase Def i ci ency) . Thi s disorder i s si mi l ar to McArdl e's
di sease and i s characterized by muscle cramping. The same enzymati c defect i n erythrocytes
leads to chronic hemolysi s.
Type VI I I ( Def i ci ent Hepat i c P hosphor yl ase K i nase) . Thi s resul ts from a defici ency i n
the regulatory enzyme control li ng the phosphoryl ase enzyme. A case report has descri bed
fever and aci dosi s during succinyl chol i ne, hal othane, and ketami ne anesthesi a.
227
Liver
transpl antati on has been used wi th success i n the more severe forms of the gl ycogen storage
di seases.
Def ect s of Fr uct ose Met abol i sm
Fructose-6-phosphate i s converted to fructose-1,6-di phosphate during gl ucose breakdown to
lactate. Conversel y, fructose-1,6-di phosphate is converted to fructose-6-phosphate by the enzyme
fructose-1,6-di phosphatase during gl uconeogenesi s.
In fructose-1,6-di phosphatase defi ci ency, there i s an i nabi li ty to produce gl ycogen from l actate.
Hypoglycemia may resul t. Acidosis has been reported because l actate i s formed preferenti al l y. In
errors of fructose metabol ism, li ke those of gl ucose metabol i sm, hypogl ycemi a and aci dosi s pose
the greatest threats to the pati ent.
228

THE MUCOPOLYSACCHARIDOSES
The mucopolysacchari des are pol ysacchari des that yiel d mixtures of monosacchari des and deri ved
products after hydrol ysi s. The mucopolysacchari des contain N-acetylated hexosamine in a
characteri sti c repeati ng unit. For exampl e, chondroiti n sul fate A i s a monosacchari de of d-
gl ucuroni c aci d and N-acetyl d-gal actosami ne 4-sulfate. Monopol ysacchari des are found in all cel ls.
The mucopolysacchari doses are geneticall y determi ned di seases in whi ch mucopol ysacchari des are
stored i n ti ssues i n abnormal quanti ti es and excreted in l arge amounts i n the urine. The disorders
resul t from a defici ency of a speci fi c l ysosomal enzyme that i s requi red to break down these
compounds. As a resul t, mucopol ysaccharides accumul ate in tissues, produci ng specific cl i ni cal
mani festati ons. There are seven basi c forms of mucopol ysacchari doses and several subgroups.
Most of the mucopolysaccharidoses are inherited as autosomal recessive trai ts. Al l the
mucopol ysacchari doses are progressi ve, and pati ents characteri sti cal l y are marked by coarse
faci al features (gargoyl ism); associ ated skel etal abnormali ties such as l umbar l ordosi s, sti ff joi nts,
chest deformi ty, dwarfi ng, and hypopl asi a of the odontoi d process (Morqui o' s syndrome); corneal
opaci ties; li mitati on of joi nt motion; and heart, l iver, and spl een enl argement resulti ng from
mucopol ysacchari de accumul ati on. Mental deterioration al so occurs frequentl y. Some cases have
been successful l y treated by bone marrow transplantati on at a young age.
The Hunter and Hurl er syndromes are the best known variants of the mucopol ysaccharidoses. The
Hunter syndrome i s an X-li nked recessi ve disease.
229
Respi ratory i nfecti on and heart disease, both
val vul ar and i schemi c, often lead to death when pati ents are young. Pati ents may commonl y
present for repair of inguinal hernia or ear, nose, and throat or orthopaedi c procedures. The thi ck,
soft tissues and the copious, thi ck secreti ons make perioperati ve and i ntraoperati ve airway
management a particul ar probl em. In Leroy and Crocker' s series, minor di ffi cul ti es occurred wi th
anesthesia i n pati ents i n more than one-third of 60 operati ons.
229
The use of a laryngeal mask
ai rway may not be successful .
230
Postoperati ve respi ratory obstructi on was noted i n several cases.
Because of the underl yi ng heart disease, these pati ents shoul d have electrocardiograms and
echocardi ographic tests performed before surgery.
Mucopolysacchari dosis IV (Morqui o' s syndrome) i s associ ated wi th perhaps the most significant
skel etal deformiti es. In additi on to cardi ovascul ar disorders and respi ratory i nsuffici ency from
marked chest wal l deformi ty, acute, subacute, or chroni c myelopathy i s extremel y common. Thi s i s
secondary to severe hypopl asi a or absence of the odontoi d process of the

second cervi cal vertebra. In anesthesia care, the head shoul d be positi oned careful l y and
precauti ons, such as avoi dance of succi nylchol ine, shoul d be taken with pati ents wi th spinal cord
compromise.
OSTEOGENESIS IMPERFECTA
Osteogenesis i mperfecta i s seen i n approxi matel y 1 of 50,000 births. Most cases are autosomal
domi nant; some are autosomal recessi ve. The pathophysi ologi c characteri sti cs i ncl ude decreased
coll agen synthesi s, which leads to osteoporosi s, joi nt l axi ty, and tendon weakness. The
mani festati ons of osteogenesi s imperfecta are smal l bowed l imbs, large head, short neck, blue
scl erae, otoscl erosi s, joint laxi ty, brittle teeth, and a tendency to fractures. An i ncreased bl eedi ng
tendency i s al so seen resul ti ng from abnormal pl atelet functi on, and aorti c and mi tral valve
dysfuncti on resul ting from di lation of the valve ri ng. Temperature elevation is common, possibl y
because of el evated basal metabol ic rate.
The pati ent shoul d be handl ed careful ly because minor trauma may lead to fractures. Ai rway
management may al so be di ffi cult because of cervi cal spi ne involvement wi th this di sorder.
Patients have short necks, and mandi bul ar fractures frequentl y occur. The patient' s cardiovascular
status shoul d be eval uated, especi all y mi tral and aorti c val ve functi on. Kyphoscoli osi s may al so
occur, wi th pul monary compromi se. Care should be taken to pad the pressure areas, parti cul arl y
for l ong procedures. One shoul d be prepared to obtain platelet transfusi ons. The patient' s core
temperature shoul d be monitored because hyperthermi a (possi bl y resulti ng from central nervous
system dysfunction or excessi ve metabol i sm i n bone) has been reported.
231
Si gns consi stent with
MH have been observed, but contracture tests for MH suscepti bi li ty have not confirmed a constant
association between osteogenesi s imperfecta and MH.
39

RILEY-DAY SYNDROME (FAMILIAL DYSAUTONOMIA)
A defi ci ency of dopami ne -hydroxyl ase that l eads to decreased norepi nephri ne at the nerve
endings i s thought to be the cause of Ri l ey-Day syndrome.
232
This syndrome is inherited in an
autosomal recessi ve fashi on. Patients with Ri l ey-Day syndrome exhi bi t copi ous pul monary
secretions, dysphagi a, denervati on supersensiti vi ty, no sensiti vi ty to pai n, no response to
hi stami ne, and impai rment of temperature control . The impai rment of temperature control l eads to
intermi ttent fevers.
There are numerous probl ems rel ated to anesthesia. These i ncl ude corneal abrasi ons, excess
secreti ons, pneumoni a, l abi l e bl ood pressure secondary to baroreceptor i nsensiti vi ty, a decreased
vascul ar vol ume, possi ble decreased response to hypoxia and hypercarbi a, i ncreased potenti al for
P.552
aspi rati on because of swal l owing probl ems, postural hypotensi on, and sensi tivity to vasopressors.
Anesthesi a management i s wel l summari zed by Axelrod et al .
233
Peri operati ve management shoul d
incl ude diazepam (0.1 to 0.2 mg/kg po) wi thout an opi oi d. Antacid may be gi ven on cal l .
Intraoperative management shoul d i ncl ude temperature monitori ng and careful blood pressure
moni tori ng. Appl icati on of regional techni ques may resul t in more stable cardi ovascul ar function.
Fresh gases shoul d be humi di fi ed. Vasopressors need to be ti trated careful ly because of the
hypersensi tivity response. After operati on secreti ons can be managed wi th chest percussi on
therapy. Postoperati vely, opioids should be used onl y wi th great care to mi ni mi ze the ri sk of
apnea.
234

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> Tabl e of Contents > Secti on IV - Prepari ng for Anesthesi a > Chapter 21 - Del i very Systems for Inhal ed
Anestheti cs
Chapter 21
Delivery Systems for Inhaled Anesthetics
Russell C. Brockwell
J. Jeffrey Andrews
KEY POINTS

P.558
The l ow-pressure ci rcui t (LPC) is the vul nerabl e area of the anesthesi a
workstation because i t is most subject to breakage and l eaks. The LPC i s l ocated
downstream from al l anesthesi a machine safety features except the oxygen
anal yzer, and it i s the porti on of the machi ne that i s mi ssed i f an i nappropri ate
LPC l eak test i s performed. Leaks in the LPC can cause del ivery of a hypoxi c
mi xture and/or pati ent awareness during anesthesi a.
Because most Ohmeda anesthesi a machi nes have a one-way check val ve i n the
LPC, a negative leak test i s requi red to detect leaks i n the LPC. A posi ti ve
pressure l eak test wi l l not detect leaks i n the LPC of most Datex-Ohmeda
products.
Internal vaporizer l eaks can onl y be detected wi th the vapori zer turned on.
Pri or to an anestheti c, the circle system must be checked for l eaks and for fl ow.
To test for l eaks, the ci rcl e system is pressuri zed to 30-cm water pressure, and
the ci rcl e system airway pressure gauge is observed (static test). To check for
appropriate fl ow to rul e out obstructi ons and faul ty val ves, the venti l ator and a
test lung (breathi ng bag) are used (dynami c test).
Some new anesthesia workstation sel f-tests do not detect internal vapori zer
leaks unless each vapori zer is indi vi duall y turned on duri ng the sel f-test.
In the event of a pi pel ine crossover, two acti ons must be taken. The backup
oxygen cyl i nder must be on, and the wal l suppl y sources must be
di sconnected.
Fai l -safe val ves and proporti oning systems hel p mi ni mi ze del i very of a hypoxic
mi xture, but they are not fool proof. Del i very of a hypoxi c mi xture can resul t
from (1) the wrong suppl y gas, (2) a defecti ve or broken safety devi ce, (3)
leaks downstream from the safety devices, (4) i nert gas admi nistrati on, and (5)
di l uti on of the i nspi red oxygen concentrati on by hi gh concentrations of i nhal ed
anesthetics.
Because of desflurane' s low boi l i ng poi nt and hi gh vapor pressure, control l ed
vapori zati on of desflurane requi res speci al sophi sti cated vaporizers such as the
Datex-Ohmeda Tec 6 and the Al adi n cassette vapori zer.
Mi sfi li ng an empty vari abl e bypass vapori zer wi th desflurane coul d theoreticall y
be catastrophi c, resul ting i n deli very of a hypoxic mi xture and a massi ve
overdose of i nhal ed desflurane anesthetic.
Inhaled anesthetics can i nteract with CO
2
absorbents and produce toxi c
compounds. During sevoflurane anesthesi a, compound A can be formed,
parti cul arl y at low fresh gas fl ow rates, and duri ng desfl urane anesthesi a,
carbon monoxi de can be produced, parti cul arl y wi th desiccated absorbents.
Desi ccated strong base absorbents (particularl y Baral yme) can react wi th
sevofl urane, produci ng extremel y hi gh absorber temperatures and combusti ble
decomposi tion products. These in combinati on wi th the oxygen or ni trous oxi de
enri ched envi ronment of the circle system can produce fi res wi thi n the breathing
system.
Anesthesi a venti lators wi th ascendi ng bel l ows (bel l ows that ascend duri ng the
expi ratory phase) are safer than descendi ng bel l ows because di sconnections wil l
readil y mani fest with ascendi ng bel l ows.
Use of the oxygen fl ush val ve duri ng the i nspiratory phase of mechani cal
ventil ati on can cause barotrauma, parti cularly in pedi atri c pati ents.
Ventil ators that use fresh gas decoupl ing technol ogy vi rtual ly eli minate the
possi bi li ty of barotrauma by oxygen fl ushi ng during the i nspi ratory phase
because fresh gas flow and oxygen flush fl ow is di verted to the reservoir
breathi ng bag. However, i f the breathi ng bag has a l eak or is absent, pati ent
awareness under anesthesi a and deli very of a l ower than expected oxygen
concentration coul d occur because of entrai nment of room air.
Wi th newer Ohmeda anestheti c venti lators such as the 7100 and 7900 Smart
Vent, both the pati ent gas and the drive gas are scavenged resul ti ng i n
substantial ly i ncreased vol umes of scavenged gas. Thus, the scavengi ng
systems must be set appropri atel y to accommodate the i ncreased volume or
pol luti on of the operati ng room envi ronment coul d resul t.
INTRODUCTION
The anesthesi a deli very system has evol ved from a simple pneumati c devi ce to a compl ex
integrated computer-control led mul tisystem workstati on (Fi gs. 21-1 and 21-2). The subsystems
within the anesthesi a workstati on function in harmony to safel y deli ver the i nhal ed anestheti c to
the pati ent. These component systems i ncl ude what was formerl y referred to as the anesthesi a
FIGURE 21-1. GE/Datex-Ohmeda S/5 Anesthesi a Del ivery Uni t (ADU) workstati on. Courtesy
GE Medical.
FIGURE 21-2. Drger Narkomed 6000 anesthesi a workstation.
machine-proper (i .e., the pressure-regul ati ng and gas-mi xi ng components), the vaporizers, the
anesthesia breathi ng ci rcui t, the venti l ator, the scavengi ng system, and respi ratory and
physi ol ogi c moni tori ng systems.
For anesthesi a providers to safely use the many features of the anesthesi a workstation, a
thorough understandi ng of i ts operati on i s essential . Because of large-scal e education efforts, in
addi ti on to improvements i n the engi neeri ng and desi gn of the anesthesia workstati on, mal practice
cl ai ms associ ated wi th gas-del i very equi pment are becomi ng less frequent. On the other hand,
because of the continual development of new vol ati l e anestheti cs, aftermarket add-on devi ces, and
even new anesthesi a workstati on features, cl ai ms are not l ikel y to go away completely. In fact, i n
a revi ew of the Ameri can Soci ety of Anesthesi ol ogi sts (ASA) Cl osed Cl ai m database, Capl an
found that al though cl ai ms rel ated to the medi cal gas-del i very system were rare, when they
occurred, they were usuall y severe, often resul ti ng i n death or permanent brai n injury.
1

In thi s chapter the anesthesi a workstati on is examined pi ece by piece. The normal operati on,
functi on, and i ntegration of major anesthesia workstati on subsystems are descri bed. More
importantl y, the potential probl ems and hazards associated wi th the various components of the
anesthesia del i very system, and the appropri ate preoperati ve checks that may help to detect and
prevent such probl ems, are i l lustrated.
ANESTHESIA WORKSTATION STANDARDS AND PRE-USE
PROCEDURES
A few years ago, a fundamental knowl edge of the basic anesthesi a machi ne pneumatics woul d
suffi ce for most anesthesi a provi ders. Today, a detai l ed understandi ng of pneumati cs, el ectronics,
and even computer sci ence i s necessary to ful ly understand the capabil i ti es and compl exiti es of
the anesthesi a workstation. Along wi th the changes i n the compositi on of the anesthesi a
workstation to i ncl ude more compl ex venti lati on systems and integrated monitori ng, recently there
has al so been increasi ng divergence between anesthesi a workstati on desi gns from di fferent
manufacturers. In 1993, a joi nt effort between the ASA and the U.S. Food and Drug Admi ni strati on
(FDA) produced the 1993 FDA Anesthesi a Apparatus Pre-use Checkout Recommendations
(Appendi x A). Thi s pre-use checkli st was versati l e and coul d be appl i ed to most commonly
avai labl e anesthesi a machines equall y well and di d not requi re users to vary the pre-use
procedure si gni fi cantl y from machi ne to machi ne.
Today, because of increasi ng fundamental anesthesia workstati on desi gn vari ati ons, the 1993 FDA
pre-use checkli st may

no longer be appl icabl e to certai n anesthesi a workstations. In such cases, anesthesi a provi ders
must be aware of thi s, and the ori gi nal equi pment manufacturer's recommended pre-use checkli st
should be foll owed. Some of the newer workstati ons even have computer-assi sted sel f-tests that
automati cal l y perform al l or a part of the pre-use machi ne checkout procedure. The avail abi l i ty of
such automated checkout features further adds to the complexi ty of constructing a standardi zed
pre-use anesthesi a machine checkli st such as the one uti l ized in the recent past. Ul ti mately, the
responsi bi l i ty of performi ng adequate pre-use testing of the anesthesi a workstati on fall s to the
individual user. That anesthesi a provi der of record must be aware of whi ch anesthesia workstati on
components are tested by these automated sel f-tests and whi ch ones are not. Because of the
number of machines avai l abl e and the vari abi l ity among their sel f-testi ng procedures, the
fol l owing discussion wil l be l i mi ted to general topi cs rel ated to these systems.
STANDARDS FOR ANESTHESIA MACHINES AND
WORKSTATIONS
Standards for anesthesi a machi nes and workstati ons provi de gui deli nes to manufacturers
regardi ng thei r mi ni mum performance, desi gn characteri sti cs, and safety requi rements. Duri ng the
past two decades, the progression of anesthesi a machine standards has been as fol lows:
P.559
1979: Ameri can Nati onal Standards Insti tute (ANSI) Z79.8-1979,
2

1988: Ameri can Soci ety for Testi ng and Material s (ASTM) F1161-88,
3

1994: ASTM F1161-94
4
(reapproved in 1994 and di sconti nued in 2000),

2000: ASTM F1850-00
5

To compl y wi th the 2000 ASTM F1850-00 standard, newl y manufactured workstati ons must have
moni tors that measure the following parameters: conti nuous breathing system pressure, exhal ed
ti dal vol ume, venti l atory CO
2
concentrati on, anestheti c vapor concentrati on, i nspi red oxygen
concentration, oxygen suppl y pressure, arteri al hemogl obin oxygen saturati on, arteri al bl ood
pressure, and conti nuous el ectrocardi ogram. The anesthesi a workstati on must have a pri ori ti zed
al arm system that groups the al arms into three categori es: hi gh, medi um, and l ow pri ori ty. These
moni tors and al arms may be automaticall y enabl ed and made to function by turni ng on the
anesthesia workstati on, or the moni tors and al arms can be manual l y enabl ed and made functi onal
by fol lowi ng a pre-use checkli st.
5

CHECKING THE ANESTHESIA WORKSTATION
A compl ete anesthesi a apparatus checkout procedure must be performed each day prior to the
first use of the anesthesi a workstati on. An abbrevi ated versi on shoul d be performed before each
subsequent case. Several checkout procedures exi st, but the 1993 FDA Anesthesia Apparatus
Checkout Recommendations reproduced i n Appendi x A are the most popul ar and remain appli cabl e
to the majori ty of anesthesia machi nes i n use worl dwi de.
6, 7, 8, 9, 10
It should be noted that many
machines have been modifi ed i n the fi eld. The addi ti on of aftermarket products may mandate
modi fi cati on of the pre-use checkli st. The user must refer to the operator' s manual for speci al
procedures or precautions.
The three most i mportant preoperative checks are (1) oxygen anal yzer cali brati on, (2) the low-
pressure ci rcui t l eak test, and (3) the ci rcl e system test. Each i s discussed in the fol lowi ng
secti ons. Addi ti onal detai l s regardi ng these systems wi l l be presented in subsequent secti ons
descri bi ng the anatomy of the anesthesi a workstati on. For a simpli fi ed di agram of a two-gas
anesthesia machi ne and the components descri bed i n the fol l owi ng di scussi on, pl ease refer to
Fi gure 21-3. A comprehensive discussion of Fi gure 21-3 can al so be found in the Anesthesi a
Workstati on Pneumatics section.

Oxygen Anal yzer Cal i br at i on
The oxygen anal yzer i s one of the most i mportant moni tors on the anesthesi a workstation. It i s
the only machi ne safety devi ce that eval uates the integri ty of the l ow-pressure ci rcui t i n an
ongoi ng fashi on. Other machi ne safety devices, such as the fai l-safe val ve, the oxygen suppl y
fai l ure al arm, and the proporti oning system, are al l upstream from the flow control valves. The
only machi ne monitor that detects probl ems downstream from the flow control valves is the
oxygen anal yzer. Cal ibrati on of thi s moni tor i s descri bed i n Appendi x A (Anesthesi a Apparatus
Checkout Recommendati ons, 1993, #9). The actual procedure for cal ibrati ng the oxygen anal yzer
has remai ned reasonabl y si mi lar over the recent generati ons of the anesthesi a workstati ons.
Generall y, the oxygen concentration sensi ng element must be exposed to room ai r for cali bration
to 21%. Thi s may requi re manual l y setti ng a di al on ol der machi nes, but on newer ones, it usual l y
only involves temporary removal of the sensor, sel ecti ng and then confirmi ng that the oxygen
cal i brati on i s to be performed from a set of menus on the workstati on' s displ ay screen, and fi nall y
rei nstal li ng the sensor.
Low-Pressure Circuit Leak Test
The l ow-pressure l eak test checks the i ntegri ty of the anesthesi a machi ne from the flow
control valves to the common outl et. It evaluates the portion of the machi ne that i s
downstream from al l safety devi ces except the oxygen anal yzer. The components l ocated withi n
this area are precisel y the ones most subject to breakage and l eaks. Leaks in the l ow-pressure
ci rcuit can cause hypoxia or pati ent awareness.
11, 12
Fl ow tubes, the most del icate pneumatic
component of the machi ne, can crack or break. A typical three-gas anesthesi a machi ne has 16 O-
ri ngs i n the low-pressure ci rcuit. Leaks can occur at the i nterface between the gl ass flow tubes
FIGURE 21-3. Di agram of a generic two-gas anesthesi a machi ne. (Modi fi ed with permi ssi on
from Check-Out, A Gui de for Preoperati ve Inspecti on of an Anesthesi a Machi ne. Park Ri dge,
Il l inoi s, Ameri can Soci ety of Anesthesi ologi sts, 1987.)
P.560
and the mani fold, and at the O-ri ng junctions between the vapori zer and i ts manifol d. Loose fi ll er
caps on vapori zers are a common source of l eaks, and these leaks can cause patient awareness
under anesthesi a.
11, 13

Several different methods have been used to check the l ow-pressure ci rcuit for l eaks. They i ncl ude
the oxygen flush test, the common gas outl et occlusi on test, the traditi onal posi tive pressure leak
test, the North Ameri can Drger posi tive pressure leak test, the Ohmeda 8000 internal posi tive
pressure leak test, the Ohmeda negative pressure leak test, the 1993 FDA universal negati ve
pressure l eak test, and others. One reason for the large number of methods is that the i nternal
desi gn of vari ous machines differs considerabl y. The most notabl e exampl e i s that most GE
Heal thcare/Datex-Ohmeda (hereafter referred to as Datex-Ohmeda) workstations have a check
val ve near the common gas outl et, whereas Drger medi cal workstations do not. The presence or
absence of the check val ve profoundl y i nfluences whi ch preoperati ve check i s indi cated.
Several mi shaps have resul ted from application of the wrong l eak test to the wrong
machine.
14, 15, 16, 17
Therefore, i t is mandatory to perform the appropri ate l ow-pressure l eak test
each day. To do thi s, i t is essenti al to understand the exact location and operati ng pri nci pl es of
the Datex-Ohmeda check val ve. Many Datex-Ohmeda anesthesi a workstations have a machi ne
outl et check valve l ocated i n the low-pressure ci rcui t (Tabl e 21-1). The check val ve i s located
downstream from the vapori zers and upstream from the oxygen fl ush valve (see Fi g. 21-3). It i s
open (Fi g. 21-4, l eft) i n the absence of back pressure. Gas flow from the mani fold moves the
rubber fl apper val ve off i ts seat and al l ows gas to proceed freel y to the common outl et. The

val ve cl oses (Fi g. 21-4, ri ght) when back pressure i s exerted on i t.
8
Back pressure sufficient to
cl ose the check valve may occur with the fol lowi ng condi ti ons: oxygen flushi ng, peak breathi ng
ci rcui t pressures generated duri ng posi ti ve pressure ventil ati on, or use of a posi ti ve pressure leak
test.
P.561
TABLE 21-1 Check Valves and Manufacturer-Recommended Leak Test
ANESTHESIA
MACHINE
MACHINE
OUTLET
CHECK VALVE
VAPORIZER
OUTLET CHECK
VALVE
LEAK TEST RECOMMENDED
BY MANUFACTURER
POSITIVE
PRESSURE
NEGATIVE
PRESSURE
(SUCTION
BULB)
Drger
Narkomed 2A,
2B, 2C, 3, 4, GS
No No X
Fabi us GS No No Self-Test
Narkomed 6000 No No Self-Test
Ohmeda Uni trol Yes Vari abl e X
Ohmeda 30/70 Yes Vari abl e X
Generall y speaki ng, the low-pressure ci rcui t of anesthesi a workstati ons without an outlet check
Ohmeda
Modul us I
Yes Vari abl e X
Ohmeda
Modul us II
Yes No X
Ohmeda Excel
series
Yes No X
Ohmeda
Modul us II Pl us
No No X
Ohmeda CD No No X
Datex-Ohmeda
Aestiva
Yes No X
Datex-Ohmeda
S5/ADU
No No Self-Test
Data from Ohi o Medi cal Products, Ohmeda, Datex-Ohmeda, North Ameri can Drger,
Drger Medical.
FIGURE 21-4. Machi ne outl et check valve. See text for detai l s. (Reproduced wi th permission
from Bowie E, Huffman LM: The Anesthesia Machi ne: Essential s for Understanding. Madison,
Ohmeda, Inc., a Di vi si on of BOC Health Care, 1985.)
val ve can be tested using a posi ti ve pressure leak test, and machi nes wi th check val ves must be
tested usi ng a negati ve pressure l eak test. When performi ng a positi ve pressure l eak test, the
operator generates posi ti ve pressure i n the l ow-pressure ci rcui t usi ng flow from the anesthesi a
machine or from a posi tive pressure bul b to detect a l eak. When performi ng a negative pressure
leak test, the operator creates negati ve pressure in the l ow-pressure ci rcui t usi ng a suction bul b
to detect l eaks. Two di fferent low-pressure ci rcui t l eak tests are descri bed bel ow.
Oxygen Flush Positive-Pressure Leak Test
Histori call y, ol der anesthesi a machines did not have check val ves i n the low-pressure ci rcui t.
Therefore, it was common practi ce to pressuri ze the breathi ng ci rcuit and the l ow-pressure
ci rcuit wi th the oxygen fl ush val ve to test for internal anesthesi a machi ne l eaks. Because many
modern Datex-Ohmeda machines now have check valves in the l ow-pressure ci rcui t, appl i cation of
a positi ve-pressure l eak test to these machines can be mi sl eading or even dangerous (Fi g. 21-5).
Inappropriate use of the oxygen flush val ve or the presence of a l eaki ng fl ush valve may l ead to
inadequate evaluati on of the l ow-pressure ci rcui t for leaks. In turn, thi s can lead the workstation
user i nto a false sense of securi ty despite the presence of large leaks.
15, 16, 17, 18, 19
Posi ti ve pressure
from the breathi ng ci rcui t resul ts in closure of the outlet check val ve, and the value on the ai rway
pressure gauge wil l fai l to decli ne. The system appears to be ti ght, but i n actuali ty, onl y the
ci rcuitry downstream from the check val ve i s l eak free.
20
Thus, a vul nerable area exists from the
check valve back to the flow control valves because thi s area is not tested by a posi ti ve pressure
leak test.
FIGURE 21-5. Inappropri ate use of the oxygen fl ush val ve to check the l ow-pressure ci rcui t
of an Ohmeda machine equi pped wi th a check val ve. The area wi thi n the rectangle i s not
checked by the i nappropriate use of the oxygen fl ush val ve. The components located wi thi n
this area are precisel y the ones most subject to breakage and leaks. Positi ve pressure wi thi n
the pati ent ci rcuit cl oses the check val ve, and the value on the ai rway pressure gauge does
not decl ine despi te l eaks i n the l ow-pressure ci rcuit.
1993 FDA Negative-Pressure Leak Test
The 1993 FDA Universal negative pressure l eak test
10
(Appendi x A, #5) was so named uni versal
because at that time i t coul d be used to check all contemporary anesthesi a machi nes regardless of
the presence or absence of check valves i n the l ow-pressure ci rcui t. It remai ns effective for many
anesthesia workstati ons and can be appl i ed to many Datex-Ohmeda machines, Drger Medical
machines, and others. Unfortunatel y, some newer machi nes are no l onger compatibl e wi th this
test. The ASA Commi ttee on Equi pment and Faci l i ti es i n conjuncti on wi th the FDA i s expected to
update the 1993 Anesthesi a Apparatus Pre-Use Checkout Recommendati ons as this chapter comes
to press. Unti l the new recommendations become avail able, the 1993 gui del i nes shoul d continue to
be foll owed as cl osel y as possibl e, si nce they remain appli cabl e to the vast majori ty of anesthesi a
workstations i n use worl dwi de.
The 1993 FDA check i s based on the Datex-Ohmeda negati ve-pressure leak test (Fi g. 21-6). It i s
performed usi ng a negati ve-pressure l eak testi ng devi ce, which i s a si mpl e sucti on bulb. The
machine master swi tch, the fl ow control val ves, and vapori zers are turned off. The suction bul b i s
attached to the common fresh gas outl et and squeezed repeatedl y unti l it i s ful l y coll apsed. Thi s
acti on creates a vacuum in the low-pressure ci rcui try. The machine i s l eak free i f the hand bulb
remai ns col lapsed for at l east 10 seconds. A l eak i s present i f the bulb rei nfl ates during thi s
peri od. The test i s repeated with each vaporizer i ndi vidual ly turned to the on posi ti on because
i nternal vapori zer l eaks can be detected only wi th the vapori zer turned on.
The FDA uni versal negati ve-pressure l ow-pressure ci rcuit l eak test has several
advantages.
21
The universal test i s qui ck and si mpl e to perform. It has an obvi ous end poi nt,
and it may hel p i sol ate the probl em. For exampl e, i f the bul b rei nflates i n less than 10 seconds, a
leak i s present somewhere i n the low-pressure ci rcui t. Therefore, i t differenti ates between
breathing-ci rcuit l eaks and leaks i n the low-pressure ci rcui t. The uni versal negative-pressure l eak
test is the most sensi tive of all contemporary leak tests because i t i s not vol ume dependent. That
is, i t does not i nvol ve the use of a breathi ng bag or corrugated hoses whose compli ance coul d
mask a si gni fi cant leak. It can detect l eaks as small as 30 mL/mi n. Final l y, the operator does not
need a detai led or in-depth knowl edge of propri etary desi gn di fferences. If the operator performs
FIGURE 21-6. FDA negati ve pressure l eak test. (Left) A negati ve-pressure l eak testing
device i s attached di rectl y to the machi ne outlet. Squeezi ng the bul b creates a vacuum i n the
low-pressure ci rcui t and opens the check valve. (Ri ght) When a l eak i s present in the low-
pressure ci rcui t, room ai r i s entrai ned through the l eak and the sucti on bulb i nfl ates.
(Repri nted with permi ssi on from Andrews JJ: Understandi ng anesthesi a machines. In 1988
Revi ew Course Lectures, p 78. Cl eveland, International Anesthesia Research Soci ety, 1988.)
the universal test correctl y, the leak wil l be detected.
Circle System Tests
The circle system tests (Appendi x A, #1112) eval uate the integri ty of the circle breathing
system, whi ch spans from the common gas outlet to the Y-pi ece (Fi g. 21-7). It has two
partsthe leak test and the fl ow test. To thoroughl y check the circle system for leaks, val ve
integrity, and obstructi on, both tests must be performed preoperati vel y. The leak test is
performed by cl osi ng the pop-off valve, occl udi ng the Y-pi ece, and pressuri zi ng the ci rcuit to 30
cm water pressure usi ng the oxygen flush val ve. The value on the pressure gauge wi ll not decli ne
if the circl e system i s leak free, but this does not assure valve integri ty. The val ue on the gauge
wil l read 30 cm water even if the unidi rectional val ves are stuck shut or if the val ves are
incompetent.
The fl ow test checks the i ntegri ty of the unidi rectional val ves, and i t detects obstructi on i n the
ci rcl e system. It can be performed by removi ng the Y-pi ece from the circle system and breathing
through the two corrugated hoses i ndi vi dual l y. The valves should be present, and they shoul d
move appropriately.

The operator should be abl e to inhal e but not be abl e to exhal e through the i nspi ratory l i mb. The
operator shoul d be abl e to exhal e but not i nhale through the expi ratory l i mb. The fl ow test can
al so be performed by usi ng the venti l ator and a breathi ng bag attached to the Y pi ece as
descri bed i n the 1993 FDA Anesthesi a Apparatus Checkout Recommendati ons (Appendi x A, #12).
10

Workstation Self-Tests
As previ ously menti oned, many new anesthesi a workstati ons now incorporate technology that
al lows the machine to ei ther automaticall y or manual l y wal k the user through a series of self-tests
to check for functi onal i ty of electroni c, mechani cal , and pneumati c components. Tested
components commonl y include the gas supply system, fl ow control val ves, the ci rcle system,
ventil ator, and i n the case of the Datex-Ohmeda ADU, even the Aladi n cassette vaporizer. The
comprehensi veness of these sel f-di agnosti c tests vari es from one model and manufacturer to
FIGURE 21-7. Components of the ci rcl e system. B = Reservoi r Bag; V = venti l ator; APL =
Adjustabl e Pressure Limi ti ng. (Reproduced wi th permission from Brockwel l RC: Inhal ed
Anestheti c Deli very Systems. In Mi ll er RD (ed): Anesthesia, 6
t h
ed, p 295. Phi l adel phi a,
Churchi l l Livingstone, 2004.)
P.562
another. If these tests are to be employed, users must be sure to read and strictly foll ow all
manufacturer recommendati ons. Al though a thorough understandi ng what the parti cular
workstation' s self-tests i ncl ude i s very hel pful, thi s i nformation is often di ffi cul t to obtai n and may
vary greatl y between devi ces.
One parti cul arl y i mportant point of cauti on wi th sel f-tests shoul d be noted on systems wi th
mani fol d mounted vapori zers such as the Drger Medi cal Fabi us GS and Narkomed 6000
seri es. A mani fol d mounted vaporizer does not become a part of an anesthesi a workstation' s gas
flow stream unti l i ts concentrati on control dial is turned to the on positi on. Therefore, to detect
internal vaporizer l eaks on thi s type of a system, the leak test porti on of the sel f-di agnosti c
must be repeated separatel y wi th each i ndi vi dual vaporizer turned to the on positi on. If thi s
precauti on i s not taken, l arge leaks that coul d potenti all y resul t i n pati ent awareness, such those
from a loose fil l er cap or cracked fi l l indi cator, could go undetected.
Anest hesi a Wor kst at i on P neumat i cs
The Anatomy of an Anesthesia Workstation
A si mpli fi ed di agram of a generic two-gas anesthesi a machi ne i s shown i n Fi gure 21-3. The
pressures wi thi n the anesthesi a workstati on can be di vi ded i nto three ci rcui ts: a hi gh-pressure, an
intermedi ate-pressure, and a low-pressure ci rcui t (see Fi g. 21-3). The hi gh- pr essur e ci r cui t is
confi ned to the cyl i nders and the cyl inder pri mary pressure regul ators. For oxygen, the pressure
range of the hi gh-pressure ci rcui t extends from a hi gh of 2,200 pounds per square i nch gauge
(psig) to 45 psig, whi ch is the regul ated cyl i nder pressure. For ni trous oxi de in the high-pressure
ci rcuit, pressures range from a high of 750 psi g in the cyl i nder to a l ow of 45 psi g. The
i nt er medi at e- pr essur e ci r cui t begi ns at the regul ated cyl i nder suppl y sources at 45 psi g and i t
incl udes the pi pel ine sources at 50 to 55 psi g and extends to the flow control val ves. Dependi ng
on the manufacturer and speci fi c machi ne desi gn, second-stage pressure regul ators may be used
to decrease the pipel ine suppl y pressures to the fl ow control val ves to even l ower pressures such
as 14 psig or 26 psi g withi n the i ntermedi ate pressure ci rcui t.
22, 23
Fi nal l y, the l ow - pr es sur e
ci r cui t extends from the fl ow control val ves to the common gas outl et. Therefore, the l ow-
pressure ci rcui t

incl udes the flow tubes, vapori zer manifold, vaporizers, and the one-way check valve on most
Datex-Ohmeda machines.
22

Both oxygen and ni trous oxi de have two suppl y sources. These consi st of a pi pel ine suppl y source
and a cyl i nder suppl y source. The pi pel i ne suppl y source i s the pri mary gas source for the
anesthesia machi ne. The hospi tal pipel i ne suppl y system provides gases to the machi ne at
approxi mately 50 psig, whi ch is the normal working pressure of most machines. The cyl i nder
supply source serves as a back-up i f the pi pel i ne suppl y fai l s or the pri mary suppl y i f the
anesthesia workstation i s bei ng used in a l ocati on wi thout the avail abil i ty of pi pel i ne suppl i ed
gases. As previ ously described, the oxygen cyl i nder source is regul ated from 2,200 to
approxi mately 45 psig, and the nitrous oxi de cyl inder source is regul ated from 745 to
approxi mately 45 psig.
22, 23, 24

A safety device tradi ti onal l y referred to as the fail-safe valve is located downstream from the
ni trous oxide suppl y source. It serves as an i nterface between the oxygen and nitrous oxi de
supply sources. Thi s valve shuts off or proporti onall y decreases the suppl y of ni trous oxi de (and
other gases) if the oxygen supply pressure decreases. To meet ASTM standards, contemporary
machines have an al arm device to monitor the oxygen supply pressure. A high-pri ority al arm is
actuated as decl i ni ng oxygen suppl y pressure reaches a predetermi ned threshol d, such as 30
psi g.
22, 23, 24

Many Datex-Ohmeda machi nes have a second-stage oxygen regul ator l ocated downstream from
the oxygen supply source in the intermedi ate pressure ci rcuit. It i s adjusted to a precise pressure
level , such as 14 psi g.
23
Thi s regulator suppl ies a constant pressure to the oxygen flow control
val ve regardl ess of fluctuating oxygen pipel i ne pressures. For exampl e, the fl ow from the oxygen
P.563
flow control val ve wi l l be constant if the oxygen suppl y pressure i s greater than 14 psi g.
The fl ow control val ves represent an i mportant anatomi c l andmark wi thin the anesthesia
workstation because they separate the intermedi ate-pressure ci rcui t from the l ow-pressure ci rcui t.
The l ow-pressure ci rcuit i s that part of the machi ne that l ies downstream from the fl ow control
val ves. The operator regul ates fl ow enteri ng the l ow-pressure ci rcui t by adjusting the fl ow control
val ves. The oxygen and ni trous oxi de fl ow control valves are li nked mechani cal l y or pneumati cal ly
by a proportioni ng system to hel p prevent i nadvertent del i very of a hypoxic mi xture. After leavi ng
the fl ow tubes, the mi xture of gases travel s through a common mani fol d and may be di rected to a
cal i brated vapori zer. Preci se amounts of inhaled anesthetic can be added, dependi ng on vapori zer
control di al setti ng. The total fresh gas fl ow pl us the anestheti c vapor then travel toward the
common gas outl et.
22, 23

Many Datex-Ohmeda anesthesi a machines have a one-way check val ve located between the
vapori zers and the common gas outlet i n the mi xed-gas pipel i ne. Its purpose i s to prevent back
fl ow i nto the vapori zer duri ng positi ve pressure venti lati on, therefore mi ni mi zi ng the effects of
downstream intermi ttent pressure fluctuations on inhal ed anestheti c concentration (see
Vapori zers: Intermi ttent Back Pressure secti on). The presence or absence of thi s check valve
pr of oundl y influences which preoperative leak test i s indi cated (see Checki ng Your Anesthesia
Workstati on). The oxygen flush connection joi ns the mi xed-gas pi peli ne between the one-way
check valve (when present) and the machi ne outl et. Thus, when oxygen fl ush val ve i s activated
the pipel i ne oxygen pressure has a strai ght shot to the common gas outl et.
22, 23

P i pel i ne Suppl y Sour ce
Under normal condi ti ons, the pi pel ine suppl y serves as the primary gas source for the anesthesi a
machine. Most hospitals today have a central pipi ng system to del iver medical gases such as
oxygen, nitrous oxi de, and ai r to the operati ng room. The central pi pi ng system must supply the
correct gases at the appropri ate pressure for the anesthesi a workstati on to functi on properl y.
Unfortunatel y, this does not al ways occur. Proven as recently as 2002, even large medi cal centers
with huge cryogeni c bul k oxygen storage systems are not immune to component fail ures that may
contri bute to cri ti cal oxygen pi pel i ne suppl y fai l ures.
25
In thi s case, a faul ty joi nt ruptured at the
bottom of the pri mary cryogenic oxygen storage tank, releasing 8,000 gal l ons of li qui d oxygen to
flood the streets i n the surroundi ng area. Thi s mi shap suddenl y compromised the oxygen del ivery
to a major medical center.
In a survey of approxi matel y 200 hospi tal s in 1976, 31% reported diffi culti es wi th pi pel i ne
systems.
26
The most common probl em was i nadequate oxygen pressure, fol l owed by excessi ve
pi pel ine pressures. The most devastating reported hazard, however, was acci dental crossi ng of
oxygen and ni trous oxide pi pel ines, whi ch has l ed to many deaths. Thi s probl em caused 23 deaths
in a newl y constructed wi ng of a general hospital in Sudbury, Ontari o, during a 5-month
peri od.
26, 27
More recentl y, i n 2002, two addi ti onal hypoxi c deaths were reported i n New Haven,
Connecti cut. These resul ted from a medi cal gas system fail ure i n whi ch an al tered oxygen
flowmeter was inadvertently connected to a wall suppl y source for ni trous oxi de.
28

In the event a pi pel ine crossover i s ever suspected, the workstati on user must immedi ately
make two correcti ve acti ons. First, the back-up oxygen cyl inder shoul d be turned on. Then,
the pipel i ne suppl y must be di sconnected. Thi s second step i s mandatory because the machi ne wi l l
preferential ly use the i nappropriate 50 psi g pi pel i ne suppl y source i nstead of the lower-pressure
(45 psi g) oxygen cyli nder source i f the wall suppl y is not di sconnected.
Gas enters the anesthesia machi ne through the pi peli ne inlet connecti ons (see Fi g. 21-3; see
arrows). The pi peli ne inl et fittings are gas-specific Di ameter Index Safety (DISS) threaded body
fittings. The DISS provi des threaded noni nterchangeabl e connecti ons for medical gas l i nes, which
minimize the risk of misconnecti on. A check valve is l ocated downstream from the i nl et. It
prevents reverse fl ow of gases from the machine to the pi peli ne or the atmosphere.
Cyl i nder Suppl y Sour ce
Anesthesi a workstati ons have E cyli nders for use when a pi pel i ne suppl y source i s not avai l abl e or
if the pi pel i ne system fai ls. Anesthesi a provi ders can easi l y become complacent and fal sel y
assume that back-up gas cyli nders are i n fact present on the back of the anesthesi a workstati on,
and further, that i f they are present, that they contai n an adequate suppl y of compressed gas. The
pre-use checkli st should contain steps that confirm both.
Medi cal gases suppl i ed i n E cyl inders are attached to the anesthesi a machine vi a the hanger yoke
assembly. The hanger yoke assembl y ori ents and supports the cyli nder, provi des a gas-ti ght seal ,
and ensures a unidi rectional fl ow of gases i nto the machi ne.
30
Each hanger yoke is equipped with
the Pi n Index Safety System (PISS). The PISS i s a safeguard introduced to el imi nate cyl i nder
i nterchangi ng and the possibi l ity of accidental ly pl aci ng the i ncorrect gas on a yoke desi gned to
accommodate another gas. Two metal pi ns on the yoke assembl y are arranged so that that they
project i nto corresponding hol es on the cyl inder valve. Each gas or combinati on of gases has a
specific pi n arrangement.
31

Once the cyli nders are turned on, compressed gases may pass from their respecti ve hi gh-pressure
cyl i nder sources into the anesthesia machi ne (see Fi g. 21-3). A check val ve i s located downstream
from each cyli nder i f a doubl e-yoke assembl y i s used. This check val ve serves several functi ons.
Fi rst, i t

minimizes gas transfer from a cyl i nder at hi gh pressure to one wi th l ower pressure. Second, i t
al l ows an empty cyl i nder to be exchanged for a ful l one whi le gas fl ow conti nues from the other
cyl i nder into the machine wi th mini mal loss of gas or suppl y pressure. Thi rd, it minimizes leakage
from an open cylinder to the atmosphere i f one cyl i nder is absent.
23, 30
A cylinder suppl y pressure
gauge is l ocated downstream from the check val ves. The gauge wi l l indicate the pressure in the
cyl i nder havi ng the hi gher pressure when two reserve cyl inders of the same gas are opened at the
same ti me.
Each cyl inder suppl y source has a pressure-reduci ng val ve known as the cyl inder pressure
regul ator. It reduces the hi gh and vari abl e storage pressure present i n a cyl i nder to a l ower, more
constant pressure sui tabl e for use i n the anesthesi a machine. The oxygen cyl i nder pressure
regul ator reduces the oxygen cyli nder pressure from a hi gh of 2,200 psi g to approximatel y 45
psi g. The nitrous oxi de cyl i nder pressure regul ator receives pressure of up to 745 psi g and
reduces i t to approxi matel y 45 psi g.
22, 23

The gas supply cyl inder val ves shoul d be turned off when not i n use, except during the
preoperati ve machi ne checking peri od. If the cyl i nder suppl y val ves are l eft on, the reserve
cyl i nder suppl y can be si l entl y depl eted whenever the pressure inside the machine decreases to a
val ue lower than the regulated cyli nder pressure. For exampl e, oxygen pressure wi thi n the
machine can decrease bel ow 45 psi g with oxygen flushi ng or possibl y even duri ng use of a
pneumati cal ly dri ven venti l ator, parti cularly at hi gh i nspi ratory fl ow rates. Additi onal l y, the
pi pel ine suppl y pressures of all gases can fal l to l ess than 45 psi g i f problems exist i n the central
pi pi ng system. If the cyli nders are left on when thi s occurs, they wi l l eventual ly become depl eted
and no reserve suppl y may be avai l abl e i f a pi pel i ne fai l ure occurs.
20, 23

The amount of ti me that an anesthesia machi ne can operate from the E-cyl i nder suppl ies i s
i mportant knowl edge. Thi s is parti cul arly true now that anesthesi a is bei ng provided more
frequently in office-based and i n remote (outside the OR) hospital setti ngs. For oxygen, the
vol ume of gas remai ni ng in the cyl inder i s proporti onal to the cyli nder pressure. One author has
proposed the foll owi ng equati on to help estimate the remai ni ng ti me.
32

It shoul d be noted that this calcul ati on wil l provi de onl y a gross esti mate of remai ni ng ti me and
may not be exact. Furthermore, users shoul d be cauti oned that use of a pneumati cal ly driven
mechani cal venti l ator wi l l dramaticall y i ncrease oxygen uti li zation rates and decrease the
P.564
remai ni ng ti me unti l cyl inder depl eti on. Hand venti l ati ng with low fresh gas fl ow rates may
consume <5% the amount of oxygen as compared to intermedi ate fl owmeter settings coupl ed wi th
the use of pneumati cal l y powered mechani cal venti lation.
25
Because piston type anesthesi a
ventil ators such as found i n the Drger Medical Fabi us GS and Narkomed 6000 seri es do not
impact oxygen consumpti on rates, they may be preferabl e to conventional gas-dri ven venti lators
in practi ce settings that are dependent on the use of compressed gas cyl i nders as the pri mary gas
sources.
Oxygen Suppl y P r essur e Fai l ur e Saf et y Devi ces
Oxygen and ni trous oxi de suppl y sources exi sted as i ndependent entiti es in ol der models of
anesthesia machi nes, and they were not pneumati cal l y or mechanicall y interfaced. Therefore,
abrupt or i nsi dious oxygen pressure fail ure had the potential to l ead to the del i very of a hypoxic
mi xture. The 2000 ASTM F1850-00 standard states that, The anesthesi a gas suppl y devi ce shal l
be desi gned so that whenever oxygen suppl y pressure i s reduced to bel ow the manufacturer
specified mi ni mum, the del i vered oxygen concentrati on shal l not decrease bel ow 19% at the
common gas outl et.
5
Contemporary anesthesi a machines have a number of safety devi ces that act
together i n a cascade manner to mi nimize the risk of del i very of a hypoxic gas mi xture as oxygen
pressure decreases. Several of these devices are descri bed in the foll owi ng secti ons.
Pneumatic and Electronic Alarm Devices
Many older anesthesi a machi nes have a pneumatic al arm device that sounds a warning when the
oxygen suppl y pressure decreases to a predetermined threshol d value such as 30 psig. The 2000
ASTM F1850-00 standard mandates that a medi um pri ori ty alarm shal l be activated wi thi n 5
seconds when the oxygen pressure decreases below a manufacturer-specific pressure threshol d.
5

El ectroni c alarm devi ces are now used to meet thi s gui deli ne.
Fail-Safe Valves
A fail -safe val ve i s present i n the gas l i ne suppl yi ng each of the flowmeters except oxygen.
Controll ed by oxygen suppl y pressure, the val ve shuts off or proportional ly decreases the
suppl y pressure of al l other gases (ni trous oxi de, air, CO
2
, hel i um, ni trogen) as the oxygen supply
pressure decreases. Unfortunatel y, the mi snomer fai l -safe has led to the misconcepti on that the
val ve prevents admi ni stration of a hypoxic mi xture. Thi s i s not the case. Machines that are ei ther
not equi pped wi th a fl ow proporti oni ng system (see Proporti oni ng Systems secti on) or ones whose
system may be di sabl ed by the user can deliver a hypoxic mixture under normal working
condi ti ons. On such a system, the oxygen fl ow control val ve can be closed intenti onall y or
acci dentall y. Normal oxygen pressure wi l l keep other gas li nes open so that a hypoxi c mi xture can
resul t.
22, 23

Many Datex-Ohmeda machines are equi pped wi th a fai l -safe val ve known as the pressure-sensor
shutoff val ve (Fi g. 21-8). Thi s valve operates i n a threshol d manner and i s either open or cl osed.
Oxygen suppl y pressure opens the val ve, and the valve return spring closes the val ve. Fi gure 21-8
shows a nitrous oxi de pressure-sensor shutoff valve wi th a threshol d pressure of 20 psig. In
Fi gure 21-8A, an oxygen suppl y pressure greater than 20 psig i s exerted on the mobil e di aphragm.
Thi s pressure moves the piston and pi n upward and the val ve opens. Ni trous oxi de fl ows freel y to
the ni trous oxi de fl ow control val ve. In Fi gure 21-8B, the oxygen suppl y pressure i s l ess than 20
psi g, and the force of the val ve return spri ng compl etel y cl oses the val ve.
23
Ni trous oxi de fl ow
stops at the closed

fai l -safe val ve, and i t does not advance to the ni trous oxi de fl ow control val ve.
P.565
North American Drger uses a different fai l -safe val ve known as the Oxygen Fai lure Protecti on
Device (OFPD) to interface the oxygen pressure with that of other gases, such as ni trous oxi de or
other i nert gases. Thi s i s i n contrast to Datex-Ohmeda' s oxygen pressure-sensor shutoff val ve,
because the OFPD i s based on a proporti oni ng pri ncipl e rather than a threshol d pri nci pl e. The
pressure of al l gases control l ed by the OFPD wi l l decrease proporti onal l y wi th the oxygen
pressure. The OFPD consi sts of a seat-nozzl e assembl y connected to a spri ng-l oaded pi ston (Fi g.
21-9). The oxygen suppl y pressure in the l eft panel of Fi gure 21-9 is 50 psi g. Thi s pressure
pushes the pi ston upward, forcing the nozzle away from the val ve seat. Ni trous oxi de and/or other
gases advance toward the flow control valve at 50 psi g. The oxygen pressure in the right panel is
zero psig. The spri ng i s expanded and forces the nozzl e agai nst the seat, preventi ng fl ow through
the devi ce. Fi nal ly, the center panel shows an intermedi ate oxygen pressure of 25 psi g. The force
of the spri ng parti al l y cl oses the val ve. The ni trous oxide pressure del i vered to the flow control
val ve is 25 psi g. There is a continuum of intermedi ate confi gurati ons between the extremes (0 to
50 psi g) of oxygen suppl y pressure. These i ntermedi ate val ve confi gurati ons are responsi ble for
the proportional nature of the OFPD. An i mportant concept to be understood wi th these parti cul ar
fai l -safe devi ces i s that the Datex-Ohmeda Pressure Sensor Shutoff Val ve i s threshol d i n nature
(all -or-nothing), whereas the Drger Oxygen Fai lure Protecti on Device i s a vari abl e flow type
proporti oni ng system.
FIGURE 21-8. Pressure-sensor shutoff val ve. The val ve i s open in A because the oxygen
suppl y pressure i s greater than the threshol d val ue of 20 psi g. The val ve i s closed in B
because of i nadequate oxygen pressure. (Redrawn wi th permi ssion from Bowie E, Huffman
LM: The Anesthesi a Machine: Essenti als for Understandi ng. Madi son, Wi sconsin, Ohmeda, a
Division of BOC Health Care, Inc, 1985.)
Second-Stage Oxygen Pressure Regulator
Most contemporary Datex-Ohmeda workstati ons have a second-stage oxygen pressure regul ator
set at a specifi c val ue rangi ng from 12 to 19 psi g. Output from the oxygen fl owmeter i s constant
when the oxygen suppl y pressure exceeds the threshold (minimal) val ue. The pressure-sensor
shutoff valve of Datex-Ohmeda is set at a higher threshold val ue (20 to 30 psi g) to ensure that
oxygen i s the l ast gas flowi ng if oxygen pressure fai l ure occurs.
Fl owmet er Assembl i es
The fl owmeter assembly (Fi g. 21-10) preci sely control s and measures gas fl ow to the common gas
outl et. With tradi tional gl ass fl owmeter assembl i es, the fl ow control val ve regul ates the amount of
fl ow that enters a tapered, transparent fl ow tube known as a Thorpe tube. A mobi l e i ndi cator fl oat
i nsi de the fl ow tube i ndi cates the amount of flow passing through the associ ated flow control
val ve. The quanti ty of fl ow i s i ndi cated on a scale associated wi th the fl ow tube.
22, 23
Some newer

anesthesia workstations have now replaced the conventi onal gl ass fl ow tubes wi th el ectronic fl ow
sensors that measure the fl ows of the indi vi dual gases. These fl ow rate data are then presented i n
ei ther numeri cal format, graphi cal format, or a combinati on of the two. The integrati on of these
el ectronic flowmeters is an essential step i n the evoluti on of the anesthesi a workstation if i t is to
become ful ly integrated with anesthesi a data-capturi ng systems such as computeri zed anesthesi a
record keepers.
FIGURE 21-9. Oxygen Fai lure Protection Devi ce/Sensi ti ve Oxygen Rati o Controll er (OFPD/S-
ORC), whi ch responds proporti onal ly to changes i n oxygen supply pressure. (Redrawn with
permi ssi on from Narkomed 2A Anesthesia System: Techni cal Servi ce Manual , 6
t h
ed. Telford,
PA, North Ameri can Drger, June 1985.)
P.566
Operating Principles of Conventional Flowmeters
Openi ng the fl ow control val ve al lows gas to travel through the space between the float and the
flow tube. Thi s space i s known as the annular space (Fi g. 21-11). The i ndi cator fl oat hovers freel y
in an equi l ibri um posi ti on where the upward force resulti ng from gas fl ow equal s the downward
force on the fl oat resul ti ng from gravi ty at a gi ven flow rate. The float moves to a new equi l ibri um
position in the tube when flow is changed. These fl owmeters are commonl y referred to as constant
pressure fl owmeters because the pressure decrease across the fl oat remai ns constant for al l
positi ons in the tube.
22, 31, 33

FIGURE 21-10. Oxygen flowmeter assembl y. The oxygen fl owmeter assembl y i s composed of
the flow control valve assembl y pl us the fl owmeter subassembl y. (Reproduced wi th
permi ssi on from Bowi e E, Huffman LM: The Anesthesia Machi ne: Essenti als for
Understandi ng. Madi son, Wisconsi n, Ohmeda, a Di vi si on of BOC Health Care, Inc, 1985.)
Fl ow tubes are tapered, wi th the smal l est di ameter at the bottom of the tube and the largest
di ameter at the top. The term variabl e ori fi ce desi gnates thi s type of uni t because the annular
space between the fl oat and the inner wall of the flow tube vari es wi th the posi tion of the fl oat.
Fl ow through the constri cti on created by the fl oat can be l aminar or turbulent, depending on the
flow rate (Fi g. 21-12). The characteristics of a gas that i nfl uence its fl ow rate through a given
constri cti on are viscosi ty (l ami nar fl ow) and density (turbul ent fl ow). Because the annular space i s
tubul ar, at low flow rates l ami nar flow i s present and viscosi ty determi nes the gas fl ow rate. The
annul ar space si mul ates an ori fi ce at hi gh fl ow rates, and turbul ent gas fl ow then depends
predomi nantly on the densi ty of the gas.
22, 33

FIGURE 21-11. The annul ar space. The clearance between the head of the float and the fl ow
tube is known as the annul ar space. It can be consi dered an equi valent to a circul ar channel
of the same cross-secti onal area. (Redrawn wi th permi ssi on from Maci ntosh R, Mushi n WW,
Epstei n HG: Physics for the Anaestheti st, 3rd ed. Oxford, Engl and, Blackwel l Sci enti fi c
Publ icati ons, 1963.)
FIGURE 21-12. Fl ow tube constri cti on. The l ower pair of i l lustrati ons represents the l ower
porti on of a fl ow tube. The cl earance between the head of the fl oat and the flow tube i s
Components of the Flowmeter Assembly
Flow Control Valve Assembly. The flow control val ve (see Fi g. 21-10) assembly i s composed of
a fl ow control knob, a needl e valve, a valve seat, and a pair of val ve stops.
22
The assembly can
recei ve its pneumati c i nput either di rectl y from the pi pel i ne source (50 psig) or from a second-
stage pressure regul ator. The l ocation of the needl e valve i n the val ve seat changes to establ ish
di fferent ori fi ces when the fl ow control val ve is adjusted. Gas fl ow increases when the fl ow control
val ve is turned countercl ockwise, and it decreases when the val ve i s turned cl ockwi se. Extreme
cl ockwise rotati on may resul t i n damage to the needl e valve and val ve seat. Therefore, flow
control valves are equi pped wi th val ve stops to prevent thi s occurrence.
23

Safety features. Contemporary flow control val ve assembl i es have numerous safety features. The
oxygen fl ow control knob i s physi cal l y di sti nguishabl e from other gas knobs. It is di sti nctively
fl uted, projects beyond the control knobs of the other gases, and i s l arger i n diameter than the
flow control knobs of other gases. All knobs are col or-coded for the appropri ate gas, and the
chemical formula or name of the gas i s permanently marked on each. Flow control knobs are
recessed or protected wi th a shi el d or barri er to minimi ze i nadvertent change from a preset
positi on. If a si ngle gas has two fl ow tubes, the tubes are arranged i n seri es and are control l ed by
a si ngl e fl ow control val ve.
5

Flowmeter Subassembly. The flowmeter subassembl y (see Fi g. 21-10) consists of the flow tube,
the indi cator fl oat wi th fl oat stops, and the indicator scale.
22

Fl ow tubes. Contemporary flow tubes are made of gl ass. Most have a si ngl e taper i n whi ch the
inner diameter of the fl ow tube i ncreases uni formly from bottom to top. Manufacturers provi de
doubl e flow tubes for oxygen and nitrous oxi de to provi de better vi sual di scri mi nati on at l ow fl ow
rates. A fine fl ow tube i ndi cates fl ow from approxi matel y 200 mL/min to 1 mL/mi n, and a coarse
flow tube indi cates flow from approxi mately 1 mL/mi n to 10 to 12 mL/min. The two tubes are
connected i n seri es and suppl i ed by a si ngl e fl ow control val ve. The total gas fl ow is that shown on
the hi gher fl owmeter.
Indicator floats and float stops. Contemporary anesthesi a machines use several different types of
bobbi ns or fl oats, i ncl udi ng pl umb-bob fl oats, rotati ng ski rted floats, and bal l fl oats. Fl ow i s read
at the top of pl umb-bob and ski rted fl oats and at the center of the bal l on the bal l -type floats.
22

Fl ow tubes are equi pped wi th fl oat stops at the top and bottom of the tube. The upper stop
prevents the float from ascending to the top of the tube and pl uggi ng the outl et. It al so ensures
that the float wil l be vi si bl e at maxi mum fl ows i nstead of bei ng hi dden i n the mani fol d. The bottom
float stop provi des a central foundation for the i ndicator when the fl ow control val ve is turned
off.
22, 23

Scal e. The flowmeter scale can be marked directl y on the fl ow tube or l ocated to the ri ght of the
tube.
5
Gradati ons correspondi ng to equal i ncrements in fl ow rate are closer together at the top of
the scale because the annul ar space i ncreases more rapi dl y than does the internal di ameter from
bottom to top of the tube. Ri b gui des are used i n some flow tubes wi th bal l -type indicators to
mi ni mi ze thi s compressi on effect. They are tapered gl ass ridges that run the length of the tube.
There are usual ly three ri b gui des that are equally spaced around the i nner circumference of the
narrow. The equival ent channel is tubular because i ts di ameter i s less than i ts length.
Viscosi ty is domi nant i n determi ni ng gas fl ow rate through thi s tubul ar constri cti on. The
upper pair of illustrations represents the upper porti on of a fl ow tube. The equi val ent channel
is ori fici al because i ts l ength i s l ess than its wi dth. Densi ty i s dominant in determi ning gas
flow rate through thi s orifici al constriction. (Redrawn with permissi on from Maci ntosh R,
Mushi n WW, Epstei n HG: Physics for the Anaestheti st, 3rd ed. Oxford, Engl and, Bl ackwel l
Sci enti fi c Publ icati ons, 1963.)
P.567
tube. In the presence of ri b guides, the annular space from the bottom to the top of the tube
increases al most proportional ly wi th the i nternal di ameter. Thi s resul ts i n a nearl y l i near scale.
22

Ri b guides are employed on many Drger Medical flow tubes.
Safety features. The flowmeter subassembl ies for each gas on the Datex-Ohmeda Modul us I,
Modul us II, Modul us II Plus, CD, and Aesti va are housed in i ndependent, col or-coded, pi n-speci fi c
modul es. The fl ow tubes are adjacent to a gas-specific, color-coded backi ng. The flow scale and
the chemi cal formul a (or name of the gas) are permanentl y etched on the backing to the ri ght of
the fl ow tube. Flowmeter scal es are individual l y hand-cali brated usi ng the speci fi c float to provi de
a hi gh degree of accuracy. The tube, fl oat, and scal e make an inseparabl e unit. The enti re set
must be repl aced i f any component i s damaged.
Drger Medi cal does not use a modular system for the flowmeter subassembl y. The fl ow scale, the
chemi cal symbol, and the gas-specific color codes are etched directl y onto the fl ow tube. The scal e
in use i s obvious when two flow tubes for the same gas are used.
Problems with Flowmeters
Leaks. Fl owmeter leaks are a substanti al hazard because the fl owmeters are located downstream
from al l machi ne safety devi ces except the oxygen anal yzer.
34
Leaks can occur at the O-ri ng
juncti ons between the gl ass fl ow tubes and the metal mani fol d or i n cracked or broken glass flow
tubes, the most fragile pneumatic component of the anesthesi a machi ne. Even though gross
damage to conventional glass fl ow tubes i s usual l y apparent, subtl e cracks and chi ps may be
overlooked, resul ting i n errors of del i vered flows.
35
The use of el ectroni c fl owmeters and the
removal of conventional gl ass fl ow tubes from some newer anesthesi a workstati ons (Datex-
Ohmeda S/5 ADU and the Drger Fabi us) may help to el iminate these potenti al sources of l eaks
(see El ectroni c Flowmeters section).
Eger et al i n 1963
36
demonstrated that, i n the presence of a fl owmeter leak, a hypoxi c mi xture is
l ess l i kel y to occur i f the oxygen fl owmeter i s l ocated downstream from al l other flowmeters.
Fi gure 21-13 is a more contemporary version of the fi gure in Eger' s origi nal publi cati on. The
unused ai r fl ow tube has a l arge leak. Ni trous oxi de and oxygen fl ow rates are set at a rati o of
3:1. A potenti al l y dangerous arrangement i s shown in Fi gure 21-13A and 21-13B because the
ni trous oxide flowmeter is l ocated in the downstream posi tion. A hypoxic mixture can resul t
because a substanti al porti on of oxygen fl ow passes through the l eak, and all nitrous oxi de i s
di rected to the common gas outl et. A safer confi gurati on i s shown i n Fi gure 21-13C and 21-13D.
The oxygen fl owmeter i s located i n the downstream positi on. A porti on of the ni trous oxide flow
escapes through the l eak, and the remai nder goes toward the common gas outlet. A hypoxi c
mi xture is l ess li kel y because al l the oxygen flow is advanced by the nitrous oxide.
36
North
Ameri can Drger fl owmeters are arranged as i n Fi gure 21-13C, and Datex-Ohmeda fl owmeters are
as i n Fi gure 21-13D.
A l eak i n the oxygen fl ow tube may resul t i n creati on of a hypoxi c mi xture even when oxygen is
located in the downstream posi ti on (Fi g. 21-14).
34, 35
Oxygen escapes through the leak and ni trous
oxi de conti nues to fl ow toward the common outl et, parti cul arl y at hi gh rati os of ni trous oxi de to
oxygen flow.
Inaccuracy. Fl ow measurement error can occur even when fl owmeters are assembled properl y
with appropri ate components. Di rt or stati c el ectrici ty can cause a float to sti ck, and the actual
flow may be higher or lower than that indicated. Sti cki ng of i ndicator float i s more common i n the
low flow ranges because the annul ar space i s smal l er. A damaged fl oat can cause i naccurate
readings because the preci se rel ati onshi p between the fl oat and the flow tube is altered. Back
pressure from the breathing circui t can cause a fl oat to drop so that i t reads less than the actual
flow. Fi nal ly, i f fl owmeters are not ali gned properl y i n the verti cal posi tion (pl umb), readings can
be inaccurate because ti lti ng di storts the annul ar space.
17, 22, 35

Ambiguous Scale. Before the standardi zati on of flowmeter scal es and the wi despread use of
oxygen anal yzers, at l east two deaths resulted from confusi on created by ambi guous scal es.
17, 35, 37

The operator read the fl oat posi ti on besi de an adjacent but erroneous scal e i n both cases. Today
this error is l ess l i kel y to occur because contemporary flowmeter scales are marked ei ther directl y
onto the fl ow tube or immedi atel y to the ri ght of i t.
5
The possi bi li ty of confusi on i s mi ni mi zed
when the scal e is etched di rectly onto the tube.
El ect r oni c Fl owmet er s
As menti oned earli er, some newer anesthesi a workstati ons such as the Datex-Ohmeda S/5 ADU
FIGURE 21-13. Fl owmeter sequencea potenti al cause of hypoxi a. In the event of a
flowmeter l eak, a potenti al l y dangerous arrangement exi sts when nitrous oxi de i s located i n
the downstream posi ti on (A and B). The safest confi gurati on exi sts when oxygen i s located i n
the downstream posi ti on (C and D). See text for detai l s. (Modified with permission from Eger
EI II, Hylton RR, Irwin RH et al : Anestheti c fl owmeter sequencea cause for hypoxia.
FIGURE 21-14. Oxygen flow tube leak. An oxygen fl ow tube l eak can produce a hypoxic
mi xture regardl ess of fl ow tube arrangement. (Reproduced wi th permi ssi on from Brockwel l
RC: Inhal ed Anestheti c Del ivery Systems. In Mi ll er RD (ed): Anesthesia, 6
t h
ed, p 281.
Phi ladelphi a, Churchi l l Livingstone, 2004.)
and the North Ameri can Drger Fabi us GS among others have conventi onal control

knobs and fl ow control val ves, but have electroni c fl ow sensors and di gi tal di spl ays rather than
glass flow tubes. The output from the flow control val ve i s represented graphi cal l y and/or
numeri cal l y in l i ters per minute on the workstation' s i ntegrated user i nterface. These systems are
dependent on el ectri cal power to provide a preci se di spl ay of gas fl ow. However, even when
el ectrical power i s total l y i nterrupted, si nce the fl ow control val ves themselves are nonel ectronic,
oxygen should continue to flow. Si nce these machines do not have i ndi vi dual fl ow tubes that
physi cal ly quanti tate fl ow of each gas, el ectroni c fl ow sensors and often a small conventional
pneumatic fresh gas or total flow indicators are provi ded that gi ve the user an esti mate of the
total quanti ty fresh gas flowi ng from al l fl ow control val ves. Thi s mi ni ature flow tube indi cator
serves to i nform the user of the approxi mate quantity of gas that is l eaving the anesthesia
workstation' s common gas outl et, and i s functi onal even i n the event of a total power fail ure.
P r opor t i oni ng Syst ems
Manufacturers equip anesthesi a workstations with proporti oni ng systems i n an attempt to prevent
creati on and del i very of a hypoxic mi xture. Ni trous oxi de and oxygen are i nterfaced mechanicall y
and/or pneumati cally so that the minimum oxygen concentrati on at the common gas outl et i s
between 23 to 25% dependi ng on manufacturer.
Datex-Ohmeda Link-25 Proportion Limiting Control System
Conventi onal Datex-Ohmeda machi nes use the Li nk-25 System. The heart of the system i s the
mechani cal i ntegrati on of the ni trous oxide and oxygen flow control valves. It al lows i ndependent
adjustment of either val ve, yet automaticall y intercedes to maintai n a mini mum 25% oxygen
concentration with a maximum nitrous oxideoxygen fl ow rati o of 3:1. The Li nk-25 automati cal l y
increases oxygen flow to prevent delivery of a hypoxic mixture.
Fi gure 21-15 il l ustrates the Datex-Ohmeda Link-25 System. The ni trous oxi de and oxygen flow
control valves are i denti cal . A 14-tooth sprocket i s attached to the nitrous oxi de fl ow control
val ve, and a 28-tooth sprocket i s attached to the oxygen fl ow control val ve. A chai n physi cal l y
li nks the sprockets. When the nitrous oxi de fl ow control val ve i s turned through two revol uti ons,
or 28 teeth, the oxygen fl ow control val ve wi l l revol ve once because of the 2:1 gear rati o. The
final 3:1 fl ow rati o resul ts because the ni trous oxi de flow control valve is suppl i ed by
approxi mately 26 psi g, whereas the oxygen fl ow control val ve i s suppl i ed by 14 psi g. Thus, the
combi nation of the mechani cal and pneumati c aspects of the system yi el ds the fi nal oxygen
concentration. The Datex-Ohmeda Link-25 proportioni ng system can be thought of as a system
which increases oxygen fl ow when necessary to prevent del i very of a fresh gas mi xture wi th
oxygen concentrati on of l ess than 25%.
P.568
A few reports have descri bed fai l ures of the Datex-Ohmeda Link-25 system.
37, 38, 39, 40, 41
The
authors of these reports descri be fai lures that resul ted in ei ther i nabi l ity to admini ster oxygen
without ni trous oxide or that al lowed creation of a hypoxi c mi xture.
North American Drger Oxygen Ratio Monitor Controller/Sensitive
Oxygen Ratio Controller System
North American Drger' s proporti oni ng system, the Oxygen Rati o Monitor Control l er (ORMC), is
used on the North Ameri can Drger Narkomed 2A, 2B, 3, and 4. An equival ent system i s known as
the Sensiti ve Oxygen Rati o Controll er (S-ORC) on some newer Drger anesthesi a workstati ons
such as the Drger Fabi us GS and Narkomed 6000 seri es. The ORMC and the S-ORC are pneumati c
oxygenni trous oxide i nterlock systems desi gned to mai ntai n a fresh gas oxygen concentrati on of
at l east 25 3%. They control the fresh gas oxygen concentrati on to l evels substanti al l y higher
than 25% at oxygen flow rates less than 1 L/min. The ORMC and S-ORC l i mi t ni trous oxi de fl ow to
prevent del i very of a hypoxi c mi xture. Thi s is unl i ke the Datex-Ohmeda Link-25, whi ch acti vel y
increases oxygen fl ow.
A schemati c of the ORMC i s shown i n Fi gure 21-16. It i s composed of an oxygen chamber, a
ni trous oxide chamber, and a ni trous oxide sl ave control val ve. Al l are i nterconnected by a mobi l e
hori zontal shaft. The pneumati c i nput i nto the devi ce is from the oxygen and the ni trous oxi de
flowmeters. These fl owmeters are uni que because they have speci fi c resi stors l ocated downstream
from the fl ow control val ves. These resi stors create back pressures directed to the oxygen and
ni trous oxide chambers. The value of the oxygen fl ow tube resi stor is three to four ti mes that of
the ni trous oxi de fl ow tube resi stor, and the rel ati ve val ue of these resistors determi nes the val ue
of the control l ed fresh gas oxygen concentrati on. The back pressure in the oxygen and nitrous
oxi de chambers pushes agai nst rubber diaphragms attached to the mobi l e hori zontal shaft.
Movement of the shaft regulates the ni trous oxide sl ave control val ve, whi ch feeds the nitrous
oxi de fl ow control val ve.
FIGURE 21-15. Ohmeda Li nk-25 Proportion Limiti ng Control system. See text for detai ls.
FIGURE 21-16. North Ameri can Drger Oxygen Ratio Moni tor Controll er. See text for detai l s.
(Redrawn wi th permission from Schrei ber P: Safety Gui del i nes for Anesthesi a Systems.

If the oxygen pressure i s proporti onal l y higher than the ni trous oxide pressure, the ni trous oxide
sl ave control val ve opens more wi dely, al l owing more ni trous oxide to fl ow. As the nitrous oxi de
flow is i ncreased manual l y, the ni trous oxide pressure forces the shaft toward the oxygen
chamber. The val ve openi ng becomes more restricti ve and l i mi ts the ni trous oxide flow to the
flowmeter.
Fi gure 21-16 il l ustrates the acti on of a si ngle ORMC/S-ORC under di fferent sets of ci rcumstances.
The back pressure exerted on the oxygen di aphragm, i n the upper configurati on i s greater than
that exerted on the ni trous oxide di aphragm. This causes the hori zontal shaft to move to the l eft,
openi ng the ni trous oxi de slave control valve. Ni trous oxi de i s then abl e to proceed to its fl ow
control valve and out through the fl owmeter. In the bottom confi gurati on, the nitrous oxi de slave
control valve i s cl osed because of i nadequate oxygen back pressure.
24
To summarize, i n contrast
to the Datex-Ohmeda Link-25 system that acti vely increases oxygen flow to mai ntai n a fresh gas
oxygen concentrati on greater than 25%, the Drger ORMC and S-ORC are systems that li mit
ni trous oxide flow to prevent deli very of a fresh gas mi xture wi th an oxygen concentrati on of l ess
than 25%.
Limitations
Proporti oni ng systems are not fool proof. Workstati ons equi pped wi th proportioni ng systems can
stil l del iver a hypoxic mi xture under certai n condi tions. Foll owi ng i s a descripti on of some of the
si tuati ons in whi ch thi s may occur.
Wrong Supply Gas. Both the Datex-Ohmeda Link-25 and the Drger ORMC/S-ORC wil l be fooled i f
a gas other than oxygen i s present i n the oxygen pi pel ine. In the Link-25 System, the nitrous
oxi de and oxygen flow control valves wi ll conti nue to be mechani cal l y l i nked. Neverthel ess, a
hypoxi c mi xture can proceed to the common gas outlet. In the case of the Drger ORMC or S-ORC,
the rubber di aphragm for oxygen wi l l refl ect adequate suppl y pressure on the oxygen si de even
though the i ncorrect gas i s present, and flow of both the wrong gas pl us nitrous oxi de wi l l resul t.
The oxygen anal yzer i s the onl y workstati on moni tor besi des an i ntegrated mul tigas anal yzer that
would detect this condi ti on i n either system.
Defective Pneumatics or Mechanics. Normal operati on of the Datex-Ohmeda Li nk-25 and the
North American Drger ORMC/S-ORC is contingent on pneumatic and mechani cal i ntegri ty.
42

Pneumati c integrity in the Datex-Ohmeda System requi res properl y functi oning second-stage
regul ators. A ni trous oxi deoxygen ratio other than 3:1 wil l result i f the regul ators are not
precise. The chai n connecti ng the two sprockets must be i ntact. A 97% ni trous oxide concentrati on
can occur if the chain i s cut or broken.
43
In the North Ameri can Drger System, a functional
Oxygen Fail ure Protecti on Devi ce (OFPD) is necessary to supply appropri ate pressure to the ORMC.
The mechanical aspects of the ORMC/S-ORC, such as the rubber di aphragms, the flow tube
resistors, and the nitrous oxi de slave control valve, must l i kewi se be intact.
Leaks Downstream. The ORMC/S-ORC and the Link-25 function at the level of the flow control
val ves. A leak downstream from these devices, such as a broken oxygen flow tube (see Fi g. 21-
14), can resul t in del ivery of a hypoxi c mi xture to the common gas outl et. In thi s situation,
oxygen escapes through the l eak, and the predomi nant gas del i vered i s ni trous oxi de. The oxygen
moni tor and/or integrated mul ti gas anal yzer are the onl y machi ne safety devi ces that can detect
this probl em.
34
For the majori ty of i ts products, Drger Medi cal recommends a preoperati ve
positi ve pressure l eak test to detect such a leak. However, in additi on to this test, for many North
Ameri can Drger products, appl i cation of the negati ve-pressure l eak test as wel l may provi de a
more sensi tive way to detect such a l eak. Datex-Ohmeda almost universal ly recommends a
preoperati ve negati ve pressure leak test for i ts workstations, because of the frequentl y present
Tel ford, Pennsyl vani a, North Ameri can Drger, 1984.)
P.569
check valve located at the common gas outl et (see Checki ng Your Anesthesia Workstati on section).
Inert Gas Administration. Admi ni strati on of a third i nert gas, such as heli um, nitrogen, or CO
2
,
can cause a hypoxi c mi xture because contemporary proportioni ng systems l i nk only ni trous oxide
and oxygen.
44
Use of an oxygen analyzer is mandatory (or preferential ly a multi gas anal yzer when
avai labl e) i f the operator uses a thi rd gas.
Dilution of Inspired Oxygen Concentration by Volatile Inhaled Anesthetics. Vol ati l e i nhal ed
anesthetics, l ike i nert gases, are added to the mi xed gases downstream from both the fl owmeters
and the proportioni ng system. Concentrati ons of l ess-potent i nhal ed anestheti cs such as
desfl urane may account for a larger percentage of the total fresh gas compositi on than more
potent agents. Thi s can be seen when the maximum vapori zer dial settings of the various vol ati le
agents are exami ned (e.g., desflurane maxi mum dial setti ng 18% versus i soflurane maxi mum di al
setti ng of 5%). Since si gnifi cant percentages of these i nhal ed anestheti cs may be added
downstream of the proportioni ng system, the resul ti ng gas/vapor mi xture may contai n an inspired
oxygen concentrati on that i s l ess than 21% oxygen despi te a functi onal proportioni ng system. The
anesthesia provider must be aware of thi s possi bi li ty, particul arl y when hi gh concentrations of l ess
potent volatil e i nhal ed anestheti cs are used.
Oxygen Fl ush Val ve
The oxygen fl ush val ve al l ows di rect communi cation between the oxygen hi gh-pressure ci rcui t and
the low-pressure ci rcui t (see Fi g. 21-3). Fl ow from the oxygen fl ush valve enters the low-pressure
ci rcuit downstream from the vaporizers and most i mportantl y downstream from the Datex-Ohmeda
machine outlet check val ve. The spri ng-loaded oxygen flush val ve stays cl osed until the operator
opens i t by depressi ng the oxygen flush button. Actuati on of the valve del i vers 100% oxygen at 35
to 75 L/mi n to the breathi ng ci rcui t.
23

The oxygen fl ush val ve can provi de a hi gh pressure oxygen source sui tabl e for jet venti l ati on
under the fol lowi ng ci rcumstances: (1) the anesthesi a machine i s equi pped wi th a one-way check
val ve positi oned between the vaporizers and the oxygen flush val ve; and (2) when a posi ti ve
pressure reli ef valve exi sts downstream of the vapori zers, thi s pressure rel ief valve must be
upstream of the outl et check val ve. Because the Ohmeda Modulus II has such a one-way check
val ve and i ts posi tive pressure rel ief valve i s upstream from the check val ve, the enti re oxygen
flow of 35 to 75 L/mi n is del ivered to the common gas outl et at a hi gh pressure of 50 psi g. On the
other hand, the Ohmeda Modul us II Pl us and some Ohmeda Excel machi nes are not capabl e of
functi oni ng as an appropri ate oxygen source for jet ventil ati on. The Ohmeda Modul us II pl us,
whi ch does not have the check val ve, provi des onl y 7 psi g at the common gas outl et because some
oxygen fl ow travel s retrograde through an i nternal rel i ef val ve located upstream from the oxygen
flush val ve. The Ohmeda Excel 210, whi ch does have a one-way check val ve, al so has a posi ti ve
pressure reli ef val ve downstream from the check val ve and therefore i s unsui tabl e for jet
ventil ati on. Ol der North Ameri can Drger machi nes such as the Narkomed 2A (whi ch al so does not
have the outlet check val ve) provi de an i ntermedi ate pressure of 18 psig to the common gas
outl et because some pressure is vented retrograde through a pressure rel i ef val ve l ocated i n the
vaporizers.
45

Several hazards have been reported with the oxygen flush valve. A defecti ve or damaged val ve
can stick in the ful ly open posi tion, resul ting i n barotrauma.
46
A val ve sti cki ng i n a parti all y open
positi on can result i n patient awareness because the

oxygen fl ow from the incompetent val ve dil utes the i nhal ed anestheti c.
19, 47
Improper use of
normal ly functi oni ng oxygen flush val ves al so can resul t in probl ems. Overzeal ous intraoperative
oxygen fl ushing can di lute inhal ed anestheti cs. Oxygen fl ushing duri ng the inspi ratory phase of
positi ve pressure venti lation can produce barotrauma i n patients i f the anesthesi a machine does
not i ncorporate fresh gas decoupl ing or an appropri ately adjusted i nspi ratory pressure li mi ter.
Anesthesi a systems (Drger Narkomed 6000 seri es, Jul ian, Fabi us GS and Datascope Anestar) with
fresh gas decoupli ng are i nherentl y safer from the standpoi nt of mi nimizing the chance of
producing barotrauma from inappropri ate oxygen fl ush valve use. These systems physi cal ly
P.570
di vorce the fresh gas i nflow from ei ther the fl owmeters or the oxygen flush val ve from the
del i vered ti dal vol ume presented to the pati ent's l ungs (see Fresh Gas Decoupl i ng secti on). Wi th
tradi tional anesthesi a breathing circui ts, excess vol ume cannot be vented duri ng the i nspi ratory
phase of mechani cal venti lation because the ventilator rel ief valve i s cl osed and the Adjustabl e
Pressure Limi ti ng (APL) val ve i s either out-of-ci rcuit or cl osed.
48
An alternative way to manage
this probl em can be seen on the Datex-Ohmeda S/5 ADU and Aesti va. These circl e systems uti li ze
an integrated adjustabl e pressure l imi ter. If thi s devi ce i s properly adjusted, it functi ons l ike the
APL valve to l i mi t the maxi mum ai rway pressure to a safe level , thereby reduci ng the possi bi li ty of
barotrauma.
Some very old anesthesia systems made use of a freestandi ng vapori zer downstream from the
common gas outl et; on these systems, oxygen fl ushi ng coul d rapi dl y del i ver l arge quanti ti es of
inhaled anesthetic to the pati ent. Final l y, i nappropriate preoperati ve use of the oxygen fl ush to
eval uate the l ow-pressure ci rcui t for leaks can be misl eadi ng, parti cul arl y on Datex-Ohmeda
machines wi th a one-way check val ve at the common outl et.
18
Si nce back pressure from the
breathing circui t cl oses the one-way check val ve air-ti ght, major low-pressure ci rcui t l eaks can go
undetected wi th this l eak test (see Checki ng Your Anesthesia Workstation secti on).
VAPORIZERS
As dramati cal l y as the evoluti on of the anesthesi a workstation has been i n recent years,
vapori zers have al so changed from rudi mentary ether inhal ers and copper kettles to the present
temperature compensated, computer-control led, and fl ow-sensi ng devices we use today. In 1993,
with the introducti on of desfl urane to the cl i ni cal setti ng, an even more sophi sti cated vaporizer
was i ntroduced to handl e the uni que physi cal properti es of this agent. Now, a new generati on of
anesthesi a vapori zers blendi ng both ol d copper kettl e-l i ke technol ogy and new computerized
control technol ogy has emerged i n the Datex-Ohmeda Aladi n cassette vapori zer system. Before
the discussion of vari abl e bypass vaporizers, the Datex-Ohmeda Tec 6 desfl urane vapori zer, and
the Datex-Ohmeda Aladi n cassette vapori zer, certai n physi cal pri nci pl es wi l l be revi ewed bri efly to
faci li tate understanding of the operating princi pl es, constructi on, and desi gn of contemporary
vol ati l e anestheti c vaporizers.
P hysi cs
Vapor Pressure
Contemporary i nhaled vol ati l e anestheti cs exi st in the l i qui d state at temperatures bel ow 20C.
When a vol ati le li qui d i s i n a cl osed container, molecul es escape from the l i qui d phase to the vapor
phase unti l the number of molecul es i n the vapor phase is constant. These mol ecul es in the vapor
phase bombard the wal l of the contai ner and create a pressure known as the saturated vapor
pressure. As the temperature increases, more molecul es enter the vapor phase, and the vapor
pressure i ncreases (Fi g. 21-17). Vapor pressure i s i ndependent of atmospheri c pressure and i s
conti ngent onl y on the temperature and physi cal characteristics of the l iqui d. The boi li ng poi nt of
a l i qui d i s defi ned as that temperature at whi ch the vapor pressure equals atmospheri c
pressure.
49, 50, 51
At 760 mm Hg, the boi li ng poi nts for desflurane, i soflurane, halothane, enfl urane,
and sevofl urane are approximatel y 22.8, 48.5, 50.2, 56.5, and 58.5C, respecti vel y. Unl ike other
contemporary i nhal ed anestheti cs, desfl urane boi l s at temperatures that may be encountered i n
cl i ni cal settings such as pediatri c and burn operati ng rooms. Thi s uni que physical characteri sti c
al one mandates a speci al vapori zer desi gn to control the deli very of desfl urane. If agent-specific
vapori zers are i nadvertentl y mi sfi l l ed wi th i ncorrect l iquid anestheti c agents, the resul ti ng
mi xtures of vol ati l e agents may demonstrate unique properti es from those of the i ndi vi dual
component agents. The al tered vapor pressure and other physi cal properti es of the resul ting
azeotropic mi xtures that result from the mi xi ng of vari ous agents may al ter the output of the
anesthetic vapori zer (see Variabl e Bypass Vapori zers: Misfi l li ng section).
52

Latent Heat of Vaporization
When a mol ecul e is converted from a l i qui d to the gaseous phase, energy i s consumed because the
mol ecul es of a li qui d tend to cohere. The amount of energy that is consumed for a gi ven li quid as
i t i s converted to a vapor i s referred to as the latent heat of vapori zation. It i s more preci sel y
defined as the number of cal ories requi red to change 1 g of li quid i nto vapor without a
temperature change. The energy for vapori zati on must ei ther come from the l i qui d i tself or from
an outsi de source. The temperature of the l iquid itself wi ll decrease during vapori zati on i n the
absence of an outside energy source. This energy l oss can l ead to si gni fi cant decreases i n
temperature of the remaining l iqui d, and can greatl y decrease subsequent vaporizati on.
49, 51, 53

Specific Heat
The specific heat of a substance i s the number of cal ori es requi red to i ncrease the temperature of
1 g of a substance by

1C.
21, 49, 51
The substance can be a sol i d, l iquid, or gas. The concept of specific heat i s important
to the desi gn, operati on, and constructi on of vapori zers because it i s appl i cabl e in two ways. Fi rst,
the speci fi c heat val ue for an i nhaled anesthetic is i mportant because it i ndi cates how much heat
must be suppl i ed to the l i qui d to mai ntain a constant temperature when heat is bei ng lost duri ng
vapori zation. Second, manufacturers select vapori zer component materi als that have a high
specific heat to mi ni mi ze temperature changes associ ated with vaporizati on.
Thermal Conductivity
Thermal conductivity is a measure of the speed with whi ch heat flows through a substance. The
hi gher the thermal conducti vi ty, the better the substance conducts heat.
49
Vaporizers are
constructed of metals that have rel ati vel y high thermal conducti vi ty, these hel p to mai ntain a
uni form i nternal temperature.
FIGURE 21-17. Vapor pressure versus temperature curves for desflurane, isoflurane,
halothane, enflurane, and sevofl urane. The vapor pressure curve for desflurane i s both
steeper and shi fted to hi gher vapor pressures when compared with the curves for other
contemporary i nhal ed anestheti cs. (From inhal ed anestheti c package insert equati ons and
from Susay SR, Smi th MA, Lockwood GG: The saturated vapor pressure of desflurane at
vari ous temperatures. Anesth Analg 83:864, 1996.)
P.571
Ambient Pressure Effects
See Datex-Ohmeda Tec-6 Vapori zer for Desflurane: Factors that Infl uence Vapori zer Output:
Vari ed Al ti tudes.
Var i abl e Bypass Vapor i zer s
The Datex-Ohmeda Tec 4, Tec 5, and Tec 7, as well as the North American Drger Vapor 19.n and
20.n vapori zers are cl assi fi ed as vari abl e bypass, flow-over, temperature-compensated, agent-
specific, out of breathi ng ci rcuit vapori zers.
49
Vari abl e bypass refers to the method for regul ati ng
the anestheti c agent concentrati on output from the vaporizer. The concentrati on control di al
setti ng determi nes the rati o of fl ow that goes through the bypass chamber and through the
vapori zing chamber as fresh gas from the fl owmeters enters the vapori zer i nl et. The gas
channel ed through the vapori zi ng chamber fl ows over a wi ck system saturated wi th the li qui d
anestheti c and subsequently al so becomes saturated wi th vapor. Thus, fl ow-over refers to the
method of vaporizati on and i s i n contrast to a bubbl e-through system that may be seen i n some
copper kettl e type vapori zers of ol d. The Tec 4, Tec 5, and Tec 7, and the DrgerVapor 19.n and
20.n are further cl assified as temperature compensated. Each of these i s equi pped wi th an
automati c temperature-compensati ng devi ce that hel ps mai ntai n a constant vaporizer output over
a wide range of operati ng temperatures. These vapori zers are agent speci fi c and out-of-ci rcuit
because each is desi gned to accommodate a si ngle anesthetic agent and to be physi cal l y l ocated
outsi de of the breathi ng ci rcuit. Variabl e bypass vapori zers are used to del i ver hal othane,
enflurane, isoflurane, and sevofl urane, but not desfl urane.
Basic Operating Principles
A diagram of a generic, variabl e bypass vapori zer i s shown i n Fi gure 21-18. Vapori zer components
incl ude the concentrati on control di al , the bypass chamber, the vapori zi ng chamber, the fi l l er port,
and the fi l ler cap. Using the fi l ler port, the operator fi l ls the vapori zi ng chamber wi th l iqui d
anesthetic. The maxi mum safe fi l l level i s predetermi ned by the posi ti on of the fil l er port, whi ch i s
positi oned to mini mi ze the chance of overfi l li ng. If a vapori zer is overfil l ed or ti lted, l iqui d
anesthetic can spi ll into the bypass chamber. If thi s were to happen, both the vapori zi ng chamber
fl ow and the bypass chamber fl ow coul d potenti al l y be carryi ng saturated anestheti c vapor, and an
overdose woul d resul t. The concentrati on control di al is a variabl e restri ctor, and it can be l ocated
ei ther i n the bypass chamber or the outlet of the vapori zi ng chamber. The function of the
concentration control dial i s to regul ate the relative fl ow rates through the bypass and vaporizing
chambers.
Fl ow from the flowmeters enters the i nl et of the vaporizer. More than 80% of the flow passes
strai ght through the bypass chamber to the vapori zer outl et, and thi s accounts for the name
bypass chamber. Less than 20% of the fl ow from the fl owmeters i s diverted through the
vapori zi ng chamber. Dependi ng on the temperature and vapor pressure of the parti cul ar i nhaled
anesthetic, the fresh gases enteri ng the vapori zi ng chamber entrai n a specific flow of the inhaled
anesthetic agent. The mi xture that exits the vapori zer i s the combi nation of fl ow through the
bypass chamber, fl ow through the vapori zi ng chamber, and flow of entrained anestheti c vapor.
The fi nal concentrati on of inhal ed anestheti c is the rati o of the fl ow of the i nhaled anesthetic to
the total gas fl ow.
49, 54

The vapor pressure of an i nhal ed anestheti c depends on the ambi ent temperature (see Fi g. 21-
17). For exampl e, at 20C the vapor pressure of i sofl urane i s 238 mm Hg, whereas at 35C the
vapor pressure al most doubl es (450 mm Hg). Vari abl e bypass vaporizers have an internal
mechani sm to compensate for variati ons i n ambient temperature. The temperature-compensati ng
val ve of the Datex-Ohmeda Tec 4 is shown i n Fi gure 21-19. At rel ati vel y high ambi ent
temperatures, such as those commonl y seen in operati ng rooms desi gnated for the care of
pedi atri c or burn patients, the vapor pressure i nsi de

the vaporizing chamber i s hi gh. To compensate for thi s i ncreased vapor pressure, the bi metal l ic
stri p of the temperature-compensating valve leans to the right, decreasi ng the resistance to fl ow
through the bypass chamber. Thi s al l ows more fl ow to pass through the bypass chamber and l ess
flow to pass through the vaporizing chamber. In contrast, i n a col d operating room envi ronment,
the vapor pressure i nside the vaporizing chamber i s reduced. To compensate for this decrease in
vapor pressure, the bi metal l ic stri p l eans to the l eft. Thi s i ncreases the resistance to fl ow through
the bypass chamber, causi ng more flow to pass through the vaporizing chamber and l ess to pass
through the bypass chamber. The net effect in both situations i s mai ntenance of rel ati vel y
constant vapori zer output.
Factors That Influence Vaporizer Output
If an i deal vapori zer exi sted, wi th a fi xed di al setti ng, i ts output woul d be constant regardless of
FIGURE 21-18. Generi c vari abl e bypass vapori zer. See text for detai l s.
P.572
FIGURE 21-19. Si mpl ified schematic of the Ohmeda Tec Type Vapori zer. See text for detai l s.
vari ed fl ow rates, temperatures, back pressures, and carri er gases. Desi gni ng such a vapori zer i s
di fficul t because as ambient condi tions change, the physi cal properti es of gases and of vapori zers
themsel ves can change.
54
Contemporary vaporizers approach ideal but stil l have some l imi tati ons.
Even though some of the most sophi sti cated vapori zer systems now avai l abl e use computer-
control led components and mul tipl e sensors, they have yet to become si gni fi cantl y more accurate
than conventi onal vapori zers. Several factors that affect vapori zer performance i n general are
descri bed bel ow.
Flow Rate. Wi th a fi xed di al setti ng, vaporizer output can vary with the rate of gas flowi ng
through the vapori zer. Thi s vari ati on i s parti cul arl y notable at extremes of flow rates. The output
of al l vari able bypass vapori zers i s l ess than the dial setti ng at low flow rates (l ess than 250
mL/mi n). This results from the relativel y hi gh densi ty of volatil e i nhal ed anestheti cs. Insuffi cient
turbul ence i s generated at l ow flow rates i n the vapori zi ng chamber to upwardl y advance the
vapor molecul es. At extremel y hi gh flow rates, such as 15 L/mi n, the output of most vari abl e
bypass vaporizers i s less than the dial setting. Thi s di screpancy is attributed to incomplete mi xi ng
and fail ure to saturate the carri er gas i n the vapori zi ng chamber. Also, the resi stance
characteri sti cs of the bypass chamber and the vapori zing chamber can vary as flow increases.
These vari ati ons can resul t in decreased output concentrati on.
54

Temperature. Because of improvements i n desi gn, the output of contemporary temperature-
compensated vapori zers i s al most li near over a wide range of temperatures. Automati c
temperature-compensati ng mechani sms i n the bypass chamber mai ntai n a constant vapori zer
output with varyi ng temperatures.
23
As previ ousl y described, a bi metal l i c stri p (see Fi g. 21-19) or
an expansion el ement (Fi g. 21-20) di rects a greater proporti on of gas fl ow through the bypass
chamber as temperatures i ncrease.
54
Additi onal l y, the wi ck systems are placed in direct contact
with the metal wal l of the vapori zer to help repl ace energy (heat) consumed duri ng vapori zati on.
The materi al s vapori zers are constructed from are chosen because they have a relatively hi gh
specific heat and hi gh thermal conductivity. These factors hel p minimi ze the effect of cool i ng
duri ng vaporizati on.
Intermittent Back Pressure. Intermi ttent back pressure that resul ts from ei ther posi ti ve
pressure ventil ati on or use of the oxygen fl ush val ve may resul t i n hi gher than expected vapori zer
output. Thi s phenomenon, known as the pumpi ng effect, i s more pronounced at l ow fl ow rates, l ow
di al settings, and l ow levels of l i qui d anestheti c in the vapori zi ng chamber.
49, 54, 55, 56, 57

Addi ti onal l y, the pumpi ng effect i s i ncreased by rapi d respi ratory rates, hi gh peak i nspi red
FIGURE 21-20. Si mpl ified schematic of the North Ameri can Drger Vapor 19.1 vapori zer.
See text for detai ls.
pressures, and rapi d drops i n pressure duri ng expi ration.
47, 48, 49, 50, 51
Newer vari abl e bypass
vapori zers such as the Datex-Ohmeda Tec 4, Tec 5, and Tec 7, and North Ameri can Drger Vapor
19.n and 20.n are relativel y immune from the pumping effect. One proposed mechani sm for the
pumpi ng effect i s dependent on retrograde pressure transmi ssi on from the pati ent ci rcuit to the
vapori zer duri ng the i nspi ratory phase of posi tive pressure venti lation. Gas mol ecules are
compressed i n both the bypass and vapori zi ng chambers. When the back pressure i s suddenl y
rel eased duri ng the expiratory phase of posi ti ve-pressure ventil ati on, vapor exi ts the vaporizing
chamber vi a both the vapori zi ng chamber outl et and retrograde through the vapori zi ng chamber
inlet. This occurs because the output resi stance of the bypass chamber i s l ower than that of the
vapori zing chamber, particul arl y at l ow dial settings. The enhanced output concentrati on results
from the increment of vapor that travel s i n the retrograde di rection to the bypass
chamber.
54, 55, 56, 57

To decrease the pumpi ng effect, the vapori zi ng chambers of newer systems are smal l er than those
of early vari able bypass vapori zers such as the Fl uotec Mark II (750 mL).
56
Therefore, no
substantial volumes of vapor can be di scharged from the vaporizi ng chamber i nto the bypass
chamber duri ng the expiratory phase. The North American Drger Vapor 19.1 and 20.n (see Fi g.
21-20) have a long spi ral tube that serves as the i nl et to the vaporizing chamber.
56
When the
pressure i n the vapori zi ng chamber i s rel eased, some of the vapor enters thi s tube but does not
enter the bypass chamber because of tube l ength.
50
The Tec 4 (see Fi g. 21-19) has an extensive
baffle system i n the vaporizing chamber, and a one-way check val ve has been inserted at the
common gas outl et to mi ni mize the pumping effect. Thi s check val ve attenuates but does not
el i mi nate the pressure increase because gas stil l fl ows from the fl owmeters to the vapori zer duri ng
the inspiratory phase of positi ve pressure venti l ati on.
49, 58

Carrier Gas Composition. Vapori zer output i s i nfl uenced by the compositi on of the carrier gas
that fl ows through the vaporizer.
59, 60, 61, 62, 63, 64, 65, 66
Duri ng experimental condi ti ons, when the
carri er gas i s rapi dl y changed from 100% oxygen to 100% ni trous oxide, a sudden transi ent
decrease i n vapori zer output occurs, fol l owed by a sl ow increase to a new steady-state val ue (Fi g.
21-21B).
64, 65
Because ni trous oxide i s more sol ubl e than oxygen i n the halogenated l i qui d wi thi n
the vaporizer sump, when this swi tch occurs the output from the vaporizing chamber i s transi entl y
reduced.
64
Once the anestheti c li qui d i s total l y saturated wi th ni trous oxi de, vapori zi ng chamber
output i ncreases somewhat, and a new steady state is establ i shed.
FIGURE 21-21. Halothane output of a North Ameri can Drger Vapor 19.1 vapori zer wi th
di fferent carrier gases. The i ni tial output concentrati on i s approximatel y 4% hal othane when
oxygen is the carri er gas at flows of 6 L/mi n (A). When the carri er gas i s qui ckl y swi tched to
100% nitrous oxi de (B), the hal othane concentration decreases to 3% wi thin 8 to 10
seconds. Then, a new steady-state concentrati on of approximatel y 3.5% i s attai ned wi thin 1
mi nute. See text for detai ls. (Modi fi ed wi th permission from Gould DB, Lampert BA, MacKrell
The expl anati on for the new steady-state output val ue i s l ess wel l understood.
66
With
contemporary vapori zers such as the North American Drger Vapor 19.n and 20.n and the Ohmeda
Tectype conventional vapori zers, the steady-state output val ue

is l ess when ni trous oxide rather than oxygen i s the carri er gas (see Fi g. 21-21B). Conversel y, the
output of some ol der vapori zers is enhanced when nitrous oxi de i s the carri er gas i nstead of
oxygen.
59, 61
The steady-state pl ateau i s achieved more rapi dl y wi th i ncreased flow rates,
regardl ess of the ul ti mate output value.
65
Factors that contri bute to the characteri sti c steady-state
response resul ti ng when various carrier gases are used i ncl ude the vi scosi ty and densi ty of the
carri er gas, the rel ati ve solubi li ties of the carrier gas in the anestheti c li quid, the fl ow-spl i tting
characteri sti cs of the speci fi c vapori zer, and the concentrati on control di al setti ng.
61, 64, 65, 66

Safety Features
Newer generati ons of anesthesi a vaporizers i ncludi ng the North American Drger 19.n and 20.n,
and the Datex-Ohmeda Tec 4, Tec 5, and Tec 7 now have buil t-in safety features that have
minimized or eliminated many hazards once associated wi th variabl e bypass vapori zers. Agent-
specific, keyed fi l li ng devi ces hel p prevent fil l ing a vaporizer with the wrong agent. Overfil l ing of
these vapori zers i s mi ni mi zed because the fi ll er port is l ocated at the maximum safe l i qui d l evel .
Fi nal ly, today' s vaporizers are firml y secured to a vapori zer mani fold on the anesthesi a
workstation. Thus, problems associ ated wi th vapori zer ti ppi ng have become much less frequent.
Contemporary i nterlock systems prevent admini stration of more than one i nhal ed anestheti c.
Hazards
Despi te many safety features, some hazards are sti l l associ ated wi th contemporary vari abl e
bypass vapori zers.
Misfilling. Vapori zers not equi pped wi th keyed fi l l ers have been occasi onall y mi sfil l ed wi th the
wrong anesthetic l i qui d.
67
A potenti al for misfi ll i ng exists even on contemporary vapori zers
equi pped wi th keyed fi l l ers.
68, 69, 70
When a vapori zer misfi l li ng occurs, patients can i nadvertentl y
be rendered inadequatel y, or excessively, anestheti zed dependi ng on whi ch drug i s pl aced i n the
vapori zer. The use of a mul ti gas anal yzer may al ert the user to such a probl em.
Contamination. Contaminati on of anestheti c vaporizer contents has occurred by fil l i ng an
isoflurane vaporizer wi th a contami nated bottle of i soflurane. A potenti al l y seri ous i nci dent was
avoi ded because the operator detected an abnormal acri d odor.
71

Tipping. Ti ppi ng of a vapori zer can occur when they are i ncorrectly swi tched out or moved.
However, ti pping i s unli kel y when a vapori zer is attached to the anesthesi a workstation mani fold
short of the entire machi ne bei ng turned over. Excessi ve ti pping can cause the li qui d agent to
enter the bypass chamber and can cause output with extremel y hi gh agent concentrati on.
72
The
Tec 4 i s sl i ghtl y more i mmune to ti ppi ng than the North Ameri can Drger Vapor 19.n because of
its extensive baffle system. However, if either vapori zer is ti pped, i t should not be used until i t
has been fl ushed for 20 to 30 mi nutes at hi gh fresh gas fl ow rates. During thi s procedure, having
the vaporizer concentrati on control dial set at a low concentrati on maximi zes bypass chamber fl ow
and wi ll ai d i n removal of any residual l i qui d anestheti c in that area.
49
After fol l owi ng thi s
procedure, the use of a multi gas anal yzer i s strongl y recommended. The Drger Vapor 20.n seri es
vapori zers now have a transport (T) di al setting that hel ps prevent ti ppi ng-rel ated probl ems.
When the dial is pl aced in thi s posi ti on, the vapori zer sump i s i solated from the bypass chamber,
thereby reduci ng the l i kel i hood of ti ppi ng and a resul ti ng accidental overdose. Therefore, any ti me
one of these vapori zers i s moved separate from the anesthesi a workstati on, the control di al shoul d
be placed in the T position.
TN: Effect of ni trous oxi de sol ubi li ty on vaporizer aberrance. Anesth Anal g 61:939, 1982.)
P.573
The design of the Tec-6 and the Al adin cassette vaporizer systems, both from Datex-Ohmeda, has
practi cal ly eli minated the possi bil i ty of tippi ng from these products. Si nce the Aladi n cassette
vapori zer' s bypass chamber i s physi cal l y separated from the cassette, and permanentl y resi des
in the anesthesi a workstation, the possi bil i ty of tippi ng is vi rtual l y el i mi nated. Tippi ng of the
Aladi n cassettes themselves when they are not install ed i n the vaporizer i s not probl emati c.
Overfilling. Improper fi l l i ng procedures combi ned wi th fai lure of the vaporizer si ght gl ass can
cause overfil l ing and pati ent overdose. Liquid anestheti c enters the bypass chamber, and up to 10
ti mes the i ntended vapor concentration can be deli vered to the common gas outl et.
73
Most modern
vapori zers are now rel ati vel y i mmune to overfil l i ng because of si de-fil l rather than top-fil l desi gns.
Side-fil l systems largel y prevent overfi ll i ng.
Underfilling. Just as wi th overfi ll i ng, underfi l li ng of anestheti c vaporizers may al so be
problematic. When a Tec 5 sevofl urane vapori zer i s in a l ow-fil l state and used under conditi ons of
hi gh fresh gas fl ow rates (>7.5 L/mi n) and hi gh di al setti ng (such as seen duri ng inhal ati onal
inducti ons), the vapori zer output may abruptl y decrease to l ess than 2%. The causes of thi s
problem are most li kel y mul tifactorial . However, the combi nation of l ow vaporizer fil l state (<25%
ful l ) i n combinati on wi th the hi gh vaporizing chamber fl ow, can resul t i n a cl inicall y si gni fi cant and
reproduci ble fal l i n vapori zer output.
74

Simultaneous Inhaled Anesthetic Administration. On some ol der anesthesi a machines from
Datex-Ohmeda that are equi pped with the Select-a-Tec three-vapori zer manifol d that does not
util i ze a vapor-interlock system, two i nhal ed anestheti cs can be admi nistered si mul taneousl y when
the center vapori zer is removed. On such machi nes, the l eft or ri ght vaporizer shoul d be moved to
the central positi on i f the central vaporizer i s removed (as i ndi cated by the mani fol d warni ng
label). Once thi s i s done, the vapori zer's i nterlock system wi l l al low only one agent to be
administered at a ti me. More contemporary Sel ect-a-Tec vapori zer mani fol ds have a bui lt-in
vapor-interlock or vapor-exclusion devi ce that prevents thi s problem. On these newer three-
vapori zer systems, a U-shaped pl asti c device l i nks the vaporizer extensi on rods even when the
vapori zers are not adjacent to one another on the mani fold. On such a system, the mani fol d pl us
the vaporizers themselves comprise the vapor-interlock or vapor-excl usi on system.
Leaks. Vaporizer l eaks occur frequentl y, and can potenti al l y resul t in pati ent awareness duri ng
anesthesia.
11, 15, 55, 75
A loose fil l er cap i s the most common source of vaporizer l eaks. With

some key-fi l l ed Penl on and Drger vapori zers, a l oose fi ll er screw clamp al l ows escape of
saturated anestheti c vapor.
11
Leaks can occur at the O-ri ng juncti ons between the vapori zer and
its mani fold. To detect a l eak wi thi n a vaporizer, the concentrati on control di al must be i n the on
positi on. Even though vaporizer l eaks in Drger Systems can potenti al l y be detected wi th a
conventi onal posi ti ve-pressure l eak test (because of the absence of an outl et check val ve), a
negati ve-pressure l eak test i s more sensi ti ve and al l ows the user to detect even smal l l eaks.
Datex-Ohmeda recommends a negati ve-pressure leak testi ng devi ce (sucti on bul b) to detect
vapori zer l eaks i n the Modul us I, Modulus II, Excel, and the Aesti va workstations because of the
check valve located just upstream of each machine' s fresh gas outlet (see Checki ng Your
Anesthesi a Workstation secti on).
Many newer anesthesia workstati ons are capabl e of performi ng sel f-testi ng procedures that, in
some cases, may eli mi nate the need for the conventional negative-pressure l eak testi ng. However,
it i s of vi tal i mportance that anesthesia providers understand that these sel f-tests may not detect
internal vaporizer l eaks on systems wi th add-on vaporizers. For the sel f-tests to determine i f an
internal vaporizer l eak i s present, the l eak test must be repeated with each vaporizer sequenti al l y
whi l e its concentrati on control di al is turned to the on positi on. Recal l that when a vapori zer' s
concentration control di al i s set i n the off positi on, i t may not be possi ble to detect even major
internal leaks such as an absent or l oose fi l ler cap.
Anesthesia Vaporizers and Environmental Considerations. Today, more than ever,
anesthetics are bei ng administered to pati ents outsi de the operating room. One such l ocati on that
has proved someti mes di ffi cul t to work in i s the MRI sui te. The presence of a powerful magnet
fiel d, the si gni fi cant noise poll uti on, and l i mi ted access to the pati ent during the procedure all
P.574
compl i cate care in thi s setti ng. It i s i mperati ve that only nonferrous (MRI compati bl e) equi pment
be used i n these setti ngs. Some anesthesi a vaporizers, although they may appear nonferrous by
testi ng wi th a horseshoe magnet, may indeed contain substanti al i nternal ferrous components.
Inappropriate use of such a device i n an MRI suite may potenti al l y turn them into a dangerous
mi ssi le i f left unsecured.
76

The Dat ex- Ohmeda Tec 6 Vapor i zer f or Desf l ur ane
Because of i ts unique physi cal characteristics, the control l ed vaporizati on of desflurane
required a novel approach to vapori zer desi gn. Datex-Ohmeda devel oped the Tec 6 vapori zer,
the fi rst such system, and rel eased i t into cl inical use i n the early 1990s. The Tec 6 vapori zer is
an electri cal ly heated, pressuri zed device speci fi cal l y desi gned to del i ver desflurane.
77, 78
The
vapor pressure of desfl urane i s three to four ti mes that of other contemporary inhal ed anestheti cs,
and it boi ls at 22.8C,
79
whi ch is near room temperature (see Fi g. 21-17). Desfl urane has a
minimum al veolar anesthetic concentrati on (MAC) value of 6 to 7%.
79
Desflurane is val uable
because i t has a l ow bl ood gas sol ubi li ty coeffi ci ent of 0.45 at 37C, and recovery from anesthesia
i s more rapi d than wi th many other potent i nhal ed anestheti cs.
79
In 2004, Drger Medical recei ved
FDA approval for i ts own versi on of the Tec 6 desfl urane vaporizer. The operati ng pri nci pl es
descri bed i n the fol l owing di scussi on are appl i cabl e to ei ther system, even though we refer to the
Tec 6 speci fi cal ly.
Unsuitability of Contemporary Variable Bypass Vaporizers for
Controlled Vaporization of Desflurane
Desfl urane' s hi gh vol ati l ity and moderate potency precl ude i ts use wi th contemporary variabl e
bypass vapori zers such as Datex-Ohmeda Tec 4, Tec 5, and Tec 7, or the North American
Drger Vapor 19.n or 20.n for two pri mary reasons:
77

1. At 20C the vapor pressure of desfl urane i s near one atmosphere.
The vapor pressures of enflurane, i soflurane, halothane, and desflurane at 20C are 172,
240, 244, and 669 mm Hg, respectively (see Fi g. 21-17).
79
Equal amounts of fl ow through a
tradi tional vapori zer would vaporize many more volumes of desflurane than any other of
these agents. For exampl e, at one atmosphere and 20C, 100 mL/min passi ng through the
vapori zi ng chamber woul d entrai n 735 mL/mi n desfl urane versus 29, 46, and 47 mL/mi n of
enfl urane, i sofl urane, and hal othane, respectively.
77
Under these same condi tions, to
produce 1% desflurane output the amount of bypass fl ow necessary to achi eve suffici ent
di l uti on of the l arge vol ume of desflurane saturated anestheti c vapor woul d be approxi matel y
73 L/min, compared to 5 L/mi n or less for the other three anesthetics. Addi ti onall y, above
22.8C at one atmosphere, desflurane wi ll boil . The amount of vapor produced woul d be
li mi ted only by the heat energy avai l abl e from the vapori zer owi ng to its speci fi c heat.
77

2. Contemporary vapori zers l ack an external heat source.
The l atent heat of vapori zati on for desflurane is approxi matel y equal to that of enflurane,
isoflurane, and hal othane; however i ts MAC i s 4 to 9 times hi gher than those of the other
three i nhal ed anestheti cs. Thus, the absolute amount of desflurane vaporized over a gi ven
ti me period i s consi derably greater than the other anestheti c drugs. Suppl yi ng desfl urane vi a
a conventi onal vaporizer i n hi gher (equi val ent MAC) concentrations woul d l ead to excessi ve
cool i ng of the vapori zer and woul d si gni fi cantl y reduce i ts output. In the absence of an
external heat source, temperature compensati on usi ng tradi ti onal mechani cal devi ces would
be al most i mpossi bl e. Because of the broad range of temperatures seen i n the cli ni cal
setti ng, and because of desfl urane' s steep vapor pressure versus temperature curve (see
Fi g. 21-17), the del i very of desfl urane i n a conventi onal anestheti c vapori zer woul d be at
best unpredi ctabl e.
77

Operating Principles of the Tec 6 and Tec 6 Plus
To achi eve control l ed vapori zati on of desfl urane, Datex-Ohmeda i ntroduced the Tec 6 vapori zer to
widespread cl inical practi ce in 1993. Thi s was the fi rst cli nical l y avai labl e vaporizer ever to be
el ectricall y heated and pressuri zed. The physical appearance and operation of the Tec 6 are
si mi l ar to contemporary vapori zers, but some aspects of the i nternal desi gn and operati ng
pri nci pl es are radi cal l y di fferent. The Tec 6 Plus represents a l ater versi on of the ori ginal Tec 6.
The Tec 6 Pl us has the same basi c Tec 6 desi gn, but also incorporates an enhanced audibl e al arm
system not previ ousl y avai labl e on the Tec 6.
Functi onall y, the Tec 6's operation is more accuratel y descri bed as a dual -gas bl ender than as a
vapori zer. A si mpl i fi ed schemati c of the Tec 6 i s shown i n Fi gure 21-22. The vapori zer has two
i ndependent gas ci rcui ts arranged i n parall el. The fresh gas circui t i s shown i n gray, and the vapor
ci rcuit i s shown i n whi te. The fresh gas from the flowmeters enters at the fresh gas inlet, passes
through a fi xed restri ctor (R1), and exi ts at the vapori zer gas outl et. The vapor circui t origi nates
at the desfl urane sump, whi ch is el ectricall y heated and thermostati cal l y control l ed to 39C, a
temperature wel l above desfl urane's boi li ng poi nt. The heated sump assembl y serves as a
reservoi r of desfl urane vapor. At 39C, the vapor pressure i n the sump i s approximatel y 1,300 mm
Hg absol ute,
80
or approximatel y 2 atmospheres absolute (see Fi g. 21-17). Just downstream from
the sump i s the shutoff valve. After the vaporizer warms up, the shutoff val ve ful ly opens when
the concentration control val ve i s turned to the on posi ti on. A pressure-regul ati ng valve located

downstream from the shutoff valve downregul ates the pressure to approxi matel y 1.1 atmospheres
absol ute (74 mm Hg gauge) at a fresh gas flow rate of 10 L/min. The operator controls desfl urane
output by adjusti ng the concentrati on control val ve (R2), which is a variabl e restri ctor.
77

The vapor flow through R2 joi ns the fresh gas flow through R1 at a poi nt downstream from the
restrictors. Unti l thi s poi nt, the two ci rcui ts are physi cal l y di vorced. They are i nterfaced
pneumati cal ly and el ectroni cal l y, however, through di fferenti al pressure transducers, a control
el ectronics system, and a pressure-regul ati ng valve. When a constant fresh gas fl ow rate
encounters the fi xed restrictor, R1, a speci fi c back pressure, proporti onal to the fresh gas fl ow
rate, pushes agai nst the di aphragm of the control differenti al pressure transducer. The differenti al
pressure transducer conveys the pressure di fference between the fresh gas ci rcuit and the vapor
P.575
FIGURE 21-22. Si mpl ified schematic of the Tec 6 desflurane vaporizer. (From Andrews JJ:
Operati ng Pri nci pl es of the Ohmeda Tec 6 Desfl urane Vapori zer: A Col l ecti on of Twel ve Col or
Il l ustrati ons. Washi ngton, DC, Li brary of Congress, Copyri ght 1996, wi th permission.)
ci rcuit to the control el ectronics system. The control electroni cs system regul ates the pressure-
regul ati ng valve so that the pressure i n the vapor ci rcuit equal s the pressure in the fresh gas
ci rcuit. This equal ized pressure suppl yi ng R1 and R2 i s the worki ng pressure, and the worki ng
pressure i s constant at a fixed fresh gas flow rate. If the operator i ncreases the fresh gas flow
rate, more back pressure is exerted upon the diaphragm of the control pressure transducer, and
the worki ng pressure of the vapori zer increases.
77

Tabl e 21-2 shows the approxi mate correlati on between fresh gas flow rate and worki ng pressure
for a typi cal vapori zer. At a fresh gas flow rate of 1 L/min, the worki ng pressure i s 10 mi l li bars, or
7.4 mm Hg gauge. At a fresh gas fl ow rate of 10 L/mi n, the worki ng pressure is 100 mi l li bars, or
74 mm Hg gauge. Therefore, there i s a li near rel ati onshi p between fresh gas flow rate and worki ng
pressure. When the fresh gas fl ow rate i s increased 10-fol d, the worki ng pressure i ncreases 10-
fold.
77

Listed bel ow are two specifi c exampl es to demonstrate the operati ng pri nci ples of the Tec 6.
77

Exampl e A: Constant fresh gas fl ow rate of 1 L/min, with an increase i n the di al setti ng.
Wi th a fresh gas fl ow rate of 1 L/mi n, the worki ng pressure of the vapori zer is 7.4 mm Hg.
That i s, the pressure suppl yi ng R1 and R2 i s 7.4 mm Hg. As the operator i ncreases the dial
setti ng, the openi ng at R2 becomes l arger, al l owi ng more vapor to pass through R2. Speci fi c
vapor fl ow values at different dial settings are shown in Tabl e 21-3.
Exampl e B: Constant dial setti ng wi th an i ncrease i n fresh gas fl ow from 1 to 10 L/min.
At a fresh gas fl ow rate of 1 L/mi n, the working pressure is 7.4 mm Hg, and at a di al setti ng
of 6% the vapor fl ow rate through R2 i s 64 mL/min (see Tabl es 21-2 and 21-3). Wi th a 10-
fol d i ncrease i n the fresh gas fl ow rate, there is a concomitant 10-fol d increase i n the
worki ng pressure to 74 mm Hg. The rati o of resistances of R2 to R1 i s constant at a fi xed
di al setting of 6%. Because R2 i s suppl i ed by 10 ti mes more pressure, the vapor fl ow rate
through R2 increases 10-fol d to 640 mL/mi n. Vaporizer output i s constant because both the
fresh gas fl ow and the vapor flow i ncrease proportionall y.
TABLE 21-2 Fresh Gas Flow Rate Versus Working Pressure
FRESH GAS FLOW RATE
(L/min)
WORKING PRESSURE AT R1 AND R2 (GAUGE)(GAS
INLET PRESSURE)
MBAR cm WATER mmHG
1 10 10.2 7.4
5 50 51.0 37.0
10 100 102.0 74.0
Reprinted wi th permission from Andrews JJ, Johnston RV Jr: The new Tec 6 desfl urane
vapori zer. Anesth Analg 76:1338, 1993.
TABLE 21-3 Dial Setting Versus Flow Through Restrictor R2
Factors that Influence Vaporizer Output
Varied al ti tude and carri er gas compositi on i nfl uence Tec 6 output. Each i s discussed in the
fol l owing sections.
Varied Altitudes. Al though ambi ent pressure changes affect conventional vapori zer output
si gni fi cantl y in terms of vol umes percent (%v/v, i.e. concentrati on), their effect on anestheti c
potency (i .e. partial pressure) is mini mal. Thi s effect is i l lustrated usi ng the example of isofl urane
shown i n Tabl e 21-4. With a constant dial setting of 0.89%, at 1 atm (760 mm Hg), if perfectly
cali brated, the %v/v deli vered woul d be 0.89% and the parti al pressure of i sofl urane woul d be 6.8
mm Hg. Maintai ni ng the same dial setting and l oweri ng ambient pressure to 0.66 atm or 502 mm
Hg (roughly equi valent to 10,000 ft el evati on) would resul t i n an increase i n the concentrati on
output to 1.75% (al most doubl e), but the parti al pressure onl y increases to 8.77 mm Hg (only a
29% i ncrease) because of the proporti onate decl i ne i n ambient pressure.
DIAL SETTING
(VOL%)
a
FRESH GAS FLOW
RATE (L/min)
APPROXIMATE VAPOR FLOW RATE
THROUGH R2 (mL/min)
1 1 10
6 1 64
12 1 136
18 1 220
a
Vol ume percent = [(vapor flow rate)/(fresh gas fl ow rate) + (vapor fl ow rate)]
100%.
Reprinted wi th permission from Andrews JJ, Johnston RV Jr: The new Tec 6 desfl urane
vapori zer. Anesth Analg 76:1338, 1993.
TABLE 21-4 Performance of Tec Type Vaporizers vs. the Tec 6 Desflurane Vaporizer at Varying
Ambient Pressures
AMBIENT
PRESSURE
ISOFLURANE VAPORIZER WITH A DIAL
SETTING OF 0.89%
TEC 6
DESFLURANE
VAPORIZER
WITH A
DIAL
SETTING OF
6%
cc
ISOFLURANE
VAPOR
ENTRAINED
OUTPUT
CONCENTRATION
IN PERCENT
PARTIAL
PRESSURE
OUTPUT
(mm Hg)
Partial
PRESSURE
OUTPUT OF
DESFLURANE
It i s general ly consi dered that the parti al pressure of the anestheti c agent i n the central nervous
system, not i ts concentration, is responsibl e for the anestheti c effect. To obtai n a consistent depth
of anesthesi a when gross changes in barometri c pressure occur, the %v/v must be changed i n
inverse

proporti on to the barometri c pressure. For the most part, tradi tional variabl e bypass vapori zers
automati cal l y compensate for thi s change and for practical purposes the effect of barometri c
pressure can general ly be i gnored.
Thi s should be consi dered i n stark contrast to the response of the Tec-6 desfl urane vapori zer at
vari ed al titudes (Tabl e 21-4). One must remember thi s device i s more accuratel y descri bed as a
dual gas blender than a vaporizer. Regardl ess of the ambi ent pressure, the Tec-6 wi ll mai ntain a
constant concentration of vapor output (%v/v), not a constant parti al pressure. Thi s means that at
hi gh al ti tudes, the parti al pressure of desfl urane for any gi ven dial setti ng wi l l be decreased i n
proporti on to the atmospheric pressure di vi ded by the cal ibrati on pressure (normal ly 760 mm Hg)
per the fol l owi ng formul a.

For example at an al ti tude of 2000 m (6564 ft) where the ambient pressure is 608 mm Hg, the
Tec-6 dial setting must be advanced from 10%v/v to 12.5%v/v to avoi d underdosi ng that coul d
potential ly resul t i n patient awareness. Conversel y, the Tec-6' s mai ntenance of a constant %v/v i n
hyperbaric condi tions coul d produce si gni fi cant i ncreases in parti al pressure output, and if not
accounted for, the potential for anesthetic overdose. Therefore, i n hyperbari c setti ngs the Tec-6
di al setti ng woul d need to be reduced to mai ntai n the desi red parti al pressure output of
ATMOSPHERES (mm Hg)
BY 100 cc O
2
(mm Hg)
0.66 (2/3) 500
(10,000
feet)
91 1.753% 8.77 30
0.74 560 74 1.429% 8.0 33.6
0.80 608
(6,564
feet)
64.32 1.25% 7.6 36.5
1.0 760 46 0.89% 6.8 45.6
1.5 1,140 26.4 0.515% 5.87 68.4
2 1,520 19 0.36% 5.5 91.2
3 2,280 11.65 0.228% 5.198 136
(The foll owing were assumed: 5,000 cc bypass chamber fl ow, 100 cc vaporizing chamber fl ow -
Equi val ent to an i sofl urane di al setti ng of 0.89%)
P.576
desfl urane.
Carrier Gas Composition. Vapori zer output approxi mates the di al setti ng when oxygen is the
carri er gas because the Tec 6 vaporizer i s cal i brated using 100% oxygen. At low flow rates when a
carri er gas other than 100% oxygen i s used, however, a clear trend toward reduction i n vaporizer
output emerges. Thi s reducti on paral lel s the proporti onal decrease i n vi scosi ty of the carri er gas.
Ni trous oxi de has a lower vi scosi ty than oxygen, so the back pressure generated by resi stor R1
(see Fi g. 21-22) i s l ess when ni trous oxide i s the carrier gas, and the worki ng pressure i s reduced.
At l ow flow rates usi ng ni trous oxi de as the carri er gas, vaporizer output i s approxi matel y 20%
less than the di al setti ng. Thi s suggests that, at cli ni cal l y useful fresh gas fl ow rates, the gas fl ow
across resistor R1 is l ami nar, and the worki ng pressure i s proportional to both the fresh gas fl ow
rate and the vi scosity of the carri er gas.
81

Safety Features
Because desfl urane's vapor pressure is near one atmosphere, mi sfil l i ng contemporary vaporizers
with desflurane coul d theoreticall y resul t i n both desfl urane overdose and creati on

of a hypoxi c gas mi xture.
82
Datex-Ohmeda has introduced a unique, anestheti c-specific fil l ing
system to mi ni mi ze occurrence of thi s potenti al hazard. The agent-specific fil l er of the desfl urane
bottl e known as the Saf-T-Fi l l adapter i s intended to prevent i ts use wi th traditi onal vapori zers.
The fi l li ng system al so mini mi zes spil l age of l i qui d or vapor anestheti c by maintai ni ng a cl osed
system duri ng the fi l li ng process. Each desfl urane bottl e has a spri ng-loaded fil l er cap wi th an O-
ri ng on the tip. The spri ng seal s the bottle unti l it i s engaged i n the fi l l er port of the vapori zer.
Thus, thi s anestheti c-specific fil l ing system interl ocks the vapori zer and the dispensi ng bottle,
preventi ng loss of anesthetic to the atmosphere. A case report descri bed the mi sfi ll i ng of a Tec 6
desfl urane vapori zer wi th sevofl urane. Thi s error was possibl e because of si mi l ari ti es between a
new type of keyed fi l l er for sevofl urane and the desflurane Saf-T-fil l adapter. In thi s case, the
desfl urane vaporizer detected thi s error and automati cal l y shut i tself off.
70

Major vaporizer faults cause the shutoff val ve l ocated just downstream from the desfl urane sump
(see Fi g. 21-22) to cl ose, producing a no-output si tuati on. The valve is cl osed and a no-output
al arm is acti vated immedi ately i f any of the fol lowi ng condi ti ons occur: (1) the anestheti c level
decreases to bel ow 20 mL; (2) the vaporizer i s til ted; (3) a power fai l ure occurs; or (4) there is a
di spari ty between the pressure i n the vapor circui t versus the pressure i n the fresh gas ci rcuit
exceedi ng a specifi ed tol erance.
Summary
The Tec 6 vapori zer is an el ectri cal ly heated, thermostaticall y control l ed, constant-temperature,
pressuri zed, el ectromechanicall y coupl ed dual ci rcui t, gas-vapor bl ender. The pressure i n the
vapor ci rcuit i s el ectroni cal l y regulated to equal the pressure i n the fresh gas ci rcui t. At a constant
fresh gas flow rate, the operator regul ates vapor fl ow usi ng a conventi onal concentrati on control
di al. When the fresh gas flow rate i ncreases, the working pressure increases proportional ly. For a
gi ven concentrati on setti ng even when varyi ng the fresh gas fl ow rate, the vapori zer output is
constant because the amount of fl ow through each ci rcui t remains proporti onal.
77

The Dat ex- Ohmeda Al adi n Casset t e Vapor i zer
The vapori zer system used in the Datex-Ohmeda S5/Anesthesi a Deli very Uni t (ADU) is uni que i n
that the si ngl e electroni cal l y controll ed vaporizer i s designed to del i ver five di fferent inhal ed
anesthetics i ncludi ng hal othane, i soflurane, enfl urane, sevoflurane, and desfl urane. The vapori zer
consi sts of a permanent i nternal control uni t housed wi thi n the ADU and an interchangeable Al adin
agent cassette that contains anestheti c li qui d. The Al adi n agent cassettes are col or coded for each
anesthetic agent, and they are al so magneticall y coded so that the Datex-Ohmeda ADU can
identi fy whi ch anestheti c cassette has been i nserted. The cassettes are fil l ed usi ng agent-specific
fil l ers.
49

P.577
Though very di fferent in external appearance, the functional anatomy of the S/5 ADU cassette
vapori zer (Fi g. 21-23) i s very simil ar to that of the Drger vapor 19.1 and 20.n and the Datex-
Ohmeda Tec 4, Tec 5, and Tec 7 vapori zers. The Al adin system is functi onal l y simi lar to these
conventi onal vapori zers because i t i s al so made up of a bypass chamber and vapori zi ng chamber.
A fi xed restri ctor i s l ocated i n the bypass chamber, and flow measurement sensors are l ocated
both i n the bypass chamber and i n the outl et of the vapori zi ng chamber. The heart of the S/5 ADU
cassette vapori zer i s the el ectroni cal l y regul ated fl ow control val ve located in the vapori zi ng
chamber outl et. Thi s val ve is controll ed by a central processi ng uni t (CPU). The CPU receives i nput
from mul tipl e sources i ncludi ng the concentration control dial , a pressure sensor l ocated i nsi de the
vapori zing chamber, a temperature sensor located i nsi de the vapori zi ng chamber, a fl ow
measurement uni t l ocated i n the bypass chamber, and a fl ow measurement unit l ocated i n the
outl et of the vaporizing chamber. The CPU al so recei ves i nput from the fl owmeters regardi ng the
composi tion of the carri er gas. Usi ng data from these mul tipl e sources, the CPU is able to
precisel y regul ate the fl ow control val ve to attain the desired vapor concentrati on output.
Appropri ate el ectronic control of the fl ow control valve is essential to the proper function of thi s
vaporizer.
49, 84

A fi xed restri ctor i s l ocated i n the bypass chamber, and i t causes flow from the vapori zer inl et to
spl i t i nto two fl ow streams (see Fi g. 21-23). One stream passes through the

bypass chamber, and the other porti on enters the i nl et of the vapori zi ng chamber and passes
through a one-way check val ve. The presence of this check val ve is uni que to the Al adi n system.
Thi s one-way valve prevents retrograde flow of the anestheti c vapor back i nto the bypass
FIGURE 21-23. Si mpl ified schematic of Datex-Ohmeda Aladi n Cassette Vaporizer. The bl ack
arrows represent flow from the fl owmeters, and the whi te ci rcl es represent anesthetic vapor.
The heart of the vapori zer is the el ectronicall y control led fl ow control val ve l ocated in the
outl et of the vapori zi ng chamber. CPU, central processing uni t; F
BC
, fl ow measurement uni t,
whi ch measures fl ow through the bypass chamber; F
VC
= flow measurement uni t, which
measures fl ow through the vapori zi ng chamber; P, pressure sensor; T, temperature sensor.
(Modified from Andrews JJ: Operati ng Pri nci pl es of the Datex-Ohmeda Aladi n Cassette
Vapori zer: A Coll ecti on of Col or Il l ustrati ons. Washington, DC, Li brary of Congress, 2000.)
P.578
chamber, and i ts presence i s cruci al when deli vering desflurane if the room temperature i s greater
than the boi l i ng poi nt for Desflurane (22.8C).
49
A preci se amount of vapor-saturated carri er gas
passes through the fl ow control val ve, whi ch i s regul ated by the CPU. This flow then joi ns the
bypass fl ow and i s di rected to the outlet of the vaporizer.
49

As menti oned duri ng the di scussi on of the Tec 6, the control led vaporizati on of desfl urane
presents a uni que chal l enge, parti cularly when the room temperature is greater than the boi li ng
poi nt of desfl urane (22.8C). At hi gher temperatures, the pressure i nsi de the vapori zer sump
increases, and the sump becomes pressurized. When the sump pressure exceeds the pressure i n
the bypass chamber, the one-way check val ve l ocated i n the vapori zi ng chamber i nl et cl oses
preventi ng carri er gas from enteri ng the vaporizing chamber. At thi s poi nt, the carri er gas passes
strai ght through the bypass chamber and i ts fl ow sensor. Under these conditi ons, the
el ectronicall y regulated fl ow control val ve si mply meters i n the appropri ate fl ow of pure desfl urane
vapor needed to achi eve the desired fi nal concentrati on sel ected by the user. At l east one case
report has descri bed a fai l ure of the vapori zi ng chamber i nl et check valve to function as desi gned.
In thi s case, an anestheti c overdose occurred as a resul t of regurgi tation of desflurane from the
vapori zing chamber in a retrograde fashi on back into the bypass chamber. Thi s report meri ts ADU
users to be cauti ous of thi s potential probl em, especi all y when desflurane is used.
84

During operati ng condi tions i n whi ch high fresh gas flow rates and/or high dial settings are used,
large quantiti es of anesthetic l i qui d are rapi dl y vapori zed. As a resul t, the temperature of the
remai ni ng l i qui d anestheti c and the vapori zer itself decrease as a resul t of energy consumpti on of
the latent heat of vaporizati on. To offset thi s cool i ng effect, the S/5 ADU is equipped with a fan
that forces warmed ai r from an agent heati ng resi stor across the cassette (vapori zer sump) to
raise i ts temperature when necessary. The fan i s acti vated during two common cl inical scenari os:
(1) desflurane induction and mai ntenance, and (2) sevofl urane i nducti on.
ANESTHETIC BREATHING CIRCUITS
As the prescri bed mi xture of gases from the flowmeters and vaporizer exits the anesthesi a
workstation at the common gas outl et, i t then enters an anesthetic breathi ng ci rcuit. The functi on
of the anesthesi a breathing ci rcuit i s not onl y to del i ver oxygen and anestheti c gases to the
patient, but al so to el iminate CO
2
. CO
2
can be removed ei ther by washout wi th adequate fresh gas
inflow or by the use of CO
2
absorbent medi a (e.g., soda li me absorption). The foll owi ng di scussi on
focuses on the semicl osed rebreathing circui ts and the ci rcl e system.
Mapl eson Syst ems
In 1954 Mapl eson descri bed and anal yzed fi ve di fferent semi cl osed anestheti c systems, and they
are now cl assicall y referred to as the Mapl eson Systems and are designated with letters A through
E (Fi g. 21-24).
85
Subsequentl y i n 1975, Wil l is et al descri bed the F system that was added to the
ori gi nal fi ve.
86
The Mapl eson Systems consist of several common components. Theses components
commonly i nclude a facemask, a spring-loaded pop-off valve, reservoi r tubi ng, fresh gas i nfl ow
tubi ng, and a reservoi r bag. Withi n the Mapleson Systems, three distinct functional groups can be
seen. They include the A, the BC, and DEF groups. The Mapl eson A, also known as the Magi l l
Circui t, has a spri ng-loaded pop-off valve l ocated near the facemask, and the fresh gas flow
enters the opposite end of the circui t near the reservoi r bag. In the B and C systems, the spri ng-
loaded pop-off valve i s l ocated near the facemask, but the fresh gas inlet tubi ng i s l ocated near
the pati ent. The reservoi r tubing and breathi ng bag serve as a bli nd li mb where fresh gas, dead
space gas, and al veolar gas can col l ect. Fi nall y, in the Mapl eson D, E, F group or T-pi ece group,
the fresh gas enters near the patient, and excess gas i s popped off at the opposi te end of the
ci rcuit.
Even though the components and component arrangement are simple, functi onal anal ysis of the
Mapl eson Systems can be compl ex.
87, 88
The amount of CO
2
rebreathi ng associ ated wi th each
system i s multi factori al , and vari abl es whi ch dictate the ulti mate CO
2
concentrati on include the
fol l owing: (1) the fresh gas infl ow rate, (2) the mi nute ventil ati on, (3) the mode of ventil ati on
(spontaneous or control led), (4) the tidal volume, (5) the respi ratory rate, (6) the I:E ratio, (7)
the durati on of the expi ratory pause, (8) the peak i nspiratory fl ow rate, (9) the vol ume of the
reservoi r tube, (10) the vol ume of the breathi ng

bag, (11) venti lation by mask, (12) venti lation through an endotracheal tube, and (13) the CO
2

sampl i ng si te.
The performance of the Mapl eson Systems i s best understood by studying the expiratory phase of
the respiratory cycle.
89
Il l ustrati ons of the various Mapl eson System component arrangements may
be found in Figure 21-24. During spontaneous ventil ati on, the Mapl eson A has the best effi ci ency
FIGURE 21-24. Mapl eson Breathi ng Systems A-F. (Redrawn wi th permi ssi on. Wi l li s BA,
Pender JW, Mapl eson WW: Rebreathi ng i n a T-pi ece: Vol unteer and Theoretical Studies of the
Jackson-Rees Modifi cati on of Ayre' s T-pi ece during spontaneous respi rati on. Br J Anaesth
47:1239, 1975.)
P.579
of the si x systems requi ri ng a fresh gas i nfl ow rate of onl y one ti mes the mi nute venti lation to
prevent rebreathi ng of CO
2
. But it has the worst effi ciency during controll ed venti l ati on, requiri ng
a minute venti l ati on as hi gh as 20 L/mi n to prevent rebreathing. Systems DEF are sl i ghtl y more
effi ci ent than systems BC. To prevent rebreathi ng CO
2
, the DEF systems requi re a fresh gas i nflow
rate of approxi mately 2.5 times the mi nute venti lati on, whereas the fresh gas infl ow rates
requi red for BC systems are somewhat hi gher.
88

The fol lowi ng summarizes the rel ati ve effi ci ency of di fferent Mapl eson Systems wi th respect to
preventi on of rebreathing, duri ng spontaneous venti lation: A > DFE > CB. Duri ng control led
ventil ati on, DFE > BC > A.
85, 88
The Mapl eson A, B, and C systems are rarely used today, but the
D, E, F systems are commonly empl oyed. In the Uni ted States, the most popul ar representati ve
from the D, E, F group i s the Bai n Ci rcui t, and i t wi l l be di scussed i n the next secti on.
Bain Circuit
The Bai n ci rcui t i s a coaxial circui t and a modificati on of the Mapl eson D system. The fresh gas
flows through a narrow inner tube wi thi n the outer corrugated tubi ng.
91
The central fresh gas
tubing enters the outer corrugated hose near the reservoi r bag, but the fresh gas actual l y empti es
into the ci rcui t at the pati ent end (Fi g. 21-25). Exhal ed gases enter the corrugated tubi ng and are
vented through the expiratory valve near the reservoi r bag. The Bai n ci rcui t may be used for both
spontaneous and control l ed venti l ation. The fresh gas i nfl ow rate necessary to prevent rebreathi ng
is 2.5 the mi nute venti l ati on.
The Bai n ci rcui t has many advantages over other systems. It i s li ghtwei ght, convenient, easi ly
steri l i zed, and may be reusabl e. Scavenging of the gases from the expi ratory val ve i s faci l i tated
because the val ve i s located away from the pati ent. Exhal ed gases i n the outer reservoi r tubing
add warmth by countercurrent heat exchange to i nspi red fresh gases. The mai n hazards rel ated to
the use of the Bai n ci rcuit are either an unrecogni zed di sconnecti on or ki nki ng of the i nner fresh
gas hose. These probl ems can cause hypercarbia from inadequate gas fl ow or i ncreased
respiratory resistance. As wi th other ci rcui ts, an obstructed anti mi crobial fi lter posi ti oned between
the Bain circui t and the endotracheal tube can result i n increased resi stance i n the circui t. Thi s
may produce hypoventi l ati on and hypoxemi a, and may even mimic the signs and symptoms of
severe bronchospasm.
92

The outer corrugated tube should be transparent to al l ow ongoi ng inspection of the i nner tube.
The i ntegri ty of the i nner tube can be assessed as descri bed by Pethi ck.
93
With hi s technique,
hi gh-flow oxygen i s fed i nto the circui t whi l e the pati ent end is occl uded unti l the reservoi r bag is
FIGURE 21-25. The Bain Circuit. (Redrawn with permi ssi on from Bai n JA, Spoerel WE: A
streaml i ned anaesthetic system. Can Anaesth Soc J 19:426, 1972.)
fil l ed. The patient end i s opened, and oxygen i s fl ushed into the ci rcuit. If the inner tube i s intact,
the venturi effect occurs at the pati ent end. Thi s causes a decrease i n pressure withi n the circui t,
and as a resul t, the reservoir bag deflates. Conversely, a leak in the i nner tube al lows the fresh
gas to escape i nto the expi ratory li mb, and the reservoir bag wi ll remai n infl ated. This test i s
recommended as a part of the pre-anesthesia check if a Bain ci rcui t is used.
Ci r cl e Br eat hi ng Syst ems
For many years, the overal l desi gn of the circl e breathi ng system has changed very l i ttl e from one
anesthesia workstation manufacturer to the next. Both the i ndi vi dual components and the order i n
whi ch they appeared in the ci rcl e system were consi stent across major pl atforms. More recentl y,
however, wi th the i ncreasing technologi cal complexi ty of the anesthesi a workstation, the ci rcl e
system has gone through some major changes as well . These changes have resul ted in part from
an effort to improve patient safety (as in the i ntegrati on of Fresh Gas Decoupl i ng and Inspiratory
Pressure Li mi ters), but have al so al l owed the deployment of new technological advances.
Exampl es of major new technol ogies i ncl ude (1) a return to the appl i cation of si ngle-ci rcuit piston-
type ventil ators and (2) use of new spi rometry devi ces that are l ocated at the Y-connector i nstead
of at the tradi ti onal location on the expi ratory ci rcuit l i mb. The fol lowi ng di scussi on fi rst focuses
on the traditi onal ci rcl e breathi ng system, and then is followed by a brief di scussion of some
vari ati ons in the desi gns of newer ci rcl e systems.
The Traditional Circle Breathing System
The circle system remains the most popular breathing system i n the United States. It i s so named
because i ts components are arranged i n a circul ar manner (see Fi g. 21-7). One versi on of the
tradi tional ci rcl e system, referred to as either a Universal F or single limb circuit, has
i ncreased i n popul ari ty over recent years. Though these systems appear very different external ly,
they have the same overal l functional layout as the traditi onal circle system and the foll owi ng
di scussi on i s appl i cabl e to both the traditi onal circle system and the Uni versal F system.
The circle system prevents rebreathi ng of CO
2
by use of CO
2
absorbents but al lows parti al
rebreathi ng of other exhal ed gases. The extent of rebreathi ng of the other exhal ed gases depends
on breathi ng ci rcui t component arrangement and the fresh gas flow rate. A circle system can be
semi open, semi closed, or cl osed, dependi ng on the amount of fresh gas inflow.
94
A semi open
system has no rebreathi ng and requi res a very high fl ow of fresh gas. A semi cl osed system i s
associated wi th some rebreathi ng of exhal ed gases and i s the most commonly used appli cati on in
the Uni ted States. A closed system is one i n which the inflow gas exactly matches that bei ng taken
up, or consumed, by the pati ent. In a cl osed system, there i s complete rebreathi ng of exhal ed
gases after absorption of CO
2
, and the overfl ow (pop-off or APL) val ve or ventil ator rel i ef valve
remai ns closed.
The circle system (see Fi g. 21-7) consists of seven primary components, i ncl udi ng the fol l owing:
(1) a fresh gas i nflow source; (2) i nspiratory and expi ratory uni di recti onal val ves; (3) i nspi ratory
and expi ratory corrugated tubes; (4) a Y-pi ece connector; (5) an overfl ow or pop-off valve,
referred to as the Adjustabl e Pressure-Li mi ti ng (APL) val ve; (6) a reservoi r bag;

and (7) a cani ster contai ning a CO
2
absorbent. The i nspiratory and expi ratory val ves are pl aced in
the system to ensure gas fl ow through the corrugated hoses remai ns uni di rectional . The fresh gas
infl ow enters the ci rcle by a connecti on from the common gas outl et of the anesthesi a machi ne.
Numerous vari ati ons of the ci rcl e arrangement are possi bl e, dependi ng on the rel ati ve posi tions of
the unidi rectional val ves, the pop-off valve, the reservoi r bag, the CO
2
absorber, and the si te of
fresh gas entry. However, to prevent rebreathing of CO
2
in a traditi onal circle system, three rul es
must be fol lowed: (1) a unidi rectional val ve must be l ocated between the pati ent and the reservoi r
bag on both the i nspi ratory and expi ratory li mbs of the ci rcuit; (2) the fresh gas infl ow cannot
enter the ci rcui t between the expiratory valve and the pati ent; and (3) the overfl ow (pop-off)
val ve cannot be l ocated between the pati ent and the i nspiratory valve. If these rul es are foll owed,
any arrangement of the other components wil l prevent rebreathi ng of CO
2
.
90
Some newer
P.580
anesthesia workstations now empl oy less traditi onal circle breathing systems. Two of these
systems are di scussed i n detai l bel ow (see Anesthesi a Workstation Variations section).
The most effi ci ent ci rcl e system arrangement wi th the highest conservati on of fresh gases i s one
in which the unidi recti onal val ves are near the pati ent and the pop-off valve i s l ocated just
downstream from the expi ratory valve. Thi s arrangement minimizes dead space gas and
preferential ly eli mi nates exhal ed al veol ar gases. A more practical arrangement, the one used on
most conventional anesthesi a machi nes (see Fi g. 21-7), i s somewhat less effi ci ent because it
al lows al veol ar and dead space gases to mi x before they are vented.
95, 96

The mai n advantages of the ci rcl e system over other breathi ng systems i ncl ude i ts (1)
maintenance of rel ati vely stabi l inspi red gas concentrati ons, (2) conservati on of respi ratory
moi sture and heat, and (3) preventi on of operating room pol luti on. Addi tional ly, the ci rcl e system
can be used for cl osed system anesthesi a or semi closed with very low fresh gas fl ows. The major
di sadvantage of the ci rcl e system stems from i ts compl ex design. Commonl y, the circle system
may have 10 or more different connections. These multi ple connection si tes set the stage for
mi sconnecti ons, di sconnecti ons, obstructi ons, and l eaks. In an ASA cl osed cl ai m anal ysi s of
adverse anestheti c outcomes ari si ng from gas del i very equi pment, over one-third (25/72) of
malpractice cl ai ms resulted from breathi ng ci rcuit misconnecti ons or disconnecti ons.
1
Mal functi on
of the ci rcl e system' s uni directi onal val ves can result i n l i fe-threatening probl ems. Rebreathing
can occur if the val ves sti ck i n the open posi ti on, and total occlusi on of the ci rcuit can occur i f
they are stuck shut. If the expi ratory valve is stuck i n the closed posi ti on, breath-stacki ng and
barotrauma or volutrauma can result. Obstructed fi lters l ocated in the expi ratory li mb of the ci rcl e
breathing system have caused i ncreased ai rway pressures, hemodynami c col lapse, and bi l ateral
tensi on pneumothorax. Causes of ci rcle system obstructi on and fai lure incl ude manufacturing
defects, debri s, pati ent secreti ons, and parti culate obstructi on from other odd sources such as
al buterol nebul i zati on.
97, 98, 99, 100
Some systems, such as the Datex-Ohmeda 7900 SmartVent, use
flow transducers located on both the i nspi ratory and expiratory l imbs of the circl e system. In one
report cracks i n the fl ow transducer tubi ng used by thi s system produced a leak i n the circle
system that was diffi cult to detect.
101

CO
2
ABSORBENTS

In the earl y 2000s, there were several reports of adverse chemi cal reacti ons between CO
2

absorbent materi al s and anesthetic agents. Some of these undesi rabl e interactions are qui te
dramati c such as sevoflurane interacti ng with desi ccated Baralyme, resul ti ng in fi res withi n the
breathing system and severe patient i njury.
102, 103
Al though other sources of ignition and fire in
the breathing system conti nue to be descri bed,
104
the Baral yme-sevofl urane probl em i s
somewhat uni que i n that nothi ng unusual is added to or removed from the breathi ng system for
this to occur. Other reactions such as desfl urane or sevofl urane with desi ccated strong base
absorbents can produce more insidi ous pati ent morbi di ty and even death from the rel ease of
byproducts such as carbon monoxi de or compound A.
105
Al though absorbent materi al s may be
problematic, they sti l l represent an important component of the ci rcl e breathi ng system. Different
anesthesia breathi ng systems el i mi nate CO
2
wi th varying degrees of effici ency. The closed and
semi cl osed ci rcl e system both require that CO
2
be absorbed from the exhal ed gases to avoi d
hypercapnea. If one coul d desi gn an i deal CO
2
absorbent, i ts characteri sti cs woul d include l ack of
reacti vi ty wi th common anesthetics, l ack of toxi ci ty, l ow resi stance to ai r fl ow, l ow cost, ease of
handl i ng, and effi ci ency i n CO
2
absorption.
The Absor ber Cani st er
On modern anesthesia machines, the absorber cani ster (see Fi g. 21-7) i s composed of two clear
pl asti c cani sters arranged in seri es. The cani sters can be fi ll ed wi th ei ther loose bulk absorbent or
wi th absorbent suppl i ed by the factory i n prefi l l ed pl asti c di sposabl e cartri dges cal led prepacks.
Free granules from bulk absorbent can create a cli ni cal l y si gnifi cant leak if they l odge between the
cl ear pl astic cani ster and the O-ri ng gasket of the absorber. Leaks have al so been caused by
defective prepacks, which were larger than factory specifi cati ons.
106
Prepacks can al so cause total
obstruction of the circl e system i f the cl ear plasti c shi pping wrapper i s not removed pri or to
use.
107

Chemi st r y of Absor bent s
Three formulations of CO
2
absorbents are commonl y avai l abl e today: soda l i me, Baral yme, and
calci um hydroxi de l ime (Amsorb). Of these agents, the most commonl y used i s soda l i me. Al l
serve to el i mi nate CO
2
from the breathi ng ci rcui t wi th varyi ng degrees of efficiency.
By weight the approximate composi ti on of hi gh moi sture soda li me is 80% calci um hydroxi de,
15% water, 4% sodi um hydroxi de, and 1% potassi um hydroxi de (an activator). Smal l amounts of
si l i ca are added to produce cal ci um and sodi um sil i cate. Thi s addi ti on produces a harder more
stabl e pel let and thereby reduces dust formation. The efficiency of the soda l ime absorpti on vari es
inversel y wi th the hardness; therefore, li ttl e si li cate i s used i n contemporary soda l i me. Sodi um
hydroxide i s the catalyst for the CO
2
absorptive properti es of soda li me.
108, 109
Baralyme is a
mi xture of approximatel y 20% bari um hydroxi de and 80% calci um hydroxi de. It may also contain
some potassi um hydroxi de. Baral yme is the pri mary CO
2
absorbent i mpl i cated as an agent that
may produce fires in the breathi ng system when used wi th sevofl urane. Cal ci um hydroxi de l ime i s
one of the newest cli ni cal l y avai labl e CO
2
absorbents. It consi sts pri maril y of cal ci um hydroxi de
and cal ci um chl ori de and contai ns two setti ng agents: cal cium sul fate and polyvi nyl pyrrol idi ne.
The l atter two agents serve to enhance the hardness and porosity of the agent.
110
The most
si gni fi cant advantage of cal cium hydroxi de li me over other agents i s its l ack of the strong bases,
sodi um and potassi um hydroxi de. The absence of these chemi cals el i mi nates the undesi rabl e
producti on of carbon monoxide, the nephrotoxi c substance known as compound A, and may reduce
or eli minate the possi bi li ty of a fi re in the breathi ng ci rcuit.
111
The most significant di sadvantages
of cal ci um hydroxi de l ime are (1) less absorptive capaci tyabout 50% l ess than strong-base
contai ning

absorbents, and (2) general l y hi gher cost per uni t than other absorbents.
112, 113

The size of the actual absorpti ve granul es has been determi ned over ti me by tri al and error. The
current size particl es represent a compromi se between resi stance to ai r flow and absorpti ve
effi ci ency.
114
The smal ler the granul e size, the greater the surface area that is avail able for
absorpti on. However, as parti cl e size decreases, air fl ow resi stance i ncreases. The granul ar size of
soda li me and Baral yme used in cli nical practi ce i s between 4 and 8 mesh, a si ze at which
absorpti ve surface area and resi stance to flow are opti mi zed. Mesh si ze refers to the number of
openi ngs per l inear i nch in a sieve through which the granul ar particl es can pass. A 4-mesh screen
means that there are four quarter-inch openings per l i near i nch. Li kewi se, an 8-mesh screen has
ei ght per l i near i nch.
108

The absorption of CO
2
by absorbents such as soda li me occurs by a seri es of chemi cal reacti ons; it
is not a physi cal process l i ke soaki ng water i nto a sponge. CO
2
combi nes with water to form
carboni c aci d. Carboni c aci d reacts wi th the hydroxi des to form sodi um (or potassi um) carbonate
and water. Cal ci um hydroxi de accepts the carbonate to form calci um carbonate and sodi um (or
potassium) hydroxi de. The equati ons are as fol l ows:
1. CO
2
+ H
2
O H
2
CO
3

2. H
2
CO
3
+ 2NaOH (KOH) Na
2
CO
3
(K
2
CO
3
) + 2H
2
O + Heat
3. Na
2
CO
3
(K
2
CO
3
) + Ca(OH)
2
CaCO
3
+ 2NaOH (KOH)
Some CO
2
may react di rectl y wi th Ca(OH)
2
, but thi s reaction is much sl ower.

The reacti on with Baralyme di ffers from that of soda lime because more water is l i berated by a
di rect reacti on of barium hydroxide and CO
2
.
1. Ba(OH)
2
+ 8H
2
O + CO
2
BaCO
3
+ 9H
2
O + Heat

P.581
2. 9H
2
O + 9CO
2
9H
2
CO
3

Then by di rect reacti ons and by KOH and NaOH,
3. 9H
2
CO
3
+ 9Ca(OH)
2
CaCO
3
+ 18H
2
O + Heat
Absor pt i ve Capaci t y
The maximum amount of CO
2
that can be absorbed by soda l i me i s 26 L of CO
2
per 100 g of
absorbent. The absorptive capaci ty of cal ci um hydroxi de l i me i s si gnificantly less, and has been
reported at 10.2 L per 100 g of absorbent.
110, 113
However, as previ ousl y menti oned, absorpti ve
capaci ty i s the product of both avai l abl e chemical reactivity and physi cal (granul e) avai l abi l ity. As
the absorbent granul es stack up in the absorber cani sters, small passageways inevi tabl y form.
These smal l passages channel gases preferential ly through l ow resi stance areas. Because of this
phenomenon, functi onal absorpti ve capaci ty of either soda l i me or cal ci um hydroxi de l i me may be
substanti al l y decreased. In practi ce, because of channel i ng, the efficiency of soda lime may be
reduced to al l ow onl y 10 to 20 L or l ess of CO
2
to actual l y be absorbed per 100 g of absorbent.
115

I ndi cat or s
Ethyl vi olet i s the pH indicator added to both soda l i me and Baral yme to help assess the functional
integrity of the absorbent. Thi s compound is a substituted tri phenyl methane dye wi th a cri ti cal pH
of 10.3.
109
Ethyl viol et changes from colorl ess to vi olet i n col or when the pH of the absorbent
decreases as a result of CO
2
absorption. When the absorbent i s fresh, the pH exceeds the cri ti cal
pH of the i ndi cator dye, and i t exi sts i n i ts col orl ess form (Fi g. 21-26, A). However, as absorbent
becomes exhausted, the pH decreases below 10.3, and ethyl vi olet changes to i ts vi ol et form (Fi g.
21-26, B) because of al cohol dehydrati on. Thi s change i n col or i ndicates the absorpti ve capacity of
the material has been consumed. Unfortunately, i n some ci rcumstances ethyl vi olet may not
al ways be a rel i abl e i ndi cator of the functi onal status of absorbent. For exampl e, prol onged
exposure of ethyl viol et to fl uorescent l i ghts can produce photodeactivati on of thi s dye. When thi s
occurs, the absorbent appears whi te even though i t may have a reduced pH and i ts absorpti ve
capaci ty has been exhausted.
116

I nt er act i ons of I nhal ed Anest het i cs wi t h Absor bent s
FIGURE 21-26A and B. Ethyl Violet. See text for detai l s. (Reprinted with permission from
Andrews JJ, Johnston RV Jr, Bee DE, Arens JF: Photodeacti vati on of ethyl viol et: A potenti al
hazard of sodasorb. Anesthesi ol ogy 72:59, 1990.)
It i s important and desi rabl e to have CO
2
absorbents that neither release toxi c parti cles or fumes
nor produce toxi c compounds when exposed to common anestheti cs. Soda l i me and Baral yme
general ly fi t this description, but i nhal ed anestheti cs do i nteract wi th absorbents to some extent.
Histori call y speaki ng, an uncommon anestheti c, tri chl oroethylene, reacts wi th soda l i me to
produce toxi c compounds. In the presence of alkal i and heat, tri chloroethyl ene degrades i nto the
cerebral neurotoxi n di chl oroacetylene, which can cause cranial nerve l esi ons and encephal i ti s.
Phosgene, a potent pulmonary irritant, i s al so produced and phosgene can cause adult respi ratory
di stress syndrome (ARDS).
117

Sevoflurane has been shown to produce degradation products upon interacti on wi th CO
2

absorbents.
105, 118, 119
The major degradati on product produced i s an ol efin compound known as
fluoromethyl -2, 2-di fl uoro-1-(trifluoromethyl ) vinyl ether, or compound A. Duri ng sevofl urane
anesthesia, factors apparentl y leading to an i ncrease i n the concentrati on of compound A incl ude:
(1) l ow fl ow or closed circui t anesthetic techni ques; (2) the use of Baralyme rather than soda
li me; (3) hi gher concentrati ons of sevofl urane i n the anestheti c ci rcuit; (4) higher absorbent
temperatures; and (5) fresh absorbent.
118, 119, 120, 121
Interesti ngl y, the dehydrati on of Baral yme
increases the concentrati on of compound A, but the dehydrati on of soda li me decreases the
concentration of compound A.
122, 123
Apparentl y, the degradati on products released during cli nical
condi ti ons do not commonl y result i n adverse effects i n humans even duri ng l ow fl ow
anesthesia,
120
but further studi es are needed to veri fy thi s.
124, 125, 126

Desi ccated strong-base absorbents can also degrade contemporary i nhal ed anestheti cs to
cl i ni cal ly significant concentrati ons of carbon monoxi de (CO) as wel l as tri fl uoromethane,
whi ch can i nterfere with anestheti c gas monitori ng.
105
Under certain condi tions, this process can
produce very high carboxyhemogl obi n concentrati ons, reachi ng 35% or more.
127
Hi gher levels of
carbon monoxi de are more li kel y after prolonged contact between absorbent and anestheti cs, and

after disuse of an absorber for at l east 2 days, especial ly over a weekend. Thus, case reports
descri bi ng carbon monoxide poi soni ng have been most common in patients anestheti zed on
Monday morni ng, presumabl y because continuous flow from the anesthesi a machi ne dehydrated
the absorbents over the weekend.
128, 129
Fresh gas fl ow rates of 5 li ters per mi nute or more
through the breathi ng system and absorbent (without a pati ent connected) are suffi cient to cause
criti cal drying of the absorbent materi al . This i s even worse when the breathi ng bag is left off the
breathing circui t. Absence of the reservoi r bag faci li tates retrograde fl ow through the ci rcl e
system (Fi g. 21-27).
127
Because the inspiratory valve leafl et produces some resistance to fl ow, the
fresh gas fl ow takes the retrograde path of l east resi stance through the absorbent and out the 22
mm breathi ng bag mount.
P.582
FIGURE 21-27. The Drger Medi cal Narkomed 6000 wi th i ts si ngl e-ci rcuit venti l ator. The
Several factors appear to i ncrease the producti on of carbon monoxi de and resulti ng el evated
carboxyhemoglobi n l evel s. Those factors i nclude (1) the i nhaled anesthetic used (for a given MAC
mul tipl e, the magni tude of CO production from greatest to l east i s desfl urane enfl urane
>isoflurane >> halothane = sevofl urane); (2) the absorbent dryness (completel y dry absorbent
produces more CO than hydrated absorbent); (3) the type of absorbent (at a given water content,
Baralyme produces more CO than does soda l i me); (4) the temperature (an increased
temperature i ncreases CO production); (5) the anestheti c concentration (more CO i s produced
from hi gher anestheti c concentrati ons);
130
(6) l ow fresh gas fl ow rates; and (7) reduced
experi mental animal (pati ent) size
105, 131
per 100 g of absorbent.

Several interventi ons have been suggested to reduce the i nci dence of carbon monoxi de exposure
in humans undergoi ng general anesthesi a.
129
These i nterventi ons i nclude (1) educating anesthesi a
personnel regardi ng the eti ology of CO production; (2) turning off the anesthesi a machi ne at the
concl usion of the l ast case of the day to eli mi nate fresh gas flow that dries the absorbent; (3)
changing CO
2
absorbent i f fresh gas was found fl owi ng duri ng the morni ng machi ne check; (4)
rehydrati ng desi ccated absorbent by addi ng water to the absorbent;
113
(5) changi ng the chemi cal
composi tion of soda li me to reduce or el imi nate potassi um hydroxi de (such products now avai l abl e
incl ude Dragersorb 800 pl us, Sofnol i me, and Spherasorb); and (6) usi ng absorbent materi als
such as cal ci um hydroxi de l ime that are free of both sodi um and postassi um hydroxides. The
el i mi nation of sodium and potassi um hydroxi des from desiccated soda l ime dimi ni shes or
el i mi nates degradation of desfl urane to carbon monoxi de and sevofl urane to compound A, but does
not compromise CO
2
absorption.
111, 132

One extremel y rare, but potential ly li fe-threatening compli cati on rel ated to CO
2
absorbent
use is the development of fi res wi thi n the breathing system. Specificall y, this can occur as
the resul t of i nteracti ons between the strong-base absorbents (particul arl y Baral yme) and the
inhaled anesthetic, sevofl urane. In August 2003, Abbott Laboratories changed the package i nsert
for sevoflurane to describe this rare phenomenon and the condi tions under whi ch it coul d occur.
Almost 1 year later, in the fal l of 2004, several case reports describi ng pati ent injuri es rel ated to
this probl em were publi shed (all i nvol vi ng Baralyme). It seems that when desi ccated strong-base
absorbents are exposed to sevoflurane, absorber temperatures of several hundred degrees may
resul t from their i nteracti on.
103
The bui l d-up of very hi gh temperatures, the formation of
combusti bl e degradati on byproducts (formaldehyde, methanol , and formic aci d), pl us the oxygen-
or ni trous oxi deenri ched envi ronment provi de all the substrates necessary for a fire to occur.
105

Avoi dance of the use of the combi nati on of sevoflurane with strong-base absorbents, parti cularly
Baralyme, especial ly i f it has become desiccated i s the best way to prevent thi s unusual
potential ly li fe-threatening compli cati on.
ANESTHESIA VENTILATORS
The venti l ator on the modern anesthesi a workstati on serves as a mechani zed substitute for the
manual squeezi ng of the reservoi r bag of the ci rcl e system, the Bai n ci rcuit, or another breathi ng
system. As recentl y as the late 1980s, anesthesi a venti l ators were mere adjuncts to the
anesthesia machi ne. Today, in newer anesthesi a workstati ons, they have attai ned a promi nent
central rol e. In additi on to the near ubi qui tous rol e of the anesthesia venti l ator i n today' s
anesthesia workstation, many advanced ICU-styl e venti l ation features have al so been i ntegrated
into anesthesi a venti l ators (see Fi g. 21-27). Although many simi lari ties exi st between today' s
anesthesia venti lator and ICU venti lator, some fundamental differences i n ventil ati on parameters
and control systems sti ll remain. This di scussi on focuses on the cl assi fi cation, operati ng
pri nci pl es, and hazards associ ated wi th contemporary anesthesi a ventil ators.
hori zontal arrow indi cates the pi ston cyli nder uni t of the Di van Venti l ator. The vertical arrow
indicates the rectangul ar val ve mani fol d for fresh gas decoupl i ng.
Cl assi f i cat i on
Ventil ators can be cl assified accordi ng to thei r power source, dri ve mechani sm, cycli ng
mechani sm, and bel l ows type.
133, 134

Power Source
The power source requi red to operate a mechani cal venti lator i s provi ded by compressed gas,
el ectri ci ty, or both. Ol der pneumatic ventil ators required onl y a pneumati c power source to
functi on properl y. Contemporary electroni c venti lators from Drger Medi cal , Datex-Ohmeda, and
others requi re either an el ectrical only or both an el ectrical and a pneumati c power source.
Drive Mechanism and Circuit Designation
Double-ci rcuit venti l ators are most commonl y used on modern anesthesi a workstations. Generall y,
these conventi onal ventil ators are pneumati cal l y driven. In a doubl e-ci rcuit venti l ator, a driving
force such as pressuri zed gas compresses a component analogous to the reservoi r bag known as
the venti lator bell ows. The bel l ows then i n turn del ivers venti lation to the pati ent. The dri vi ng gas
in the Datex-Ohmeda 7000, 7810, 7100, and 7900 i s 100% oxygen. In the North Ameri can Drger
AV-E

and AV-2+, a venturi device mixes oxygen and ai r. Some newer pneumati c anesthesi a
workstations have the abil i ty for the user to select whether compressed ai r or oxygen i s used as
the dri vi ng gas.
In recent years, with the i ntroduction of ci rcl e breathi ng systems that i ntegrate fresh gas
decoupl ing, resurgence has been seen i n the util i zati on of mechani cal l y driven anesthesia
ventil ators. These pi ston-type ventil ators uti li ze a computer-control led stepper motor i nstead of
compressed drive gas to actuate gas movement i n the breathing system. In these systems, rather
than havi ng dual ci rcui ts wi th pati ent gas in one and dri ve gas i n another, a si ngl e pati ent gas
ci rcuit i s present. Thus, they are cl assi fi ed as pi ston-dri ven si ngle-ci rcuit venti l ators. The piston
operates much li ke the plunger of a syri nge to del i ver the desi red ti dal vol ume or airway pressure
to the pati ent. Sophi sticated computerized control s are able to provi de advanced types of
ventil atory support such as synchroni zed i ntermi ttent mandatory ventil ati on (S-IMV), pressure-
control led ventil ati on (PCV), and pressure supportassi sted venti lation, in additi on to the
conventi onal control mode venti l ati on. Si nce the pati ent's mechani cal breath i s del i vered wi thout
the use of compressed gas to actuate a bel l ows, these systems consume dramati cal ly l ess
compressed gas during venti lator operati on than tradi tional pneumati c venti l ators. Thi s
improvement in effi ciency may have cli ni cal si gni fi cance when the anesthesi a workstation is used
in a setting where no pi pel ine gas supply i s avai labl e (e.g., remote locati ons or offi ce-based
anesthesia practices).
Cycling Mechanism
Most anesthesia machine venti lators are time cycled and provi de venti lator support i n the control
mode. Inspi ratory phase i s i ni tiated by a ti mi ng device. Older pneumatic venti lators use a fl ui dic
ti mi ng device. Contemporary electroni c venti lators use a sol id-state el ectroni c timi ng devi ce and
are thus cl assified as ti me cycl ed and el ectronicall y control led. More advanced ventil ati on modes
such as S-IMV, PCV, and modes that uti li ze a pressure-support option may have an adjustabl e
threshol d pressure tri gger as wel l. In these modes, pressure sensors provide feedback to the
ventil ator control system to al low i t to determi ne when to i ni ti ate and/or termi nate the respi ratory
cycl e.
Bellows Classification
The di recti on of bel l ows movement duri ng the expi ratory phase determi nes the bel l ows
cl assi ficati on. Ascendi ng (standi ng) bel lows ascend duri ng the expi ratory phase (Fi g. 21-28B,
ri ght), whereas descendi ng (hangi ng) bell ows descend duri ng the expi ratory phase. Ol der
P.583
pneumati c ventil ators and some new anesthesia workstati ons use wei ghted descendi ng bell ows,
whi l e most contemporary electroni c venti lators have an ascendi ng bell ows desi gn. Of the two
confi gurati ons, the ascending bell ows i s general ly safer. An ascendi ng bell ows wi ll not fil l i f a total
di sconnecti on occurs. However, the bell ows of a descendi ng bell ows venti lator wi l l conti nue its
upward and downward movement despi te a patient disconnecti on. The dri vi ng gas pushes the
bel l ows upward during the i nspi ratory phase. During the expi ratory phase, room ai r i s entrai ned
into the breathi ng system at the si te of the di sconnection because gravi ty acts on the weighted
bel l ows. The disconnecti on pressure monitor and the volume moni tor may be fooled even i f a
di sconnecti on i s compl ete (see Breathing Ci rcui t Probl ems secti on).
34
Some contemporary
anesthesia workstation desi gns have returned to the descendi ng bel l ows to i ntegrate fresh gas
decoupl ing (Drger Medi cal Jul ian and Datascope Anestar). An essential safety feature on any
anesthesia workstation that uti l izes a descending bel lows i s an i ntegrated CO
2
apnea al arm that
cannot be di sabl ed whi l e the ventil ator is i n use.
FIGURE 21-28A and B. Inspiratory (A) and expi ratory (B) phases of gas fl ow i n a tradi ti onal
ci rcl e system wi th an ascending bell ows venti lator. The bel l ows physi cal ly separates the
dri vi ng-gas ci rcuit from the pati ent gas ci rcui t. The dri vi ng-gas circui t is l ocated outsi de the
bel l ows, and the pati ent gas ci rcuit i s i nside the bel l ows. Duri ng i nspi ratory phase (A), the
dri vi ng gas enters the bel l ows chamber, causing the pressure wi thi n i t to increase. Thi s
Oper at i ng P r i nci pl es of Ascendi ng Bel l ows Vent i l at or s
Contemporary examples of ascending bell ows, doubl e-ci rcuit, electroni c venti lators incl ude the
Drger Medi cal AV-E, AV-2+, the Datex-Ohmeda 7000, 7800, and 7900 series. A generi c ascendi ng
bel l ows ventil ator is il l ustrated i n Fi gure 21-26. It may be vi ewed as a breathi ng bag (bell ows)
l ocated wi thi n a cl ear pl asti c box. The bel l ows physi cal l y separates the dri vi ng gas circui t from the
pati ent gas ci rcui t. The dri vi ng gas ci rcui t is l ocated outsi de the bel l ows, and the pati ent gas
ci rcuit is i nsi de the bel lows. Duri ng the i nspiratory phase (Fi g. 21-28A, l eft) the dri vi ng gas enters
the bell ows chamber, causi ng the pressure wi thin i t to i ncrease. Thi s i ncrease in pressure is
responsi bl e for two events. First, the venti lator rel i ef val ve cl oses, preventi ng anestheti c gas from
escapi ng into the scavengi ng system. Second, the bel l ows is compressed, and the anestheti c gas
within the bel lows i s deli vered to the patient' s l ungs. Thi s compressi on acti on i s anal ogous to the
hand of the anesthesiol ogi st squeezi ng the breathi ng bag.
48

During the expi ratory phase (see Fi g. 21-28B), the dri vi ng gas exi ts the bell ows housi ng. This
produces a drop to atmospheri c pressure withi n both the bel lows housi ng and the pi l ot l i ne to the
ventil ator rel i ef val ve. The decrease i n pressure to the venti l ator reli ef valve causes the
mushroom valve porti on of the assembly to open. Exhal ed pati ent gases refil l the bel lows before
any scavengi ng can begi n. The bel l ows refi l l fi rst because a wei ghted ball [l ike those used i n bal l -
type posi ti ve end-expi ratory pressure (PEEP) valves] or si mi l ar devi ce is i ncorporated into the
base of the venti l ator rel ief valve. Thi s bal l produces 2 to 3 cm water of back pressure; therefore,
scavengi ng occurs onl y after the bell ows fi l ls compl etel y and the pressure i nsi de the bel l ows
exceeds the pressure threshol d of the bal l valve. Thi s desi gn causes al l ascendi ng bel l ows
ventil ators to produce 2 to 3 cm water pressure of PEEP withi n the breathi ng ci rcui t when the
ventil ator is i n use. Scavengi ng occurs onl y duri ng the expi ratory phase, as the venti lator rel i ef
val ve is open onl y duri ng expi rati on.
48

It i s important to understand that on most anesthesi a workstati ons, gas flow from the anesthesi a
machine i nto the breathi ng ci rcui t is continuous and i ndependent of venti lator activity. During the
inspi ratory phase of mechani cal venti l ati on, the ventil ator rel ief valve is cl osed (see Fi g. 21-28A),
and the breathi ng system' s Adjustabl e Pressure Limi ti ng Val ve (pop-off val ve) i s most commonl y
out of ci rcuit. Therefore, the pati ent's l ungs recei ve the vol ume from the bel l ows pl us that from
the fl owmeters during the i nspi ratory phase. Factors that infl uence the correlation between set
ti dal vol ume and exhal ed ti dal vol ume incl ude the fl owmeter settings, the i nspiratory ti me, the
compl i ance of the breathing ci rcui t, external l eakage, and the locati on of the ti dal vol ume sensor.
Usuall y, the volume gai ned from the flowmeters duri ng i nspirati on i s counteracted by the volume
lost to compl i ance of the breathi ng ci rcui t, and set ti dal vol ume general ly approxi mates the
exhaled ti dal vol ume. However, certai n condi tions such as inappropri ate acti vati on of the oxygen
flush val ve duri ng the inspiratory phase can resul t i n barotrauma and/or vol utrauma because
excess pressure and volume may not be able to be vented from the ci rcl e system.
48

P r obl ems and Hazar ds
Numerous hazards are associ ated with anesthesi a ventil ators. These include probl ems wi th the
causes the venti l ator relief val ve to close, preventi ng anestheti c gas from escapi ng into the
scavengi ng system, and the bell ows to compress, deli vering anestheti c gas withi n the bel lows
to the pati ent' s lungs. Duri ng expi ratory phase (B), pressure wi thin the bel l ows chamber and
the pil ot li ne decreases to zero, causi ng the mushroom porti on of the venti lator rel i ef val ve
to open. Gas exhaled by the patient refi l ls the bel l ows before any scavengi ng occurs, because
a weighted bal l is i ncorporated into the base of the venti l ator rel ief valve. Scavenging occurs
only during the expi ratory phase, because the venti l ator reli ef valve is onl y open during
expirati on. (Repri nted wi th permi ssi on from Andrews JJ: The Ci rcl e System. A Col l ecti on of
30 Col or Il lustrati ons. Washi ngton, DC, Li brary of Congress, 1998.)
breathing circui t, the bell ows assembl y, and the control assembl y.

Traditional Circle System Problems
Breathi ng ci rcui t mi sconnecti ons and di sconnection are a leadi ng cause of criti cal i ncidents i n
anesthesia.
1, 135
The most common disconnecti on si te i s at the Y-pi ece. Di sconnections can be
compl ete or parti al (leaks). In the past, a common source of l eaks with ol der absorbers was
fai l ure to cl ose the Adjustabl e Pressure Limiti ng Val ve (APL or pop-off valve) upon i ni tiation of
mechani cal venti l ation. On today' s anesthesi a workstati ons, the bag/venti l ator sel ector swi tch has
virtuall y eli mi nated thi s probl em, as the APL val ve i s usual ly out of circui t when the venti l ator
mode is sel ected. Preexi sti ng undetected l eaks can exist i n compressed, corrugated, disposabl e
anesthetic ci rcui ts. To detect such a leak preoperati vel y, the ci rcuit must be full y expanded before
the ci rcuit i s checked for leaks.
136
As previ ousl y menti oned, di sconnecti ons and l eaks mani fest
more readi l y wi th the ascendi ng bel lows ventil ator systems because they resul t i n a situati on in
whi ch the bel l ows wil l not refil l .
34

Several disconnecti on monitors exi st, al though none shoul d repl ace vi gi l ance. Moni tori ng of breath
sounds and observati on of chest wall excursion shoul d conti nue despi te use of both mechanical
(spi rometers and pressure sensors) and physi ol ogi c moni tors.
Pneumati c and electroni c pressure moni tors are hel pful i n diagnosing di sconnections. Factors that
infl uence monitor effecti veness incl ude the di sconnection si te, the pressure sensor l ocati on, the
threshold pressure al arm l imit, the inspi ratory flow rate, and the resi stance of the di sconnected
breathing circui t.
137, 138
Vari ous anesthesi a workstations and ventil ators have di fferent l ocati ons
for the ai rway pressure sensor and different values for the threshol d pressure alarm l imi t. The
threshold pressure al arm limit may be preset at the factory or adjustable. An audi bl e or vi sual
al arm is actuated i f the peak i nspiratory pressure of the breathi ng ci rcuit does not exceed the
threshold pressure al arm li mi t. When an adjustabl e threshol d pressure alarm li mit i s avai l abl e,
such as on many workstati ons from Drger Medical , the operator shoul d set the pressure alarm
li mi t to withi n 5 cm water of the peak inspiratory pressure. On systems that have an autoset
feature, when acti vated, the threshol d l imi t i s automati cal ly set at 3 to 5 cm water

pressure bel ow the current peak inspi ratory pressure. On such systems, fai lure to reset the
threshold pressure al arm limit may result in either an Apnea Pressure or Threshol d Low al ert.
Fi gure 21-29 il l ustrates how a parti al disconnection (leak) may be unrecogni zed by the l ow-
pressure monitor i f the threshol d pressure al arm limit i s set too l ow or i f the factory preset val ue
is relati vel y low.
P.584
P.585
Respi ratory vol ume moni tors are useful i n detecti ng disconnecti ons. Vol ume monitors may sense
exhaled ti dal vol ume, i nhal ed tidal volume, mi nute volume, or al l three. The user shoul d bracket
the hi gh and l ow threshold volumes sl i ghtl y above and bel ow the exhal ed volumes. For exampl e, i f
the exhal ed mi nute volume of a pati ent i s 10 L/mi n, reasonabl e al arm l imits woul d be 8 to 12
L/min. Many Datex-Ohmeda venti lators are equi pped wi th vol ume moni tor sensors that use
infrared li ght/turbi ne technol ogy. These vol ume sensors are usual ly l ocated i n the expi ratory l i mb
of the breathi ng ci rcui t and thus measure exhaled ti dal volume. In the case of the Datex-Ohmeda
S/5 ADU, a speci al attachment known as the D-Lite spi rometry connector is pl aced i n the
breathing circui t. Thi s devi ce is actual l y pl aced at or near the l evel of the pati ent connection and
permi ts measurement of both i nhal ed and exhal ed vol umes and pressures (see Anesthesi a
Workstati on Vari ati ons secti on). Wi th the ol der infrared type sensors, exposure to a di rect beam of
li ght from the overhead surgi cal l i ghting could cause erroneous vol ume readings as the surgi cal
beam interfered wi th the i nfrared sensor.
139
Other types of expiratory volume sensors can be seen
in systems such as the Datex-Ohmeda Aesti va, Aespi re, and other workstations that i ncorporate
the 7100 venti lator or 7900 SmartVent. These systems generall y util i ze di fferenti al pressure
transducti on technology to determi ne inhaled and exhal ed volumes as wel l as to measure ai rway
pressures. The Drger Medi cal Narkomed 6000 seri es, 2B and GS workstati ons commonl y use an
ul trasoni c fl ow sensor located on the expi ratory l imb. Sti ll other systems from Drger measure
exhaled vol ume usi ng hot wire sensor technol ogy. Wi th thi s type of sensor, a ti ny array of two
pl ati num wi res i s el ectri cal ly heated to a hi gh temperature. As gas fl ows past the heated wi res,
they tend to be cooled. The amount of energy required to maintai n the temperature of the wi re i s
proporti onal to the vol ume of gas fl owing past i t. Thi s system has been associ ated i n at l east one
report wi th acci dental devel opment of a fi re i n the breathi ng ci rcui t.
104

CO
2
monitors are probably the best devi ces for reveal i ng pati ent di sconnections. CO
2

concentration is measured near the Y-pi ece either di rectl y (mai nstream) or by aspi rati on of a gas
sampl e to the instrument (si destream). Either a sudden change i n the differences between the
i nspi ratory and end-ti dal CO
2
concentrati ons or the acute absence of measured CO
2
indi cates a
di sconnecti on, a nonventil ated patient, or other probl ems.
34
Importantl y, an absence of exhal ed
CO
2
can be an indication of absent cardi ac output rather than a mechani cal equi pment problem.
Mi sconnecti ons of the breathi ng system are unfortunately, rel ati vel y common. Despi te the efforts
of standards commi ttees to el imi nate thi s probl em by assi gni ng di fferent di ameters to vari ous
hoses and hose terminal s, they continue to occur. Anesthesia workstati ons, breathi ng systems,
ventil ators, and scavenging systems incorporate many of these diameter-specific connections. The
abi li ty of anesthesi a providers to outwi t these fool -proof systems has led to vari ous hoses
bei ng cl everly adapted or forcefull y fi tted to i nappropri ate terminal s and even to vari ous other
sol i d cyl i ndri cal l y shaped protrusi ons of the anesthesi a machi ne.
34

Occl usi on (obstructi on) of the breathi ng ci rcui t may occur. Tracheal tubes can become ki nked.
Hoses throughout the breathi ng ci rcui t are subject to occl usion by i nternal obstructi on or external
mechani cal forces, whi ch can impinge on flow and have severe consequences. For exampl e,
bl ockage of a bacteri al fi l ter i n the expi ratory l imb of the ci rcl e system has resul ted in bil ateral
tensi on pneumothorax.
98
Incorrect insertion of fl ow directi onsensi ti ve components can result i n a
no-flow state.
34
Exampl es of these components i ncl ude some PEEP val ves and cascade humi di fi ers.
Depending on the location of the occlusi on rel ative to the pressure sensor, a hi gh-pressure al arm
FIGURE 21-29. Threshol d pressure al arm l imit. (Top) The threshol d pressure alarm li mit
(dotted l i ne) has been set appropri atel y. An al arm is actuated when a parti al di sconnecti on
occurs (arrow) because the threshol d pressure alarm l i mi t is not exceeded by the breathi ng
ci rcuit pressure. (Bottom) A parti al disconnecti on i s unrecogni zed by the pressure moni tor
because the threshol d pressure alarm l i mi t has been set too low. (Redrawn wi th permi ssi on
from Baromed Breathi ng Pressure Monitor: Operator' s Instruction Manual. Tel ford,
Pennsyl vani a, North Ameri can Drger, August 1986.)
may alert practi tioners to the probl em.
Excess i nflow to the breathi ng ci rcuit from the anesthesia machi ne during the i nspi ratory phase
can cause barotrauma. The best example of thi s phenomenon i s oxygen flushi ng. Excess vol ume
cannot be vented from the system during i nspi rati on because the venti l ator reli ef val ve i s closed
and the APL valve is out of ci rcui t.
48
A high-pressure al arm, i f present, may be acti vated when the
pressure becomes excessive. Wi th many Drger Medi cal systems, both audi bl e and vi sual al arms
are actuated when the hi gh-pressure threshold i s exceeded. In the Modul us II Pl us System, the
Datex-Ohmeda 7810 ventil ator automaticall y swi tches from the i nspi ratory to the expi ratory phase
when the adjustabl e peak pressure threshol d i s exceeded.
On workstati ons equi pped wi th adjustabl e i nspiratory pressure li miters such as the Datex-Ohmeda
S/5 ADU, Aesti va, Drger Medi cal ' s Narkomed 6000 series, 2B, 2C, GS and Fabi us GS, maxi mal
i nspi ratory pressure may be set by the user to a desi red peak ai rway pressure. An adjustable
pressure reli ef valve wi ll open when the predetermined user-sel ected pressure i s reached. Thi s
theoreti cal ly prevents generation of excessive ai rway pressure. Unfortunately, thi s feature i s
dependent on the user having preset the appropri ate pop-off pressure. If the setting i s too low,
insuffi cient pressure for venti l ati on may be generated, resul ti ng i n inadequate minute venti lation;
if set too high, the excessi ve airway pressure may sti ll occur, resul ti ng in barotrauma. The piston-
dri ven Fabi us GS, as wel l as others may al so i ncl ude a factory preset inspiratory pressure safety
val ve that opens at a preset airway pressure such as 75 cm of water pressure to mi ni mi ze the ri sk
of barotrauma. These strategi es may reduce the ri sk of barotrauma and volutrauma; however,
they are no substi tute for vigi l ance.

Bellows Assembly Problems
Leaks can occur i n the bel lows assembl y. Improper seati ng of the plasti c bel lows housi ng can
resul t in i nadequate ventil ati on because a porti on of the dri vi ng gas i s vented to the atmosphere.
A hol e in the bel l ows can l ead to al veol ar hyperi nfl ation and possi bly barotrauma i n some
ventil ators because hi gh-pressure dri vi ng gas can enter the pati ent ci rcuit. The oxygen
concentration of the pati ent gas may i ncrease when the driving gas is 100% oxygen, or i t may
decrease i f the dri vi ng gas i s composed of an ai roxygen mi xture.
140

The venti l ator reli ef val ve can cause probl ems. Hypoventi l ati on occurs if the val ve i s incompetent
because anestheti c gas i s deli vered to the scavengi ng system during the i nspi ratory phase i nstead
of to the pati ent. Gas molecul es preferenti al l y exi t i nto the scavengi ng system because i t
represents the path of l east resi stance, and the pressure wi thi n the scavengi ng system can be
subatmospheri c. Venti lator rel i ef val ve i ncompetency can result from a disconnected pil ot l i ne, a
ruptured val ve, or from a damaged fl apper val ve.
141, 142
A venti lator rel i ef val ve stuck i n the cl osed
or partial ly closed positi on can produce ei ther barotrauma or undesi red PEEP.
143
Excessi ve sucti on
from the scavengi ng system can draw the ventil ator rel ief valve to i ts seat and close the valve
duri ng both the i nspiratory and expi ratory phases.
34
In thi s case, breathi ng ci rcui t pressure
escal ates because excess anestheti c gas cannot be vented. It i s worthwhi le to note that duri ng
expiratory phase, some newer machi nes from Datex-Ohmeda (S/5 ADU, 7100 and 7900
SmartVent) scavenge both excess pati ent gases and the exhausted ventil ator dri ve gas. That i s,
when the venti l ator rel i ef val ve opens, and waste anesthetic gases are vented from the breathi ng
ci rcuit, the dri ve gas from the bell ows housi ng joi ns wi th i t to enter the scavengi ng system. Under
certai n condi ti ons, the l arge vol ume of exhausted gases coul d overwhel m the scavengi ng system,
resul ti ng in poll uti on of the operating room wi th waste anestheti c gases (see Scavengi ng Systems
secti on). Other mechani cal probl ems that can occur i nclude l eaks withi n the system, faul ty
pressure regul ators, and faul ty valves. Unl i kel y probl ems such as an occl uded muffl er on the
Drger AV-E venti l ator can resul t i n barotrauma. In this case, obstructi on of dri vi ng gas outflow
cl oses the venti lator rel i ef val ve, and excess pati ent gas cannot be vented.
144

Control Assembly and Power Supply Problems
The control assembly can be the source of both el ectrical and mechani cal probl ems. Electri cal
P.586
fai l ure can be total or parti al; the former i s the more obvi ous. As anesthesi a workstati ons are
becomi ng more dependent on integrated computer-control led systems, power interrupti ons
become more si gnifi cant. Battery back-up systems are designed to continue operati on of essenti al
el ectroni cs duri ng bri ef (up to several hours' ) outages. However, even wi th these systems, i n the
event of a failure, some time may be requi red to reboot after an electri cal outage has occurred.
During thi s ti me the avai l abi l ity of certai n workstation features such as manual or mechani cal
ventil ati on can be vari abl e. One cl uster of el ectri cal fai l ures that could have potenti al l y resulted i n
operating room fires was reported earl y on after the rel ease of the Drger Medi cal Narkomed
6000. Probl ems with the workstati on' s power supply pri nted circui t boards prompted a corrective
recal l action in November 2002.
145

ANESTHESIA WORKSTATION VARIATIONS
Wi th the introducti on of new technology, often comes the need for adaptati on of current
technol ogy to successfull y al l ow its i ntegrati on i nto exi sti ng systems. Otherwi se, a more
comprehensi ve redesi gn of an entire anesthesi a system from the ground up coul d be necessary.
One such exampl e of adaptati on in the anesthesia workstati on can be seen wi th two new desi gn
vari ati ons of the ci rcl e breathi ng system. The fi rst of these i s found on the Datex-Ohmeda S/5
ADU (Fi g. 21-1), and the second i s incorporated i nto the Drger Narkomed 6000 seri es (Fi g. 21-2)
and Fabi us GS workstations. Si nce use of the circl e system i s fundamental to the day-to-day
practi ce for most anesthesi ol ogi sts, a comprehensi ve understandi ng of these new systems is
cruci al for their safe use.
THE DATEX-OHMEDA S/5 ADU (FIG. 21-1)
The Datex-Ohmeda S/5 ADU debuted as the AS/3 ADU in 1998. Al ong wi th i ts more comprehensi ve
safety features and i ntegrated desi gn that el i mi nated gl ass fl ow tubes and conventi onal anesthesi a
vapori zers i n exchange for a computer screen wi th di gi tal fresh gas flow scal es and the bui lt-in
Al adi n Cassette vapori zer system, the machi ne had a radi cal l y di fferent appearance i n general . It
is not until cl oser i nspecti on that the other uni que properties of the ADU begin to stand out. The
pri nci pal di fference in the ADU' s ci rcl e system li es i n the incorporation of the speci ali zed D-li te
flow and pressure transducer fitting i nto the circl e at the l evel of the Y-connector. On most
tradi tional circl e systems, exhal ed tidal volume i s measured by a spirometry sensor located i n
proxi mi ty to the expiratory valve. The pl acement of the D-li te fi tti ng at the Y-connector provides a
better l ocati on to perform exhaled vol ume measurement; al lows ai rway gas composi ti on and
pressure monitori ng to be done wi th a single adapter i nstead of with mul tipl e fitti ngs added to the
breathing ci rcuit; and i t provi des the abil i ty to assess both inspi ratory and expi ratory gas fl ow and
therefore generati on of compl ete flow-vol ume spirometry. The rel ocati on of the spi rometer sensor
to the Y-connector also makes i t possibl e to move the l ocation of the fresh gas i nlet to the
patient si de of the inspiratory valve wi thout adversel y affecti ng accuracy of exhaled ti dal vol ume
measurement.
Thi s atypi cal circle system arrangement with the fresh gas enteri ng on the pati ent si de of the
inspi ratory val ve i s advantageous for several reasons. It i s li kel y to be more effi ci ent i n deli vering
fresh gas to the pati ent, whil e preferenti all y el i mi nating exhal ed gases. Importantly, i t i s also less
li kel y to cause desi ccati on of the CO
2
absorbent (see Interactions of Inhal ed Anestheti cs wi th
Absorbents secti on). Other notabl e changes on the S/5 ADU ci rcle system i ncl ude a compact
propri etary CO
2
absorbent cani ster desi gn that can be changed duri ng venti l ation wi thout loss of
ci rcl e system integri ty, and the relocati on of the i nspi ratory and expi ratory uni di recti onal val ves
from a hori zontal posi tion to a verti cal posi ti on on the compact bl ock assembly just bel ow the
absorbent canister. The reori entati on of the uni di recti onal valves reduces the breathi ng ci rcui t
resistance encountered by a spontaneousl y venti lated pati ent. The verticall y ori ented
uni di recti onal valves onl y have to be ti pped away from the verti cal posi ti on to be opened, unl i ke
conventi onal hori zontal val ve di scs, whi ch have to be physi cal l y l i fted off of the val ve seat agai nst
gravi ty to be opened.
THE DRGER MEDICAL NARKOMED 6000 SERIES (FIG. 21-2)
AND FABIUS GS
Several important di fferences exi st between the traditi onal circle breathi ng systems of the newest
Drger products. At fi rst gl ance, the most notabl e difference li es in the appearance and desi gn of
the venti lators used wi th these systems. From the i nconspicuous hori zontal l y mounted Di van
pi ston venti lator

of the Narkomed 6000 to the verti cally mounted and vi si bl e pi ston venti l ator of the Fabi us GS wi th
its absent flow tubes and gl owi ng el ectroni c fresh gas flow i ndi cators, these systems appear
drasti cal ly di fferent from tradi tional anesthesi a systems. The pi ston venti lators of the Drger
Narkomed 6000 and Fabi us Series anesthesi a systems are cl assi fi ed as el ectri cal l y powered, pi ston
dri ven, si ngl e ci rcui t, electroni cal ly control l ed wi th fresh gas decoupl i ng.
The circle breathing systems uti l i zed by these Drger workstati ons incorporate a feature known as
Fresh Gas Decoupl ing (FGD). The i ncorporati on of thi s patient safety enhancing technology has
requi red a si gni fi cant redesign of the traditi onal ci rcl e system. A functi onal schemati c of a ci rcl e
system si mi lar to the one used by the Drger Narkomed 6000 seri es during both i nspi ratory and
expiratory phase of mechani cal venti l ati on can be seen i n Fi gure 21-30A and 21-30B. To
understand the operati ng pri nci pl es of FGD, i t i s important to have a good understandi ng of gas
flows i n a tradi tional circle system both duri ng i nspi ratory and expiratory phases of mechani cal
ventil ati on. A compl ete discussion of this was presented earl i er i n the secti on entitl ed Operati ng
Pri nci pl es of Ascending Bel l ows Ventil ators.
P.587
FIGURE 21-30A and B. Inspiratory and expi ratory phase gas fl ows of a Drger Narkomed
6000type ci rcl e system wi th pi ston venti l ator and fresh gas decoupl i ng. NPR val ve =
The key concept of the fresh gas decoupl ed breathi ng system can be il l ustrated duri ng the
inspi ratory phase of mechani cal venti lation. Wi th the traditi onal circle system, several events are
occurri ng (see Fi g. 21-28A): (1) continuous fresh gas fl ow from the fl owmeters and/or the oxygen
flush val ve i s enteri ng the circl e system at the fresh gas i nlet; (2) the venti lator i s del i vering the
prescribed ti dal vol ume to the pati ent's l ungs; and (3) the ventil ator rel ief valve (ventil ator
exhaust valve) i s closed, so no gas is escapi ng the ci rcl e system except into the patient' s l ungs.
146

In a tradi ti onal circle system, when these events coi ncide and fresh gas i nfl ow i s coupl ed di rectl y
into the ci rcl e system, the total vol ume deli vered to the patient' s l ungs is the sum of the vol ume
from the venti lator pl us the vol ume of gas that enters the ci rcl e vi a the fresh gas inl et. In
contrast, when FGD i s used, during the i nspi ratory phase (see Fi g. 21-30A) the fresh gas comi ng
from the anesthesi a workstati on vi a the fresh gas inlet i s diverted i nto the reservoi r bag by a
decoupl ing val ve that is l ocated between the fresh gas source and the venti l ator ci rcuit. The
reservoi r (breathi ng) bag serves as an accumul ator for fresh gas unti l the expi ratory phase
begi ns. During expi ratory phase (see Fi g. 21-30B), the decoupli ng valve opens, al l owi ng the
accumul ated fresh gas i n the reservoi r bag to be drawn i nto the ci rcle system to refi l l the pi ston
ventilator chamber or descendi ng bel l ows. Si nce the venti l ator exhaust val ve also opens during
expiratory phase, excess fresh gas and exhal ed pati ent gases are al lowed to escape to the
scavengi ng system.
Current fresh gas decoupled systems are designed wi th ei ther piston-type or descendi ng bel l ows
type ventil ators. Since the bell ows in ei ther of these type of systems refi ll s under sl i ght negati ve
pressure, i t all ows the accumul ated fresh gas from the reservoi r bag to be drawn i nto the
ventil ator for deli very to the pati ent duri ng the next venti l ator cycl e. Because of thi s desi gn
requi rement, i t is unl i kel y that fresh gas decoupli ng, as

descri bed here, can be used with conventional ascendi ng bel l ows venti lators, whi ch refi ll under
sl i ght posi ti ve pressure.
The most si gni fi cant advantage of circle systems usi ng FGD i s decreased risk of barotrauma
and volutrauma. Wi th a tradi ti onal ci rcl e system, i ncreases i n fresh gas flow from the
flowmeters or from inappropri ate use of the oxygen flush val ve may contri bute directl y to ti dal
vol ume, whi ch i f excessi ve, may result i n pneumothorax or other i njury. Si nce systems with FGD
isol ate fresh gas coming i nto the system from the pati ent whi le the venti l ator exhaust val ve i s
cl osed, the ri sk of barotrauma i s greatl y reduced.
Possi bl y the greatest disadvantage to the new anesthesi a ci rcl e systems that uti li ze FGD i s the
possi bi li ty of entrai ning room ai r i nto the pati ent gas ci rcui t. As previousl y di scussed, i n a fresh
gas decoupled system the bel lows or pi ston refi l ls under sl i ght negati ve pressure. If the vol ume of
gas contai ned i n the reservoi r bag vol ume pl us the returni ng vol ume of gas exhal ed from the
patient' s l ungs is i nadequate to refil l the bel l ows or piston, negati ve patient ai rway pressures
coul d devel op. To prevent thi s, a negative pressure rel ief valve i s pl aced in the breathi ng system
(see Fi g. 21-30A and 21-30B). If breathi ng system pressure fal l s bel ow a preset val ue such as -2
cm H
2
O pressure, then the rel i ef val ve opens and ambi ent air i s entrai ned i nto the pati ent gas
ci rcuit. If thi s goes undetected, the entrai ned atmospheri c gases coul d l ead to di lution of either or
both the inhaled anesthetic agents or an enri ched oxygen mixture (l oweri ng an enri ched oxygen
concentration toward 21%). If unchecked, thi s could lead to either i ntraoperati ve awareness or
hypoxi a. Hi gh-pri ori ty al arms with both audi bl e and vi sual alerts shoul d noti fy the user that fresh
gas fl ow i s i nadequate and room ai r i s bei ng entrai ned.
Another potenti al problem wi th an FGD system such as seen on the Narkomed 6000 seri es l i es in
its rel i ance on the reservoi r bag to accumul ate the incoming fresh gas. If the reservoi r bag is
Negati ve Pressure Rel ief Val ve. See text for detai l s. (Repri nted with permission from
Brockwel l RC: New Ci rcl e System Designs: A Collection of fi gures pri vatel y publ i shed i n
Bi rmingham, AL 2003.)
P.588
removed duri ng mechani cal venti lation, or i f i t has a si gni fi cant leak from poor fit on the bag
mount or a perforation, room air may enter the breathing ci rcui t as the ventil ator piston unit
refi l ls duri ng expiratory phase. Thi s may al so result i n dil uti on of ei ther or both the i nhal ed
anesthetic agents or an enri ched oxygen mi xture, potenti all y resul ting i n awareness duri ng
anesthesia or hypoxi a. Furthermore, thi s type of a disruption coul d l ead to signi fi cant poll uti on of
the operati ng room wi th anestheti c gases as fresh gases woul d be al l owed to escape i nto the
atmosphere. Other FGD designs, such as those seen i n the Drger Medi cal Fabi us GS and the
recently rel eased Apoll o anesthesi a systems do not use the breathing bag as the fresh gas
reservoi r, but instead have an al ternate l ocati on for fresh gas accumul ati on duri ng i nspi ratory
phase.
SCAVENGING SYSTEMS
Scavengi ng i s the col lecti on and the subsequent removal of waste anestheti c gases from the
operating room.
147
In most cases, the amount of gas used to anestheti ze a patient for a gi ven
anesthetic far exceeds the mi ni mal amount needed. Therefore, scavengi ng mi ni mi zes operati ng
room pol l uti on by removi ng thi s excess of gases. In 1977, the Nati onal Institute for Occupati onal
Safety and Health (NIOSH) prepared a document enti tl ed Cri teri a for a Recommended Standard:
Occupati onal Exposure to Waste Anestheti c Gases and Vapors.
148
Al though it was mai ntained that
a mini mal safe l evel of exposure coul d not be defi ned, the NIOSH proceeded to issue the
recommendations shown i n Tabl e 21-5.
148
In 1991 the Ameri can Soci ety for Testing and Material s
(ASTM) rel eased the ASTM F1343-91 standard enti tled Standard Speci fi cation for Anestheti c
Equi pmentScavengi ng Systems for Anestheti c Gases.
149
The document provi ded gui deli nes for
devices that safel y and effecti vely scavenge waste anestheti c gases to reduce contami nation in
anesthetizing areas.
149
In 1999, the ASA Task Force on Trace Anestheti c Gases devel oped a
bookl et enti tled Waste Anestheti c Gases: Informati on for Management i n Anestheti zi ng Areas and
the Postanesthesia Care Unit. Thi s publ i cati on addresses anal ysi s of the li terature, the rol e of
regul atory agenci es, scavenging and monitori ng equipment, and recommendati ons.
150

TABLE 21-5 Niosh Recommendations for Trace Gas Level
ANESTHETIC GAS MAXIMUM TWA
a
CONCENTRATION(ppm)
Hal ogenated agent al one 2
Ni trous oxi de 25
Combinati on of hal ogenated
agent pl us ni trous oxi de:

Hal ogenated agent 0.5
Ni trous oxide 25
Dental facil i ti es (ni trous oxide al one) 50
a
TWA, time-weighted average. Time-weighted average sampl i ng, al so known as time-
integrated sampl i ng, is a sampli ng method that eval uates the average concentrati on of
anestheti c gas over a prol onged period of ti me, such as 1 to 8 hours.
The two major causes of waste gas contami nati on i n the operati ng room are the anesthetic
technique empl oyed and equi pment issues.
150, 151
Regarding the anestheti c techni que, the fol l owing
factors cause operati ng room contami nati on: (1) fai l ure to turn off gas flow control val ves at the
end of an anestheti c, (2) poorly fi tti ng masks, fl ushi ng the circuit, (3) fi ll i ng anestheti c
vapori zers, (4) use of uncuffed endotracheal tubes, and (5) use of breathi ng ci rcui ts such as the
Jackson-Rees, whi ch are di ffi cul t to scavenge. Equipment fail ure or lack of understandi ng of
proper equipment use can also contribute to operati ng room contami nation. Leaks can occur in the
hi gh-pressure hoses, the ni trous oxide tank mounti ng, the hi gh-pressure ci rcui t and low-pressure
ci rcuit of the anesthesia machi ne, or i n the ci rcl e system, particul arl y at the CO
2
absorber
assembly. The anesthesi a provider must be certain that the scavengi ng system is operati onal and
adjusted properly to ensure adequate scavengi ng. If si de stream CO
2
or mul ti gas anal yzers are
used, the analyzed gas (50 to 250 cc/mi n) must be directed to the scavengi ng system or returned
to the breathi ng system to prevent pol l uti on of the operati ng room.
150, 151

Component s
Scavengi ng systems generall y have fi ve components (Fi g. 21-31): (1) the gas-coll ecti ng assembl y,
(2) the transfer means, (3) the scavengi ng interface, (4) the gas-di sposal assembl y tubi ng, and
(5) an acti ve or passive gas-di sposal assembl y.
149
An acti ve system uses a central evacuati on
system to eli mi nate waste gases. The weight or pressure of the waste gas itself produces fl ow
through a passi ve system.
Repri nted wi th permi ssi on from US Department of Heal th, Education, and Wel fare:
Cri teri a for a recommended standard: Occupati onal exposure to waste anestheti c gases
and vapors. March ed, Washi ngton DC, 1977.
Gas-Collecting Assembly
The gas-coll ecti ng assembl y captures excess anestheti c gas and deli vers it to the transfer
tubing.
134
Waste anestheti c gases are

vented from the anesthesi a system either through the APL valve or through the ventil ator rel i ef
val ve. All excess pati ent gas i s either vented into the room (e.g., from a poor facemask fit or
endotracheal tube l eak) or exi ts the breathi ng system through one of these valves. Gas passi ng
through these val ves accumulates i n the gas-coll ecti ng assembl y, and i s di rected to the transfer
means. In some newer Datex-Ohmeda systems such as the S5/ADU and others that incorporate
ei ther the 7100 or 7900 venti lators, the venti l ator drive gas i s also exhausted i nto the scavengi ng
system. Thi s i s signi ficant, because under condi ti ons of hi gh fresh gas flows and high mi nute
ventil ati on, the gases fl owi ng i nto the scavengi ng interface may overwhelm the evacuati on
system. If this occurs, waste anesthetic gases may overfl ow the system vi a the posi tive-pressure
rel ief valve (cl osed systems) or through the atmospheri c vents (open systems) pol l uting the
operating room. In contrast, most other pneumati c venti lators from both Datex-Ohmeda and
Drger exhaust thei r dri ve gas (100% oxygen or oxygen/ai r mixture) i nto the operati ng room
through a smal l vent on the back of the venti l ator control housi ng.
Transfer Means
The transfer means carries excess gas from the gas-coll ecti ng assembl y to the scavengi ng
interface. The tubi ng must be ei ther 19 or 30 mm, as speci fi ed by the ASTM F1343-91 standard.
149

The tubi ng shoul d be suffi ci entl y ri gi d to prevent ki nki ng, and as short as possi bl e to minimi ze the
chance of occl usi on. Some manufacturers col or code the transfer tubi ng wi th yell ow bands to
di sti ngui sh i t from 22-mm breathing system tubi ng. Many machi nes have separate transfer tubes
for the APL valve and for the venti lator rel i ef val ve. The two tubes frequentl y merge into a si ngl e
hose before they enter the scavengi ng i nterface. Occl usi on of the transfer means can be
parti cul arl y probl emati c since it i s upstream from the pressure-buffering features of the
scavengi ng i nterface. If the transfer means i s occl uded, basel ine breathi ng ci rcui t pressure wi ll
increase, and barotrauma can occur.
Scavenging Interface
The scavenging i nterface i s the most i mportant component of the system because i t protects the
breathing circui t or venti l ator from excessi ve posi ti ve or negati ve pressure.
147
The i nterface
should li mi t the pressures immedi atel y downstream from the gas col l ecti ng assembl y to between -
0.5 and +10 cm water wi th normal worki ng condi tions.
149
Posi ti ve pressure reli ef i s mandatory,
irrespecti ve of the type of disposal system used, to vent excess gas in case of occlusi on
downstream from the i nterface. If the di sposal system i s an acti ve system, negati ve pressure
rel ief is necessary to protect the breathi ng ci rcuit or venti l ator from excessi ve subatmospheri c
pressure. A reservoi r is highl y desi rabl e wi th acti ve systems, since i t stores waste gases unti l the
evacuation system can remove them. Interfaces can be open or cl osed, dependi ng on the method
used to provide positi ve and negati ve pressure rel i ef.
147

Open Interfaces. An open interface contains no val ves and i s open to the atmosphere, al lowi ng
both positi ve and negati ve pressure reli ef. Open interfaces should be used only with active
di sposal systems that use a central evacuation system. Open interfaces requi re a reservoi r
because waste gases are intermi ttentl y di scharged i n surges, whereas fl ow from the evacuation
system i s conti nuous.
147

Many contemporary anesthesia machi nes are equipped wi th open i nterfaces l i ke those i n Fi gure
FIGURE 21-31. Components of a scavengi ng system. APL = adjustable pressure l i mi ti ng
val ve.
P.589
21-32A and 21-32B.
152
An open cani ster provi des reservoi r capaci ty. The cani ster volume should
be large enough to accommodate a vari ety of waste gas fl ow rates. Gas enters the system at the
top of the canister and travels through a narrow inner tube to the canister base. Gases are stored
in the reservoi r between breaths. Posi ti ve and negati ve pressure rel ief i s provi ded by hol es in the
top of the cani ster. The open interface shown i n Fi gure 21-32A differs somewhat from the one
shown i n Fi gure 21-32B. The operator can regul ate the vacuum by adjusti ng the vacuum control
val ve shown i n Fi gure 21-32B.
152

The effi ciency of an open interface depends on several factors. The vacuum flow rate per minute
must equal or exceed the minute vol ume of excess gases to prevent spi ll age. The vol ume of the
reservoi r and the fl ow characteri sti cs wi thin the i nterface are i mportant. Spi l lage wi l l occur i f the
vol ume of a single exhal ed breath exceeds the capaci ty of the reservoi r. The fl ow characteri sti cs
of the system are i mportant because gas leakage can occur long before the vol ume of waste gas
equal s the reservoir vol ume if significant turbulence occurs withi n the i nterface.
153

Closed Interfaces. A closed interface communicates wi th the atmosphere through valves. All
cl osed i nterfaces must have a posi ti ve-pressure reli ef val ve to vent excess system pressure if
obstruction occurs downstream from the i nterface. A negati ve-pressure reli ef val ve is mandatory
to protect the breathi ng system from subatmospheri c pressure i f an active disposal system is
used.
147
Two types of cl osed i nterfaces are commerci all y avai l abl e. One has posi tive pressure
rel ief only; the other has both posi ti ve and negati ve pressure rel ief. Each type i s discussed in the
fol l owing sections.
Positi ve pressure rel i ef onl y. Thi s interface (Fi g. 21-33, l eft) has a singl e posi ti ve-pressure reli ef
val ve and i s desi gned to be used onl y with passive disposal systems. Waste gas enters the
interface at the waste gas i nl ets. Transfer of the waste gas from the i nterface to the di sposal
system reli es on the weight or pressure of the waste gas i tself since a negati ve pressure
evacuation system i s not used. The posi ti ve-pressure reli ef val ve opens at a preset value such as
5 cm water i f an obstructi on between the i nterface and the disposal system occurs.
154
On thi s type
of system, a reservoi r bag i s not required.
FIGURE 21-32A and B. Two open scavengi ng interfaces. Each requires an active di sposal
system. APL, adjustabl e pressure li mi ting val ve. See text for detail s. (Modi fi ed wi th
permi ssi on from Dorsch JA, Dorsch SE: Control l ing trace gas l evel s. In Dorsch JA, Dorsch SE
(eds): Understandi ng Anesthesia Equi pment, 4
t h
ed, p 355. Bal timore, Wil l i ams & Wi lkins,
1999.)
P.590
Positi ve and negative pressure rel ief. Thi s interface has a positi ve-pressure reli ef val ve, and at
least one negati ve-pressure reli ef val ve, in additi on to a reservoir bag. It is used with active
di sposal systems. Fi gure 21-33 (ri ght) is a schemati c of Drger Medi cal 's cl osed i nterface for
sucti on systems. A vari able volume of waste gas i ntermi ttently enters the interface through the
waste gas inl ets. The reservoi r intermi ttentl y accumulates excess gas until the evacuation system
el i mi nates i t. The operator shoul d adjust the vacuum control valve so that the reservoi r bag i s
properl y i nflated (A), not over di stended (B), or compl etel y defl ated (C). Gas i s vented to the
atmosphere through the posi ti ve-pressure reli ef val ve if the system pressure exceeds +5 cm
water. Room ai r i s entrained through the negati ve-pressure reli ef val ve if the system pressure is
more negative than -0.5 cm water. On some systems, a back-up negati ve-pressure reli ef val ve
opens at -1.8 cm water i f the pri mary negati ve-pressure reli ef val ve becomes occl uded.

The effectiveness of a cl osed system i n preventi ng spi l lage depends on the rate of waste gas
inflow, the evacuation flow rate, and the size of the reservoi r. Leakage of waste gases i nto
the atmosphere occurs only when the reservoi r bag becomes ful l y i nflated and the pressure
increases suffi cientl y to open the positi ve pressure rel i ef val ve. In contrast, the effecti veness of
an open system to prevent spil l age depends not onl y on the volume of the reservoi r but al so on
the fl ow characteri sti cs wi thin the interface.
153

Gas-Disposal Assembly Conduit
The gas-di sposal assembl y condui t (see Fi g. 21-31) conducts waste gas from the scavengi ng
interface to the gas-di sposal assembl y. It shoul d be col l apse proof and should run overhead, if
possi bl e, to mi ni mi ze the chances of acci dental occl usi on.
149

Gas-Disposal Assembly
The gas-di sposal assembl y ulti matel y el i mi nates excess waste gas (see Fi g. 21-31). There are two
types of di sposal systems: active and passi ve.
FIGURE 21-33. Cl osed scavenging interfaces. (Left) Interface used with a passive disposal
system. (Ri ght) Interface used with an active system. See text for detai l s. (Modi fi ed with
permi ssi on (left) from Scavenger Interface for Air Condi tioni ng: Instructi on Manual . Tel ford,
Pennsyl vani a, North Ameri can Drger, October 1984; (ri ght) from Narkomed 2A Anesthesia
System: Technical Servi ce Manual . Tel ford, Pennsyl vani a. North American Drger, 1985.)
P.591
The most common method of gas disposal i s the active assembl y, whi ch uses a central evacuati on
system. A vacuum pump serves as the mechani cal fl ow-inducing devi ce that removes the waste
gases usuall y to the outside of the bui l ding. An interface wi th a negati ve-pressure reli ef val ve is
mandatory because the pressure withi n the system is negati ve. A reservoir i s very desi rabl e, and
the larger the reservoir, the lower the sucti on flow rate needed.
147, 153

A passive di sposal system does not use a mechanical fl ow-i nduci ng devi ce. Instead, the weight
or pressure from the heavi er-than-ai r anesthetic gases produces flow through the system. Positi ve
pressure reli ef is mandatory, but negative pressure rel ief and a reservoi r are unnecessary. Excess
waste gases can be eli minated from the surgi cal sui te i n a number of ways. Some i ncl ude venti ng
through the wal l, cei l ing, fl oor, or to the room exhaust gri l l of a nonreci rculating air conditi oning
system.
147, 153

Hazar ds
Scavengi ng systems mini mi ze operati ng room poll uti on, yet they add compl exi ty to the anesthesi a
system. A scavengi ng system functi onal l y extends the anesthesi a ci rcuit al l the way from the
anesthesia machi ne to the ul ti mate disposal site. This extensi on i ncreases the potential for
problems. Obstruction of scavengi ng pathways can cause excessi ve positi ve pressure i n the
breathing ci rcuit, and barotrauma can occur. Excessive vacuum appli ed to a scavengi ng system
can resul t i n undesi rabl e negati ve pressures withi n the breathi ng system. Fi nal l y, i n 2004, another
unusual problem that resul ted from waste gas scavengi ng was reported by Lees et al .
155
They
reported cases of fi res i n engineeri ng equipment rooms that house the vacuum pumps used for
waste anestheti c gas evacuati on. It seems that i n some hospi tal s, waste gases are not di rectly
vented outsi de, but may be vented i nto machi ne rooms that have vents that open to the outside.
Since some new anesthesi a machi nes such as the Datex-Ohmeda S5/ADU and Aestiva, among
others, now also scavenge ventil ator dri ve gas (which i s 100% oxygen i n most cases) i n additi on
to gas from the breathi ng system, the envi ronments in these machi ne rooms may become hi ghl y
enri ched with oxygen gas. The resul t of this has been the production of fi res i n these spaces
outsi de the operati ng room. These sites may contain equi pment or materi al s such as petroleum
di sti l l ates (pumps/oi l/grease) that i n the presence of an oxygen-enri ched atmosphere coul d be
excessivel y combusti bl e and a severe fi re hazard.
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isoflurane effects on renal functi on usi ng sensiti ve markers of tubular toxi city. Anesthesi ology
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126. Bi to H, Ikeuchi Y, Ikeda K: Effects of l ow-fl ow sevofl urane anesthesi a on renal functi on:
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127. Berry PD, Sessl er DI, Larson MD: Severe carbon monoxi de poi soni ng duri ng desfl urane
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formation from desfl urane i n an anesthesi a machi ne. Anesthesi ol ogy 86:1061, 1997
129. Woehl i ck HJ, Dunning M, Connoll y LA: Reducti on i n the incidence of carbon monoxi de
exposures in humans undergoi ng general anesthesi a. Anesthesi ology 87:228, 1997
130. Fang ZX, Eger EI, Laster MJ et al : Carbon monoxi de producti on from degradati on of
desfl urane, enfl urane, isofl urane, hal othane, and sevoflurane by soda l i me and baral yme.
131. Bonome C, Belda J, Alavarez-Refojo F et al : Low-flow anesthesia and reduced ani mal si ze
increase carboxyhemogl obi n level s i n swi ne during desflurane and i sofl urane breakdown in
dri ed soda l ime. Anesth Anal g 89:909, 1999
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hydroxides from desi ccated soda l i me di mi ni shes degradati on of desflurane to carbon
monoxi de and sevoflurane to compound A but does not compromi se carbon di oxi de absorption.
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1984
136. Rei nhart DJ, Fri z R: Undetected leak in corrugated ci rcuit tubi ng in compressed
confi gurati on. Anesthesi ol ogy 78:218, 1993
137. Raphael DT, Wel ler RS, Doran DJ: A response al gori thm for the low-pressure al arm
condi ti on. Anesth Anal g 67:876, 1988
138. Slee TA, Pavli n EG: Fai lure of low pressure al arm associ ated wi th use of a humi difi er.
139. Sattari R, Rei chard PS, Ri ddl e RT: Temporary malfuncti on of the Ohmeda modulus CD
series vol ume moni tor caused by the overhead surgi cal li ghti ng. Anesthesi ology 91:894, 1999
140. Feel ey TW, Bancroft ML: Problems with mechani cal venti lators. Int Anesthesi ol Cl in
20:83, 1982
141. Khal il SN, Ghol ston TK, Binderman J: Fl apper val ve malfuncti on i n an Ohio cl osed
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143. Bourke D, Tolenti no D: Inadvertent posi ti ve end-expiratory caused by a malfuncti oning
ventil ator rel i ef val ve. Anesth Analg 97:492, 2003
144. Roth S, Tweedie E, Sommer RM: Excessive ai rway pressure due to a malfunctioni ng
anesthesia ventil ator. Anesthesi ology 65:532, 1986
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(Letter to the Edi tor). Anesthesi ol ogy 99:762, 2003
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ed, p 309. Bal timore, Wil l iams and Wi l ki ns, 1999

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148. US Department of Heal th, Educati on, and Wel fare: Cri teri a for a Recommended Standard:
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Equi pment-Scavengi ng Systems for Anestheti c Gases (ASTM F1343-91). Phi l adel phi a,
Ameri can Soci ety for Testi ng and Materi al s, 1991
150. ASA Task Force on Trace Anesthetic Gases: McGregor DG, Chair: Waste
Anesthetic Gases; Information for Management in Anesthetizing Areas and the
Postanesthesia Care Unit (PACU), p 3. Park Ridge, Illinois, American Society of
Anesthesiologists, 1999
151. Kanmura Y, Sakai J, Yoshinaka H et al : Causes of nitrous oxi de contaminati on i n
operating rooms. Anesthesi ology 90:693, 1999
152. Open Reservoi r Scavenger: Operator' s Instructi on Manual . Telford, Pennsyl vania, North
Ameri can Drger, 1986
153. Gray WM: Scavenging equi pment. Br J Anaesth 57:685, 1985
154. Scavenger Interface for Air Condi tioni ng: Instructi on Manual . Tel ford, Pennsyl vania,
North American Drger, 1984
155. Allen M, Lees DE. Fires in Medical Vacuum Pumps: Do you need to be concerned?
ASA Newsletter 68(10):22, 2004
Appendix A
Anesthesia Apparatus Checkout Recommendations
Thi s checkout, or a reasonabl e equi valent, shoul d be conducted before admi ni strati on of
anesthesia. These recommendations are onl y vali d for an anesthesi a system that conforms to
current and rel evant standards and i ncl udes an ascendi ng bell ows venti lator and at least the
fol l owing moni tors: Capnograph, pul se oximeter, oxygen anal yzer, respi ratory vol ume monitor
(spi rometer), and breathi ng system pressure moni tor wi th high- and low-pressure al arms. This i s
a gui deli ne that users are encouraged to modify to accommodate di fferences i n equi pment desi gn
and vari ati ons in l ocal cl i ni cal practice. Such l ocal modificati ons shoul d have appropriate peer
revi ew. Users shoul d refer to the operator' s manual for the manufacturer's specific procedures and
precauti ons, especi al l y the manufacturer' s low-pressure l eak test (step #5).
Emer gency Vent i l at i on Equi pment
1. *Verify Back-up Ventilation Equipment is Available & Functioning
Hi gh- P r essur e Syst em
2. *Check Oxygen Cylinder Supply
a. Open O
2
cyli nder and veri fy at l east hal f ful l (about 1,000 psi ).
b. Close cyli nder.

3. *Check Central Pipeline Supplies
a. Check that hoses are connected and pi pel i ne gauges read about 50 psi .
Low- P r essur e Syst em
4. *Check Ini tial Status of Low-Pressure System
a. Cl ose fl ow control val ves and turn vaporizers off.
b. Check fil l l evel and tighten vapori zers' fi l ler caps.
5. *Perform Leak Check of Machine Low-Pressure System
a. Veri fy that the machi ne master switch and fl ow control val ves are OFF.
b. Attach Sucti on Bul b to common (fresh) gas outlet.
c. Squeeze bulb repeatedl y until ful ly col l apsed.
d. Verify bulb stays ful l y col lapsed for at l east 10 seconds.
P.594
e. Open one vaporizer at a ti me and repeat c and d as above.
f. Remove sucti on bul b, and reconnect fresh gas hose.
6. *Turn on Machine Master Switch and all other necessary el ectri cal equi pment.
7. *Test Flowmeters
a. Adjust flow of all gases through their full range, checki ng for smooth operation of
fl oats and undamaged fl ow tubes.
b. Attempt to create a hypoxi c O
2
/N
2
O mi xture and veri fy correct changes i n flow and/or
al arm.
Scavengi ng Syst em
8. *Adjust and Check Scavenging System
a. Ensure proper connecti ons between the scavengi ng system and both APL (pop-off)
val ve and venti lator rel i ef val ve.
b. Adjust waste gas vacuum (i f possi bl e).
c. Full y open APL val ve and occl ude Y-pi ece.
d. Wi th mini mum O
2
fl ow, all ow scavenger reservoir bag to col l apse compl etel y and veri fy
that absorber pressure gauge reads about zero.
e. Wi th the O
2
fl ush acti vated, al l ow the scavenger reservoi r bag to di stend ful l y, and
then veri fy that absorber pressure gauge reads < 10 cm H
2
O.
Br eat hi ng Syst em
9. *Calibrate O
2
Monitor
a. Ensure monitor reads 21% i n room air.
b. Verify low O
2
al arm i s enabl ed and functi oni ng.
c. Rei nstal l sensor i n ci rcui t and fl ush breathi ng system with O
2
.
d. Veri fy that moni tor now reads greater than 90%.
10. Check Initial Status of Breathing System
a. Set sel ector swi tch to Bag mode.
b. Check that breathi ng ci rcui t i s compl ete, undamaged, and unobstructed.
c. Verify that CO
2
absorbent i s adequate.
d. Install breathi ng ci rcuit accessory equi pment (e.g., humi difier, PEEP val ve) to be used
duri ng the case.
11. Perform Leak Check of the Breathing System
a. Set al l gas fl ows to zero (or mi ni mum).
b. Close APL (pop-off) val ve and occlude Y-pi ece.
c. Pressuri ze breathi ng system to about 30 cm H
2
O with O
2
fl ush.
d. Ensure that pressure remai ns fi xed for at least 10 seconds.
e. Open APL (pop-off) val ve and ensure that pressure decreases.
Manual and Aut omat i c Vent i l at i on Sys t ems
12. Test Ventilation Systems and Unidirectional Valves
a. Pl ace a second breathi ng bag on Y-pi ece.
b. Set appropriate venti lator parameters for next pati ent.
c. Swi tch to automati c ventil ati on (Venti lator) mode.
d. Turn venti l ator ON and fil l bel l ows and breathi ng bag wi th O
2
fl ush.
e. Set O
2
flow to mini mum, other gas flows to zero.
f. Veri fy that duri ng i nspi ration bel l ows del i vers appropri ate ti dal vol ume and that duri ng
expirati on bel lows fi l ls compl etel y.
g. Set fresh gas fl ow to about 5 L/mi n.
h. Veri fy that the ventil ator bel l ows and si mul ated l ungs fi ll and empty appropri atel y
without sustained pressure at end expi rati on.
i. Check for proper acti on of unidi recti onal valves.
j. Exerci se breathi ng ci rcui t accessori es to ensure proper functi on.
k. Turn venti l ator OFF and swi tch to manual venti lati on (bag/APL) mode.
l. Ventil ate manual ly and assure i nflati on and defl ation of artifi ci al l ungs and appropri ate
feel of system resi stance and compl i ance.
m. Remove second breathi ng bag from Y-pi ece.
Moni t or s
13. Check, Calibrate, and/or Set Alarm Limits of all Monitors
Capnometer
Oxygen Anal yzer
Pressure monitor with Hi gh- and Low-Ai rway Pressure Al arms
Pul se Oxi meter
Respi ratory Volume Moni tor (Spirometer)
Fi nal P osi t i on
14. Check Final Status of Machine
a. Vapori zers off.
b. APL valve open.
c. Sel ector switch to Bag.
d. All fl owmeters to zero (or mini mum).
e. Patient sucti on l evel adequate.
f. Breathi ng system ready to use.
ACKNOWLEDGMENT
Porti ons of thi s chapter have appeared wi th permi ssi on i n Andrews JJ, Brockwel l RC: Inhal ed
anesthesia del i very systems. In Mil l er (ed): Anesthesi a, 6th ed., p 273. Phi l adel phi a, Churchil l
Livingstone, 2004.
Footnote
*If an anesthesi a provi der uses the same machine in successi ve cases, these steps need not be
repeated or may be abbrevi ated after the i ni tial checkout.
> Tabl e of Contents > Secti on IV - Prepari ng for Anesthesi a > Chapter 22 - Ai rway Management
Chapter 22
Airway Management
William H. Rosenblatt
KEY POINTS
Three mechani sms account for 75% of ai rway management injuri es: i nadequate
ventil ati on, esophageal i ntubati on, and diffi cult tracheal intubati on.
Several physi cal evaluati on measures of the diffi cul t ai rway have become
popul ari zed, though their reproduci bi li ty and predi ctabil i ty are di sputed.
Mul ti vari ate composi te indexes of airway exam fi ndi ngs have improved posi ti ve
predi cted val ue and speci fi ci ty.
Tracheal i ntubation should be consi dered nonrouti ne under the fol l owing
condi ti ons: (1) the presence of equall y important pri ori ti es to the management
of the ai rway (ful l stomach, open globe, etc.), (2) abnormal ai rway
anatomy, (3) an emergency, or (4) di rect injury to the l arynx and/or trachea.
It must be noted that the pati ent with normal l ung compl i ance should require no
more than 20 to 25 cm H
2
O pressure to i nfl ate the lungs.
Laryngeal mask airway (LMA) size sel ecti on i s cri ti cal to its successful use, and
to the avoidance of minor as wel l as more si gnifi cant compl i cations.
Ti ming of the removal of the LMA at the end of surgery i s cri tical to avoi d
compl i cati ons.
It i s important to assure that the fi rst attempt at laryngoscopy i s a best
attempt.
The Functi onal Ai rway Assessment (FAA) places an emphasis on the
interdependence of anatomi c characteristics rather than on thei r i ndi vi dual si ze
or functi onal integrity.
If, during the l aryngoscopy, a satisfactory l aryngeal vi ew i s not achi eved, the
backward-upward-ri ghtward pressure (BURP) maneuver may ai d i n i mprovi ng
PERSPECTIVES ON AIRWAY MANAGEMENT
The airway manager of the twenty-first century is faced wi th a mi nd-boggl ing choice of devi ces
and techni ques. The penul ti mate decade of the last century rei ntroduced the concept of
supralaryngeal venti lation for a l arge number of surgi cal procedures. Thi s was followed in the late
1990s by a prol iferati on of capabl e supragl ottic ai rways (SGA). Two promi nent movements i n
medici ne fuel ed thi s movement: evi dence-based analysi s of medi cal therapi es and a trend toward
reduced i nvasi veness in i nstrumentati on. Techniques of difficult ai rway management are i nfl uenced
by both the expanded cl ini cal appl i cations and cl i ni cian comfort with SGA venti l ati on, and new,
noni rritati ng inhal ation agents.
Techni ques and practi ces i n ai rway management have long been an i mportant concern of the
Ameri can Soci ety of Anesthesi ol ogi sts (ASA). In 1991, Caplan et al reported that 24% of
1,541 l i abi l i ty cl ai ms i n the ASA cl osed cl ai ms database were rel ated to adverse respi ratory
events.
1
Three mechanisms accounted for 75% of these injuri es: i nadequate venti lati on,
esophageal i ntubati on, and di ffi cul t tracheal intubati on. A more recent anal ysi s of the cl osed
cl ai ms data exami ned

ai rway injuri es (6% of 4,460 cl ai ms as of 1996). Interestingly, most injuri es to the l arynx occurred
the vi ew.
Extubati on of the trachea must not be consi dered a beni gn procedure. Most
adult pati ents are extubated after the return of consci ousness and spontaneous
respirati on, the resol ution of neuromuscul ar bl ock, and the abi li ty to foll ow
si mpl e commands.
The LMA had been reposi ti oned from the emergency to the routi ne
management pathway of the Ameri can Soci ety of Anesthesi ol ogi sts (ASA)
Difficult Airway Algorithm.
The ASA defines the di ffi cul t ai rway as the si tuati on i n whi ch the conventi onal l y
trai ned anesthesiol ogi st experi ences di ffi cul ty wi th mask venti l ati on or both.
Entry i nto the al gori thm begins wi th the eval uati on of the ai rway.
Awake ai rway management remai ns a mai nstay of the ASA' s Di ffi cul t Ai rway
Al gori thm.
There is no true or firm indication for fi beropti c bronchoscope (FOB)ai ded
intubati on, as there might be wi th di rect l aryngoscopy.
Retrograde wi re i ntubati on (RWI) can be a pri mary i ntubati on techni que
(el ecti ve or urgent) and al so employed after fail ed attempts at di rect
l aryngoscopy, fi beropti c-ai ded i ntubati on, and LMA-gui ded intubati on.
The ASA Diffi cul t Ai rway Al gori thm l i sts transtracheal jet venti l ati on as an
option in the cannot-mask venti late, cannot-intubate si tuati on.
P.596
duri ng routi ne tracheal i ntubations.
2

Airway management remai ns as much art as sci ence. Experience matters holds as much truth for
ai rway management as vigi l ance does for the entire fi el d of anesthesi ol ogy. In part, thi s i s
because of the l ack of adequate means of preoperatively detecting the pati ent who is di fficul t to
tracheal ly intubate by di rect laryngoscopy (DL). More i nformati on has surfaced showi ng that
routine pati ent eval uati on fai ls to detect a major source of these fail ures.
3
Fortunatel y, this has
become a l ess si gnifi cant probl em as SGA use prol i ferates and new means of i ntubati on are
adopted.
4
Sti l l DL remains the fastest means of achi evi ng tracheal i ntubati on across al l operators.

It is clear that management of the airway is paramount to safe perioperati ve care and the
fol l owing steps become necessary to favorabl y affect outcome: (1) a thorough airway history and
physi cal exami nati on; (2) consi derati on of management pl ans for use of a supraglotti c means of
ventil ati on (e.g., facemask, Laryngeal Mask Airway [LMA]); (3) a management pl an for intubati on
and extubati on techni ques; and (4) an alternati ve pl an of acti on shoul d diffi culti es arise.
Revi ew of Ai r way Anat omy
The term ai rway, refers to the upper ai rwayconsi sti ng of the nasal and oral caviti es, pharynx,
larynx, trachea, and pri nci pal bronchi . The ai rway i n humans is pri mari l y a conducti ng pathway.
Because the oroesophageal and nasotracheal passages cross each other, anatomi c and functi onal
compl exi ti es have evol ved for protection of the subl aryngeal airway agai nst aspi rati on of food that
passes through the pharynx. Anatomi cal l y compl ex, the airway undergoes growth and devel opment
and si gnificant changes i n i ts si ze, shape, and rel ati on to cervical spi ne between infancy and
chil dhood.
5
Si mi lar to other systems i n the body, it i s not immune from the infl uence of geneti c,
nutriti onal , and hormonal factors. Tabl e 22-1 il l ustrates the anatomic di fferences in the l arynx
between the i nfant and adult.
The l aryngeal skel eton consists of ni ne carti lages (three paired and three unpai red); together,
these house the vocal folds, whi ch extend in an anteri orposterior plane from the thyroi d cartil age
to the arytenoi d cartil ages. The shi el d-shaped thyroid carti l age acts as the anteri or protecti ve
housing of the vocal mechanism (Fi g. 22-1). Movements of the laryngeal structures are control led
by two groups of muscles: the extri nsi c muscl es, whi ch move the l arynx as a whol e, and the
intrinsic muscl es, which move the vari ous cartil ages i n rel ati on to one another. The larynx is
innervated bil ateral l y by two branches of each vagus nerve: the superi or l aryngeal nerve and the
recurrent l aryngeal nerve. Because the recurrent laryngeal nerves supply al l of the i ntrinsi c
muscles of the larynx (with the excepti on of cri cothyroid), trauma to these nerves can resul t in
vocal cord dysfuncti on. As a resul t of unil ateral nerve injury, ai rway function is usually
uni mpai red, but the protecti ve rol e of larynx i n preventi ng aspi rati on may be compromi sed.
TABLE 22-1 Anatomic Differences Between The Pediatric and Adult Airways
Proporti onatel y smal ler i nfant/chi ld larynx
Narrowest porti on: cricoid carti lage i n infant/chi l d; vocal folds i n adult
Rel ati ve vertical location: C3, C4, C5 in infant/child; C4, C5, C6 in adult
Epi glotti s: l onger, narrower, and sti ffer i n infant/chi l d
Aryepi gl otti c fol ds cl oser to midl i ne in i nfant/chi ld
Vocal fol ds: anterior angle with respect to perpendi cul ar axi s of l arynx i n i nfant/chi l d
Pl i abl e l aryngeal carti l age i n infant/chil d
Mucosa more vul nerabl e to trauma i n infant/chil d
The cricothyroid membrane (CTM) provides coverage to the cri cothyroi d space. The membrane,
whi ch i s typi call y 9 mm i n height and 3 cm i n wi dth, i s composed of a yel low el asti c ti ssue that
li es directl y beneath to the skin and a thi n faci al layer. It i s l ocated i n the anteri or neck between
the thyroi d cartil age superi orl y and the cri coi d carti l age i nferi orl y. It can be identi fi ed 1 to 1.5
fi ngerbreadths bel ow the l aryngeal prominence (thyroi d notch, or Adam' s apple). It is often
crossed hori zontall y i n i ts upper thi rd by the anastomosi s of the l eft and ri ght superi or
cricothyroi d arteri es. The membrane has a central portion known as the conus el asti cus and two
lateral porti ons, whi ch are thi nner and l ocated directly over the laryngeal mucosa. Because of
anatomic vari abi l ity i n the course of vei ns and arteri es and its proxi mi ty to the vocal folds (which
are 0.9 cm above the l igaments' upper border), i t is suggested that any i ncisi ons or needl e
punctures to the cri cothyroi d membrane be made i n i ts i nferi or thi rd and be di rected posteri orl y.
At the base of the l arynx, suspended by the undersi de of the cri cothyroi d membrane, i s the si gnet
ri ngshaped cricoi d carti lage. Thi s carti l age i s approxi matel y 1 cm i n height anteriorly, but almost
2 cm i n height in i ts posterior aspect as i t extends in a cephal ad di recti on, behind the cri cothyroi d
membrane and the thyroi d carti l age (see Fi g. 22-1). The trachea i s suspended from the cri coi d
carti lage by the cri cotracheal l i gament (CTL). The trachea measures ~15 cm i n adul ts and i s
ci rcumferential ly supported by 17 to 18 C-shaped cartil ages, wi th a posteri or membranous aspect
overlying the esophagus (Fi g. 22-2).
FIGURE 22-1. The major l andmarks of the airway mechanism. Note that the cri coi d carti l age
is l ess than 1 cm i n hei ght i n i ts anteri or aspect, but may be 2 cm i n hei ght posteri orl y
(smal l arrow).
The fi rst tracheal ri ng i s anteri or to the si xth cervi cal vertebrae. The tracheal cartil ages are
interconnected by fi broelasti c ti ssue, whi ch al l ows for expansi on of the trachea both in l ength

and di ameter wi th i nspi rati on/expirati on and fl exi on/extensi on of the thoracocervical spi ne. The
trachea ends at the cari na at the l evel of the fifth thoraci c vertebra, where i t bifurcates i nto the
pri nci pal bronchi (Fi g. 22-3). The right pri nci pal bronchus is l arger i n di ameter than the left, and
deviates from the plane of the trachea at a less acute angl e. Aspi rated material s, as well as a
deepl y i nserted tracheal tube, tend to gain entry i nto the ri ght pri nci pal bronchus though left
si ded posi ti on shoul d be excl uded. Carti lagi nous ri ngs support the fi rst seven generations of the
bronchi .
FIGURE 22-2. Bronchoscopi c vi ew of the adul t trachea. The carti l agi nous, C-shaped tracheal
ri ngs are seen anteri orly, and the membranous porti on, overlying the esophagus, i s
posterior.
P.597
P at i ent Hi st or y and P hysi cal Exam
Preoperati ve eval uati on of the pati ent shoul d eli cit a thorough hi story of airway-rel ated untoward
events as wel l as rel ated symptoms. A search for documentation to confi rm or el uci date these
problems should be conducted. Si gns and symptoms related to the ai rway should be eli cited, such
as snori ng (e.g., obstructi ve sleep apnea), chi pped teeth, changes i n voi ce, dysphagi a, stri dor,
bl eedi ng, cervical spi ne pai n or l imited range of moti on, upper extremi ty neuropathy,
temporomandi bul ar joi nt pai n or dysfuncti on, and si gnifi cant or prol onged sore throat/mandi bl e
after a previ ous anestheti c. Many congenital and acquired syndromes are associ ated with difficult
ai rway management (Tabl e 22-2).
FIGURE 22-3. The adul t tracheal carina. The cartil aginous ri ngs of the pri nci pal bronchi are
easil y vi sual i zed beyond the carina.
TABLE 22-2 Syndromes Associated with Difficult Airway Management
Pathologic Condition Principal Pathologic Clinical Features
Pertaining to Airway
CONGENITAL
Pi erre Robin syndrome Mi crognathi a, macrogl ossi a, glossoptosis, cl eft
soft palate
Treacher Col li ns syndrome
(mandi bul ofaci al dysostosi s)
Auricul ar and ocul ar defects; mal ar and
mandi bul ar hypopl asi a, mi crostomi a, choanal
atresi a
Gol denhar' s syndrome (oculo
auri cul overtebral syndrome)
Auricul ar and ocul ar defects; mal ar and
mandi bul ar hypopl asi a; occi pitali zation of atl as
Down' s syndrome (mongol i sm) Poorl y devel oped or absent bri dge of the nose;
macrogl ossi a, mi crocephal y, cervical spi ne
abnormali ties
Kl ippel -Fei l syndrome Congeni tal fusi on of a variabl e number of cervi cal
vertebrae; restri cti on of neck movement
Alpert' s syndrome
(acrocephal osyndactyl y)
Maxi l lary hypopl asi a, prognathi sm, cl eft soft
pal ate, tracheobronchial carti l agi nous anomal i es
Beckwi th' s syndrome (i nfanti l e
gi ganti sm)
Macroglossi a
Cherubism Tumorous lesion of mandi bles and maxi ll ae wi th
intraoral masses
Cretini sm (congenital
hypothyroi di sm)
Absent thyroi d ti ssue or defective synthesi s of
thyroxi ne; macrogl ossia, goiter, compressi on of
trachea, devi ati on of l arynx/trachea
Cri du chat syndrome Chromosome 5-P abnormal ; mi crocephal y,
mi crognathia, laryngomal aci a, stri dor
Meckel ' s syndrome Mi crocephal y, mi crognathi a, cl eft epigl otti s
von Reckli nghausen di sease
(neurofi bromatosi s)
Increased i nci dence of pheochromocytoma;
tumors may occur i n the larynx and ri ght ventri cle
outfl ow tract
Hurler' s syndrome
(mucopolysacchari dosi s I)
Sti ff joi nts, upper ai rway obstruction because of
infi ltration of lymphoi d tissue; abnormal
tracheobronchi al carti l ages
Hunter's syndrome
(mucopolysacchari dosi s II)
Same as i n Hurl er' s syndrome, but l ess severe;
pneumonias
Pompe' s di sease (gl ycogen
storage II)
Muscl e deposi ts, macrogl ossi a
ACQUIRED
Infections
Supragl ottiti s Laryngeal edema
Croup Laryngeal edema
Abscess (i ntraoral ,
retropharyngeal )
Distorti on and stenosi s of the ai rway and tri smus
Papi ll omatosis Chronic viral i nfecti on formi ng obstructi ve
papi l l omas, pri maril y supraglotti c
Ludwi g' s angi na Distorti on and stenosi s of the ai rway and tri smus
Arthritis
Rheumatoi d arthri ti s Temporomandi bul ar joint ankyl osi s, cri coarytenoi d
arthri tis, devi ati on of l arynx, restri cted mobi li ty
of cervi cal spi ne
Ankylosing spondyl iti s Ankylosis of cervical spi ne; l ess commonl y
ankyl osi s of temporomandi bul ar joi nts; l ack of
mobi l i ty of cervi cal spi ne
Benign Tumors
Cysti c hygroma, l i poma, adenoma, goi ter
Stenosis or distorti on of the ai rway
Malignant Tumors
Carcinoma of tongue, carci noma
of larynx, carci noma of thyroi d
Stenosis or distorti on of the ai rway; fi xati on of
larynx or adjacent ti ssues (e.g., i nfil trati on or
fi brosi s from i rradi ati on)
Over the l ast two decades, several physi cal evaluati on measures have become popul ari zed,
though thei r reproduci bi li ty and predi ctabi l i ty are di sputed.
6
The di ffi cul ty i n devel opi ng the
perfect ai rway evaluati on tool li es i n two i nterrelated areas: si mpli city and interdependency.
Though si mpl e bedsi de eval uati on tool s are useful , adequate evaluati on may requi re endoscopi c,
radiol ogi c, or other uncommon exami nations.
3
Interdependency refers to the predictive val ue of
one ai rway exam measure based on the fi ndi ngs of another. This is discussed under the topi c of
functi onal ai rway assessment (FAA) in a l ater secti on.
El -Ganzouri et al desi gned a model for stratifyi ng ri sk of diffi cult di rect l aryngoscopy usi ng a l arge
popul ati on.
7
This group examined five common i ndi ces i ndi vi duall y and in a mul ti vari ate model to
assess predi cti ve power. As can be seen i n Tabl e 22-3, no i ndi vi dual measure proved both
sensi ti ve and speci fi c. Though the Mall ampati cl assifi cati on (Fi g. 22-4) was the most sensiti ve
index, i t had l ow speci fi ci ty (many fal se-positi ves), and l ow-positi ve predictive value (4% for a
grade IV laryngeal vi ew).
8
Posi ti ve predictive values were low for all the commonly used i ndi ces.

Trauma
Head i njury, faci al i njury, cervi cal
spi ne i njury
Cerebrospinal rhi norrhea, edema of the ai rway;
hemorrhage; unstabl e fracture(s) of the maxil l ae
and mandi bl e; intralaryngeal damage
Miscellaneous Conditions
Morbid obesity Short, thi ck neck and l arge tongue are l i kel y to be
present
Acromegal y Macroglossi a; prognathism
Acute burns Edema of ai rway
TABLE 22-3 Statistical Accuracy of Commonly Applied Physical Airway Indexes
7, 8, 9

SENSITIVITY
a
% SPECIFICITY
a
% POSITIVE
PREDICTIVE VALUE
a
Mouth opening (<4
cm)
26.3 94.8 25
Thyromental di stance
(<6 cm)
7 99.2 38.5
Mal lampati Cl ass III 44.7 89.0 21
Neck movement <80 10.4 98.4 29.5
Thi s mul tivari ate i ndex (MI) assigned rel ati ve wei ghts to each exam finding based on the
odds of a hi gh-grade l aryngeal view on DL wi th i ncreasi ng exam score. The scori ng of each of
these physical exams is li sted in Tabl e 22-4. The authors noted that at i ncreasi ng MI scores,
positi ve predictive value i ncreased, but sensi ti vi ty decreased (i .e., hi gher MI scores occur when
there are more posi tive physi cal fi ndi ngs, but not al l di ffi cul t laryngoscopy pati ents wi l l mani fest
mul tipl e fi ndings). Compared to the Mal lampati cl assi fi cati on al one, the mul ti vari ate composi te
i ndex had an i mproved posi ti ve predi cti ve and speci fi ci ty val ue at equal sensi tivity. Of course,
some pathology wil l onl y present on the i nduction of anesthesi a and/or attempts at l aryngoscopy
(Fi g. 22-5).
10

Inabi l ity to prognath 16.5 95.8 20.6
Body wei ght >110 11.1 94.6 11.8
Hi story of di ffi cul t
intubati on
4.5 99.8 69.0
a
For fi ndi ng of grade III/IV view on direct l aryngoscopy.
FIGURE 22-4. Mal l ampati /SamsoonYoung classi fi cati on of the oropharyngeal vi ew.
10
Class
I: uvul a, fauci al pi l l ars, soft pal ate visi ble; Class II: faucial pi ll ars, soft pal ate visi ble; Class
III: soft and hard pal ate vi si bl e; Class IV: hard palate visible onl y (added by Samsoon and
Young).
TABLE 22-4 Techniques of Common Airway Indexes Measurement
Few studi es have objecti vel y determined those findings that i denti fy the di ffi cul t-to-mask venti l ate
patient. Thi s basi c ai rway maneuver was exami ned i n a control study by Langeron et al.
11
Of 1,502
pati ents (excl udi ng pl anned rapi d-sequence i nducti on or emergency cases), 5% were characteri zed
as di ffi cul t mask venti l ati on (DMV). Only one pati ent i n the seri es was i mpossi bl e to venti late by
face mask. Tabl e 22-5 describes the cri teri a for defi ning a DMV and the fi ve i ndependent cl i ni cal
predi ctors. The presence of two predi ctors i ndi cted a hi gh l ikel i hood of DMV.
Thyromental di stance: measured al ong a strai ght l i ne from ti p of mentum to thyroi d
notch in neck-extended posi ti on
Mouth opening: interi ncisor di stance (or i nter-al veolus distance when edentul ous) with
the mouth ful l y opened
7

Mal l ampati score (see l egend, Fi g. 22-4)
Head and neck movement: the range of motion from ful l extension to full flexi on
9

Abil i ty to prognath: capaci ty to bri ng the l ower i nci sors i n front of the upper incisors
7
FIGURE 22-5. A 40-year-ol d mal e whose epigl otti c cyst was di scovered at laryngoscopy.
TABLE 22-5 Assessment and Predictability of Difficult Mask ventilation
11

Cri teri a for di ffi cul t mask ventilation
Inabi li ty for one anesthesi ol ogi st to mai ntain oxygen saturati on >92%
In general , tracheal intubati on shoul d be consi dered nonrouti ne under the fol lowi ng
condi ti ons: (1) the presence of equall y important pri oriti es to the management of the airway
(ful l stomach, open globe, etc.), (2) abnormal ai rway anatomy, (3) an emergency, or (4)
di rect i njury to the larynx and/or trachea. Although the finding of abnormal anatomy is not
necessari ly synonymous wi th the di fficul t airway, i t shoul d ki ndl e a hei ghtened l evel of suspi ci on.
Several investi gators have identi fi ed anatomi c features as having unfavorable influences on the
mechani cs of di rect laryngoscopy; these are expl ai nabl e on the basis of i nabi l ity to create a l i ne of
si ght from the operator' s eye to the aperture of the larynx. In the earl i est attempt to descri be
anatomic correlates of di fficul t i ntubati on, Cass et al placed emphasi s on a short muscul ar neck
with a

ful l dentiti on, a recedi ng mandibl e with obtuse mandibular angl es, protruding maxillary incisor
teeth, decreased mobi l i ty at temporomandi bul ar joi nts, a l ong hi gh arched palate, and i ncreased
al veolarmental di stance.
12
Earl y radiographi c studi es showed that the posteri or depth of the
mandi ble (the di stance between the bony al veolus immedi atel y behi nd the thi rd mol ar tooth and
the lower border of mandi bl e) was an important factor i n determining the ease or di ffi cul ty of
laryngoscopy.
13
As is di scussed l ater, thi s anatomi c feature i s receiving renewed i nterest.

CLINICAL MANAGEMENT OF THE AIRWAY
Significant gas leak around face mask
Need for IS 4 mi n gas fl ow (or use of fresh gas flow button more than twice)
No chest movement
Two-handed mask venti lation needed
Change of operator required
Independent risk factors for di ffi cul t mask venti lation
Odds rati o
Presence of a beard 3.18
Body mass i ndex >26 ng/m
2
2.75
Lack of teeth 2.28
Age >55 2.26
History of snori ng 1.84
P.598
P.599
P r eoxygenat i on
Preoxygenation (also commonl y termed denitrogenati on) shoul d be practiced in all cases when
ti me permi ts.
14
Thi s procedure entai ls the repl acement of the ni trogen vol ume of the l ung
(upwards of 69% of the functional resi dual capaci ty [FRC]) wi th oxygen to provi de a reservoi r for
di ffusion into the al veolar capi ll ary blood after the onset of apnea.
15
Preoxygenati on wi th 100% O
2

via a ti ght-fitting facemask for 5 mi nutes i n a spontaneousl y breathi ng pati ent can furni sh up to
10 mi nutes of oxygen reserve foll owing apnea (i n a pati ent wi thout si gnifi cant cardiopul monary
di sease and a normal oxygen consumption).
16
In one study of healthy, nonobese patients who
were al lowed to breathe 100% O
2
preoperati vel y, subjects sustai ned an oxygen saturation of
greater than 90% for 6 0.5 mi n, whereas obese patients experi enced oxyhemogl obi n
desaturation to under 90% i n 2.7 0.25 mi n.
17
The patient breathing room ai r (21% O
2
) wil l
experi ence oxyhemogl obi n desaturati on to a l evel of under 90% after approxi mately 2 mi nutes
under i deal condi ti ons. Pati ents in respi ratory fai lure, or wi th conditi ons affecti ng metabol i sm or
lung vol umes, frequentl y evi dence desaturati on sooner owing to increased O
2
extracti on,
decreased FRC, or ri ght-to-left transpulmonary shunti ng. The most common reason for not
achi evi ng a maximum alveol ar FIO
2
during preoxygenati on i s a l oose-fitting mask, al lowi ng the
entrainment of room ai r.
14
Less ti me-consuming methods of preoxygenati on have al so been
descri bed. Usi ng a seri es of four vi tal capaci ty breaths of 100% O
2
over a 30-second peri od, a
hi gh arterial PaO
2
(339 mm Hg) can be achi eved, but the time to desaturati on i s consi stentl y
shorter as compared to techni ques of breathi ng 100% O
2
for 5 minutes.
18
A modi fi ed vi tal capaci ty
technique, wherei n the patient is asked to take ei ght deep breaths i n a 60-second peri od, shows
promi se in terms of prol ongi ng the ti me to desaturation.
14, 19
I prefer the techni que of appl yi ng a
ti ght-fi tti ng mask for 5 mi nutes or more of ti dal vol ume breathi ng; the mask i s pl aced immedi atel y
after the pati ent has been made comfortabl e on the operati ng room tabl e and remains in pl ace
duri ng i ntravenous catheter i nsertion and appli cati on of moni tors. Pharyngeal i nsuffl ati on of
oxygen i s a technique that has been descri bed to prol ong the durati on that an apnei c patient
sustains an oxyhemogl obi n saturati on of >90%. In this techni que, oxygen is i nsuffl ated at a rate
of 3 L/min vi a a catheter passed through the nares. Thi s technique rel i es on the phenomenon of
apnei c oxygenation, a process by whi ch gases are entrained into the al veolar space during apnea,
as l ong as there i s a patent airway.
20
Thi s entrai nment can provi de enough oxygen to sustain
hemoglobi n saturation for prol onged peri ods. It i s based on the decrease in i ntrathoracic pressure,
rel ati ve to atmospheri c pressure, produced as approximatel y 210 cm
3
of oxygen diffuses into the
al veol ar capi l l ary bed each minute whi l e as l i ttl e as 12 cm
3
of carbon di oxi de di ffuses into

the al veolar space (the remai nder of the carbon di oxi de bei ng buffered i n the bl ood or ti ssues).
The alveol ar carbon dioxi de i s not removed i n thi s si tuati on, l i mi ti ng the durati on of thi s techni que
of oxygenati on.
Suppor t of t he Ai r way wi t h t he I nduct i on of Anest hesi a
Wi th the inducti on of anesthesia and the onset of apnea, venti lation and oxygenation are
supported by the anesthesi ologi st. Tradi tional methods incl ude the anesthesi a facemask and the
tracheal tube. Duri ng the last decade several SGA devi ces have been i ntroduced i nto worl dwi de
cl i ni cal practi ce. Of these, the LMA has gai ned signi fi cant acceptance among anesthesi ol ogi sts i n
the Uni ted States, wi th use rates as hi gh as 35% of al l general anesthesi a cases, in some
setti ngs.
21
The use of the LMA i n routine surgery, incl uding cases traditi onal l y managed wi th
tracheal i ntubati on, has been previ ousl y di scussed.
58

The Anesthesia FaceMask
The anesthesi a facemask is the device most commonly used to del i ver anestheti c gases and
oxygen, as wel l as to venti late the pati ent who has been made apnei c.
The ski ll ful use of a facemask may be chal lengi ng and, despi te the many advances i n ai rway
management, remains a mainstay in the delivery of anesthesi a and resuscitati on. When the
inducti on of anesthesia i s i ni ti ated, the pati ent's l evel of consci ousness changes from the awake
P.600
state, with a competent and protected airway, to the unconsci ous state, with an unprotected and
potential ly obstructed airway. Thi s drug-induced central venti latory drive depressi on with a
rel axation of the musculature of the upper airway can rapidl y lead to hypercapnea and hypoxi a.
Facemask venti lation i s minimal l y i nvasi ve and vi rtual ly universal and requires the least
sophi sti cated equi pment, thus maki ng it criti cal to management of the airway.
Appropri ate posi tioni ng of the pati ent i s paramount to successful mask venti l ati on. With the
patient in the supi ne posi ti on, the head and neck are placed i n the sniffi ng posi ti on, whi ch i s
di scussed extensivel y later i n the chapter. Thi s posi tion improves mask venti l ati on by anteri orizing
the base of the tongue and the epi glotti s.
The mask i s gentl y hel d over the pati ent' s face with the l eft hand, leavi ng the ri ght hand free for
other uses (Fi g. 22-6).

El asti c mask straps may be used to hel p secure the mask in the awake or anesthetized pati ent
who i s breathing spontaneously and wi thout obstructi on, or to complement the l eft-hand grip. The
mask straps can be parti cularly hel pful for the cl ini ci an with short fingers. However, prol onged use
of ti ght-fitting mask straps has been associ ated with motor and sensory neuropraxias.
P.601
FIGURE 22-6. Holdi ng the anesthesi a mask on the face. The thumb and the first fi nger gri p
the mask i n such a fashion that the anesthesia ci rcui t (or ambu bag) connecti on abuts the
web between these di gi ts. Thi s al l ows the pal m of the hand to apply pressure to the l eft si de
of the mask, whi le the ti ps of these three di gi ts appl y pressure over the ri ght. The third
finger hel ps to secure under the mentum, whi le the fourth finger is under the angl e of the
mandi ble or al ong the lower mandi bul ar ri dge. Mask straps (on pi l low) may be used to
After i nducti on of anesthesi a, a ti ght fit of the facemask i s achi eved by downward di spl acement of
the mask between the thumb and first/second fingers with concurrent upward di spl acement of the
mandi ble with the remai ning fi ngers. Thi s latter maneuver, commonly known as a jaw thrust,
raises the soft ti ssues of the anterior ai rway off of the pharyngeal wal l and al lows for improved
ventil ati on. In those pati ents who are obese, edentul ous, or bearded, two hands or a mask strap
may be requi red to ensure a ti ght-fi tti ng mask seal . When two hands are required for holdi ng the
facemask, a second operator wi l l obviousl y be requi red to venti l ate the pati ent (Fi g. 22-7). If need
be, the second operator can l end a thi rd hand to the mask fi tti ng, provi di ng for both jaw thrust
and chin lift.
It must be noted that the pati ent with normal l ung compl i ance should require no more than
20 to 25 cm H
2
O pressure to infl ate the l ungs. If more pressure than thi s i s requi red, the
cl i ni ci an shoul d reeval uate the adequacy of the ai rway, then adjust the mask fit, seek the aid of a
second operator to perform two- or three-handed mask hol ds, and/or consi der other devi ces that
ai d i n the creati on of an open passage for ai rfl ow through the upper airway. Both ri gi d oral
ai rways and soft nasal ai rways create an artifi ci al passage between the roof of the mouth, tongue,
and the posteri or pharyngeal wal l (Fi g. 22-8).
compl ement the hand gri p by securing the right si de of the mask.
FIGURE 22-7. When mask venti l ati on i s di ffi cul t owi ng to upper ai rway obstructi on, a second
operator may be required so that (A) two or (B) three hands can be used i n a jaw-thrust
maneuver.
Oral airways, whi ch come i n a wi de variety of si zes, can sti mul ate the semi conscious patient and
provoke coughi ng, vomiti ng, and/or laryngospasm. The l evel of anesthesi a must be assessed
before they are inserted. Likewi se, an SGA may be used at this juncture if the anestheti c i s
adequate. Nasal ai rways, less sti mulating to the pati ent, can cause si gni fi cant nasal trauma

and bl eedi ng and shoul d be used with extreme cauti on i n patients with known coagul opathy or
nasal deformi ties. These devices are contraindicated i n the pati ent wi th a basil ar skull fracture.
Obstruction to mask ventil ati on may be caused by l aryngospasm, a refl ex cl osure of the vocal
fol ds. Laryngospasm occurs as a result of foreign body (e.g., oral or nasal airway); sal iva, blood,
or vomi tus touching the glotti s; or even a li ght pl ane of anesthesi a. Hypoxi a as well as
noncardiogeni c pul monary edema can result i f there i s conti nued spontaneous venti lation agai nst
cl osed vocal cords. Treatment of l aryngospasm i ncl udes removal of an offendi ng sti mulus (i f it can
be identi fi ed), conti nuous positi ve ai rway pressure, deepening of the anesthetic state, and the use
of a rapid-acti ng muscl e rel axant.
If there are no contrai ndi cati ons (e.g., a ful l stomach or other aspi rati on ri sk), mask venti l ation
can be the techni que empl oyed for the durati on of anesthesi a mai ntenance. Otherwi se, i t i s
commonly used to administer anestheti c gases unti l the anestheti c state is adequate for use of
another means of ai rway support (e.g., SGA, tracheal tube). Thi s deci si on is made after careful
consi derati on of the patient' s coexi sti ng diseases and surgi cal requirements.
Supraglottic Airways
The LMA ushered i n the fi rst major use of SGAs i n the Uni ted States. But, by the time of i ts i ni tial
introducti on i n 1989 and approval by the U.S. Federal Drug Admi ni strati on (FDA) i n 1991, it was
bei ng used i n more than 500 hospi tal s i n the Uni ted Ki ngdom. Though ini ti al l y approved for use as
a substi tute for facemask venti l ati on and when tracheal intubati on was not achi evabl e, i t soon
enjoyed wi de use i n surgi cal cases traditi onal l y managed wi th tracheal i ntubati on.
21

Though other SGAs were avai l abl e i n the early 1990s (e.g., COPA J. Mal l inkroft Medi cal , Athl one,
Ireland), i t was not unti l the patent of origi nal LMA design, the LMA-Classi c, expired i n 2002
that there was a prol i feration of si mil ar devi ces. A weal th of i nformati on exi sts on the LMA and i ts
subsequent iterations (all by the ori ginal i nventor, Dr. Archi e Brai n). Much of thi s knowl edge may
appl y to newer SGAs but studi es on those devi ces are few at the ti me of this wri ting. Thi s chapter
devotes consi derable text to the fami l y of LMAs. Thi s i s not meant to i nfer preference, but rather a
FIGURE 22-8. A variety of oral (A) and nasal (B) ai rways are avail abl e. The goal of these
devices i s to hol d the base of the tongue forward to create an ai r passage.
P.602
rel ati ve avai l abi l i ty of i nformati on.
The advent of the LMA as wel l as other supral aryngeal airways have led some to questi on the
rel ati ve safety of tracheal i ntubati on.
22
A recent study by Tanaka et al demonstrated vocal cord
edema and i ncreased ai rflow resi stance i n pati ents undergoi ng mi nor surgery wi th a tracheal
tube.
23
These changes were not seen wi th LMA use. Thi s, al ong with ASA cl osed cl ai m database
information, lends support to the search for safe alternati ves to tracheal intubati on whenever
possi bl e.
24

LMA Design. The LMA is composed of a smal l mask desi gned to si t i n the hypopharynx, wi th an
anterior surface aperture overlying the l aryngeal i nl et (Fi g. 22-9). The ri m of the mask i s
composed of an i nfl atabl e si l icone cuff that fi ll s the hypopharyngeal space, creati ng a seal that
al lows posi tive-pressure ventil ati on wi th up to 20 cm H
2
O pressure.
25
The adequacy of the seal i s
dependent on correct pl acement and appropri ate si ze. It i s l ess dependent on the cuff fi l l i ng
pressure or volume. Attached to the posteri or surface of the mask i s a barrel (ai rway tube) that
extends from the mask' s central aperture through the mouth and can be connected to an ambu
bag or anesthesi a ci rcuit.
LMA si ze sel ecti on i s cri ti cal to its successful use, and to the avoidance of minor as well as
more si gni fi cant compl icati ons. Neonatal to large adult si zes are avail abl e. Tabl e 22-6 gives
the recommended si ze for pati ent wei ght and the maximum inflation volumes. The manufacturer
recommends that the cli nici an choose the l argest si ze that wi ll comfortabl y fit i n the oral cavi ty,
then i nflate to the mini mum pressure that al l ows ventil ati on to 20 cm H
2
O without an ai r leak. The
intracuff pressure should never exceed 60 cm H
2
O (and shoul d be peri odi cal ly moni tored if ni trous
oxi de i s used as part of the anestheti c). When an adequate seal cannot be obtai ned wi th 60 cm
H
2
O cuff pressure, the LMA may be mal posi ti oned and/or si zi ng shoul d be reeval uated. Li ght
anesthesia may also contribute to poor seal or parti al or compl ete laryngospasm.
FIGURE 22-9. The ori gi nal LMA desi gn: a si ze 1 and si ze 6 LMA-Classi c. The two bars over
the ai rway aperture prevent the epigl ottis from obstructi ng the LMA barrel .
TABLE 22-6 LMA Sizing and Inflation Volumes
LMA
SIZE
PATIENT WEIGHT INCREASE IN
SIZE (%)
MAXIMUM
INFLATION
VOLUME (mL)
TEST
INFLATION
VOLUME (mL)
LMA Insertion. The i nserti on of the LMA as descri bed by i ts inventor, Dr. Archi e J. I. Brain, has
been modi fi ed by a number of writers. Di scussi on of these various alternati ves i s beyond the
scope of thi s text. Dr. Brai n' s ini ti al contempl ati ons

of this uni que ai rway consi dered routi ne and natural pl acement of a forei gn body i n the
hypopharynxfood. It was Dr. Brai n' s i ntent to mimi c the pl acement of food i nto the hypopharynx
and thereby establi sh the pl acement of a devi ce, whi ch coul d then serve as an airway. All vari eti es
of the LMA (wi th the exception of the LMA-Fastrach) fol l ow the same insertion technique.
To understand the i nserti on techni que, we must therefore revi ew the processes of degl uti nation:
lubri cation wi th sal i va; formation of a flat oval food bol us by the tongue; initi ati on of the
swal lowi ng refl ex by sti mul ation of the palate; upward pressure by the tongue fl atteni ng the food
bol us agai nst the pal ate; di recti ng of the food bol us toward the posterior pharyngeal wal l and into
the hypopharynx by the shape of the pal ate and pharyngeal wal l ; head extension and neck flexi on
openi ng the space behi nd the l arynx to allow passage of the food bol us i nto the hypopharynx; and
finall y, openi ng of the upper esophageal sphi ncter to all ow esophageal entry of the food bol us.
These functi ons al l ow the food bol us to reach i ts mark bli ndl y, whi l e avoi di ng the anteri or
pharyngeal structures and avoi di ng refl ex responses meant to protect the airway.
Prototype i nsertion methods i nvol ved rotation through 180 and the early use of an introducer to
prevent down-fol di ng of the epigl ottis. The currentl y recommended techni que, il l ustrated i n Fi gure
22-10, has been found to be l ess traumati c and has a 98% success rate. In thi s technique the
mask is l ubri cated wi th a nonsi li cone, nonl ocal anestheti ccontai ning l ubricant (si mulating the
sali va) and i s full y deflated to form a thin, flat wedge shape (masticated food bolus). The
operator' s nondomi nant hand i s placed under the occi put to fl ex the neck on the thorax and
extend the head at the atl anto-occi pi tal joint (creating a space behi nd the larynx; this acti on also
tends to open the mouth).
26
The i ndex fi nger of the domi nant hand i s placed in the cleft between
the mask and barrel . The hard pal ate i s vi sual i zed and the superi or (nonaperture) surface of the
mask is pl aced against i t. Force i s appl i ed by the i ndex fi nger i n an upward di recti on toward the
top of the pati ent's head. Thi s wi ll cause the mask to fl atten out agai nst the palate and foll ow the
shape of the pal ate as i t sl ides i nto the pharynx and hypopharynx. The i ndex fi nger conti nues
1 Neonates/infants
up to 5 kg
4 6
1.5 510 kg 21 7 10
2 1020 kg 21 10 15
2.5 2030 kg 18 14 21
3 >30 kg 15.7 20 30
4 Small adul ts 14.4 30 45
5 Normal adul ts 13.8 40 60
6 Large adul ts 8.1 50 80
P.603
al ong thi s arc, always appl yi ng an outward pressure unti l the resi stance of the upper esophageal
sphincter is met. The most common error made by cl i ni cians i s appl yi ng pressure wi th a posteri or
vector. Thi s tends to catch the ti p of the LMA on the posteri or pharyngeal wal l , causi ng foldi ng
with resul tant mi spl acement and trauma.
Once i nserti on i s compl ete, removal of the i nserti ng hand i s faci l itated by gentl e stabil i zati on of
the LMA barrel with the nondomi nant hand. Pri or to attachment of the anesthesia circui t, the LMA
is inflated with the minimum amount of gas to form an effective seal . Though i t i s difficult to
suggest a parti cul ar vol ume of gas to be used, the operator should be

accustomed to the feel of the pi l ot bul b when i t is i nflated to 60 cm H
2
O pressure, the maxi mum
suggested seal pressure. Accompanyi ng the i nfl ati on, one should be abl e to observe a ri si ng of the
cri coi d and thyroi d cartil age and l ifti ng of the barrel out of the mouth by approximatel y 1 cm as
the mask is lifted off the upper esophageal sphi ncter. The mask i s fi xed i n posi ti on by bri ngi ng the
barrel down against the chin and tapi ng i n the midl ine whil e a gentl e upward pressure i s exerted
against the hard pal ate. If a mi dli ne posi ti on i s not possibl e owi ng to the nature of the pati ent
positi on or surgi cal procedure, a fl exibl e LMA (di scussed l ater) shoul d be consi dered. A bite bl ock
is recommend to prevent biti ng and occl usi on of the LMA barrel .
The LMA and Gastroesophageal Reflux. Al though the di stal tip of the LMA' s mask sits i n the
esophageal i nl et, it does not rel iabl y seal i t. A predominant cli ni cal perception is that the LMA
does not protect the trachea from regurgi tated gastri c contents. As of 2004, just 23 cases of
suspected pul monary aspi ration have been reported (with an esti mated 200,000,000 uses of the
LMA worl dwi de). Of these, only 13 were veri fi ed as true aspi rati on events and none resul ted i n
death, though fi ve pati ents requi red posi ti ve-pressure ventil ati on. There were predi sposi ng factors
in most of the cases, incl uding obesi ty, dementi a, emergency surgery, upper abdomi nal surgery,
Trendel enburg positi on, i ntraperi toneal i nsuffl ation, or a di ffi cul t
ai rway.
27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40
Indeed, when used i n pati ents at l ow risk for regurgi tati on,
FIGURE 22-10. Insertion of the LMA. The LMA is i nserted wi th the index finger of the
domi nant hand pressi ng wi th a force vector agai nst the hard pal ate (A and B). The outward
force vector is continued from the hard pal ate to the pharynx and hypopharynx (C) unti l the
index fi nger meets resi stance agai nst the upper esophageal sphincter (D).
P.604
the rate of aspi rati on duri ng LMA use i s simil ar to that in all non-LMA general anestheti cs (~2 i n
10,000 cases), though the incidence of gastroesophageal reflux may be increased when compared
to use of the facemask.
41, 42, 43, 44, 45

Some evi dence suggests that there may be more gastroesophageal refl ux duri ng LMA use wi th a
patient in the Trendel enburg or l i thotomy posi ti on.
43, 45
If regurgi tated gastri c contents are noted
in the LMA barrel, maneuvers simi lar to those appl i ed when usi ng an ETT shoul d be insti tuted:
Trendel enburg positi on, admi ni ster 100% oxygen, l eave the LMA in place and use a flexi bl e
sucti on devi ce down the barrel , deepen anestheti c i f necessary.
When popul ati ons of pati ents consi dered to have a ful l stomach are studi ed (i n controll ed tri als,
prospecti ve series, or anecdotal ly), there i s a very l ow i nci dence of aspi ration noted wi th el ecti ve
or emergency LMA use. Reports have incl uded pati ents who are morbidl y obese or experi ence
frequent gastroesophageal refl ux and those undergoi ng electi ve cesarean secti on or ai rway rescue
duri ng l abor and those presenti ng to emergency departments or paramedi c
crews.
46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56
Duri ng cardi opulmonary resusci tati on, the i nci dence of
gastroesophageal regurgi tation is four ti mes greater wi th a bag-val ve mask than wi th the LMA.
57

Unconventional Use of the LMA. Si nce its introducti on, a weal th of cl inical data has indicated
that the LMA can be safel y used i n the operati ng room in a vari ety of cli nical si tuati ons. A l arge
number of cli ni cal si tuati ons tradi tional ly managed wi th tracheal intubati on and mechani cal
ventil ati on have been performed wi th the LMA.
58

LMA and Positive-Pressure Ventilation. Though fi rst i ntroduced for use wi th spontaneous
ventil ati on, the LMA has proved useful for cases in whi ch posi tive-pressure ventil ati on i s either
desi red or preferred.
59, 60
Contrary to i ni tial i mpressi on, posi ti ve-pressure venti lation can be safel y
accompl i shed wi th the LMA.
61, 62, 63, 64
There is no difference found in gastric infl ati on wi th positi ve
pressure (<17 cm H
2
O) when compari ng the LMA and the ETT.
65, 66
When using the LMA, one
should li mi t tidal volumes to 8 mL/kg and ai rway pressure to 20 cm H
2
O si nce thi s is the seali ng
pressure of the devi ce under normal ci rcumstances. LMA use has been descri bed wi th the supi ne,
prone, l ateral , obli que, Trendel enburg, and l i thotomy positi ons.
67
Though the manufacturer
recommends use for a maximum of 2 to 3 hours, reports of use lasti ng more than 24 hours can be
found.
68

The LMA-Flexible. The advent of the LMA-flexibl e (Fi g. 22-11) has permi tted extensi on of LMA
use to a variety of cases i n whi ch the ai rway is shared wi th the surgi cal team (e.g.,
otol aryngol ogic surgery).
69
The LMA-flexible differs from the ori gi nal desi gn by virtue of a thin-
wal l ed, smal l -di ameter, wire-rei nforced (ki nk-resistant) barrel, whi ch can be posi ti oned out of the
mi dl i ne wi thout affecti ng the hypopharyngeal posi ti on of the mask. It was desi gned to be used
with a tonsi ll ar mouth gag, as empl oyed in surgery on the mouth and pharynx.
70, 71
The LMA-
flexible has also proved useful when heavy drapes are pl aced over the head and ai rway (e.g.,
mastoi dectomy), when there i s movement of the head posi ti on duri ng surgery (e.g., typanostomy
tubes), or when the LMA barrel cannot be secured i n the mi dl i ne (e.g., mi d or l ateral faci al
surgery). The use of this mask in surgery above the l evel of the hypopharynx, i ncl udi ng
tonsi ll ectomy, affords a number of cl i ni cal l y i mportant advantages over tracheal intubati on (Tabl e
22-7).
When correctl y pl aced, the LMA mask serves to block the ai rway from blood, secreti ons, and
TABLE 22-7 Advantages of the LMA in Supraglottic Surgery
Improved protecti on of the ai rway from bl ood and surgi cal debri s
Reduced cardi ovascul ar responses
Reduced coughi ng on emergence
Reduced l aryngospasm after ai rway device removal
Improved oxygen saturati on after airway device removal
Abil i ty to admi ni ster oxygen unti l complete restorati on of ai rway reflexes
FIGURE 22-11. An LMA-flexible in place with a Crow-Davis mouth gag during a tonsi l lectomy
and uvul opharyngopalatopl asty. The uvul a has been removed. The LMA mask i s not vi si bl e to
the surgeon when correctl y placed.
surgi cal debri s above the l evel of the mask, as compared to the tracheal tube, which i s known not
to protect the trachea from l iqui ds insti l led i nto the pharynx
72, 73, 74, 75
(Fi g. 22-12).

The LMA and Bronchospasm. As a supragl ottic airway, the LMA appears to be wel l sui ted to the
patient wi th a hi story of extri nsi c asthma. The LMA presents a uni que opportuni ty for the cl i ni cian
to conveni entl y and effecti vel y control the ai rway wi thout havi ng to introduce a forei gn body i nto
the trachea. Thus, i t may be an i deal airway tool in the asthmati c pati ent who is not at ri sk for
refl ux and aspi rati on.
76, 77, 78
Because the hal ogenated inhal ed anestheti cs are potent
bronchodil ators, i t i s at the time of emergence (when the anestheti c is di sconti nued)

that the patient at ri sk for bronchospasm i s most l i kel y to wheeze. In the pati ent managed with
the LMA, there is no foreign body in the sensiti ve bronchorespi ratory tree and the pati ent can be
ful l y emerged pri or to removal of the devi ce. In the event that uncontroll able bronchospasm does
occur intraoperatively (e.g., from vagal stimul i such as tracti on on the peritoneum), intubati on
can be performed through the LMA or after i ts removal .
79

LMA Removal. Timi ng of the removal of the LMA at the end of surgery is criti cal .
80, 81
The
LMA shoul d be removed either when the pati ent is deepl y anesthetized or after protective
refl exes have returned and the patient is able to open the mouth on command. Removal during
exci tati on stages of emergence can be accompani ed by coughing and/or l aryngospasm. Many
cl i ni ci ans remove the LMA ful ly i nfl ated; thus, i t acts as a scoop for secreti ons above the mask,
bri ngi ng them out of the airway.
82
Thi s has been parti cularly useful in otol aryngol ogi c surgery (see
Fi g. 22-12).
Contraindications to LMA Use. The pri mary contrai ndi cati on to el ecti ve use of the LMA i s a ri sk
of gastri c-contents aspi rati on (e.g., ful l stomach, hiatus herni a wi th signi fi cant gastroesophageal
refl ux, morbi d obesi ty, i ntesti nal obstructi on, del ayed gastri c emptyi ng, poor hi story). Other
contrai ndi cations i ncl ude poor l ung compli ance or high airway resi stance, glotti c or subgl otti c
ai rway obstructi on, and l i mi ted mouth openi ng (<1.5 mm).
67

LMA Use Complications. Apart from gastroesophageal refl ux and aspi rati on, reported
compl i cati ons have incl uded laryngospasm, coughing, gagging, retchi ng, bronchospasm, and other
events characteri sti c of airway mani pul ati on. The i nci dence of sore throat is approximatel y 10%,
as compared to 30% with tracheal i ntubati on, but has been reported as 0 to 70%.
67
Al so reported
are hoarseness (4 to 47%) and dysphagi a (4 to 24%). The LMA may cause transi ent changes in
vocal cord function.
80
Thi s i s possi bl y rel ated to cuff overi nfl ati on duri ng prol onged procedures.

FIGURE 22-12. Fol lowi ng endoscopi c si nus surgery, (A) the superi or, pharyngeal surface of
the LMA i s bl ood-stai ned, whereas (B) the l aryngeal surface remains clean.
P.605
There have been few reports of nerve injury associated wi th LMA use. As of March 2004, 14 cases
of nerve pal sy have been reported: recurrent (7), hypoglossal (5), and li ngual (2).
84, 85
Al l but one
of these resol ved spontaneousl y. In al l cases, size 3 and 4 LMAs were i n use and, i n al l but one
case, ni trous oxide was one of the i nhal ati on agents (whi ch can i ncrease cuff pressures by 9 to
38%).
86
Cuff pressures were not monitored i n any of the cases. It i s hypothesized that l i ngual
nerve injuri es occur as the nerve is trapped between the mandibl e and the LMA barrel l yi ng lateral
to the tongue. The hypogl ossal nerve runs rostral and lateral to the hyoi d bone and may be
trapped agai nst it. The recurrent nerve may be compressed between the LMA cuff and the cri coi d
or thyroi d cartil age. Unmoni tored increases i n pressure as a resul t of N
2
O di ffusion, li ght
anesthesia with constri cti on of pharyngeal muscul ature, ti ssue edema and venous engorgement
from a head-down posi tion, and li docai ne gel l ubri cant have been bl amed for nerve injury.
87
To
prevent such injury, the cuff of the LMA should be inflated to no more than 60 cm H
2
O and should
be moni tored if N
2
O i s i n use. The use of a l arger LMA, with less pressure, has al so been
recommended.
88
Li docai ne shoul d not be present i n cuff l ubri cants.

One death has been associ ated wi th an LMA devi ce. An el derl y woman suffered a tear of her
esophagus after use of the intubati ng LMA (LMA-Fastrach), dying 9 weeks later from septi c
shock after a series of related compl i cations.
89
Interesti ngl y, the actual compl i cation was most
li kel y a smal l esophageal tear from an i nadvertent esophageal i ntubation. Therefore, thi s
compl i cati on was more of a mi sadventure of bl i nd intubati on not i nherentl y attri butabl e to the
LMA-Fastrach itself. No other deaths because of compli cati on of LMA use have been reported in the
li terature. It has been estimated, though, that 600 deaths occur each year i n the devel oped worl d
because of compli cati ons of diffi cult tracheal intubati on.
90

The LMA-Proseal. Although the ori gi nal LMA and the LMA-fl exi bl e have been used successful l y
for posi tive-pressure venti lation, they are not i deall y suited to this task for two reasons: first, i f
poorl y seated i n the hypopharynx, gastric i nflation may occur; second, the seal pressure is l i mi ted
to approxi matel y 20 cm H
2
O. In 1994, an LMA prototype that incl uded a gastri c drain was
descri bed.
91
The LMA-Proseal was i ntroduced to cli ni cal practi ce in 2001 (Fi g. 22-13). It was
bel i eved that such a desi gn woul d reduce both the ri sk of gastric i nflation (by provi ding a low-
resistance pathway for pressure transmi tted to the esophagus) and the ri sk of aspi ration of
refl uxed gastri c contents. Subsequently, i t was found that the desi gn, whi ch al so i ncorporates a
second, posteri or cuff, coul d rel i abl y al l ow posi ti ve-pressure ventil ati on wi th 40 cm H
2
O pressure.
It i s inserted in an i denti cal manner as descri be previ ously for the LMA-cl assi c. A metal l ic
inserti on devi ce i s avai labl e from the manufacturer. Tabl e 22-8 lists the uni que features of the
LMA-Proseal and the resultant cl i ni cal advantage.
P.606
TABLE 22-8 Features of the LMA-Proseal
FEATURE CLINICAL IMPACT
Gastric drain Positi on confi rmati on
Acti ve gastri c emptyi ng
Passi ve gastri c emptyi ng
Protecti on from gastri c content aspi ration
92
Posterior cuff Increased seal pressure
Bi te bl ock Prevents pati ent bi ting obstructi on
Wi re-rei nforced ai rway barrel Reduced overal l si ze
Decreased abil i ty to tracheall y intubate
Large barrel /bite bl ock
confi gurati on
Fi rst attempt i nserti on l ess successful than LMA-
cl assi c
Confers rotati onal stabil i ty
Size choi cesi ze down from LMA-cl assi c
The LMA-Proseal has been shown to achi eve a hi gher effective seal than the LMA-cl assi c (40 to 45
cm H
2
O) and al low easier and quicker gastri c tube pl acement.
93, 94
A wi de variety of surgi cal cases
have been performed wi th the LMA-Proseal. Many of these have previ ously been considered
contrai ndi cated for supraglotti c ai rway use.
93
Mal tby et al have pi oneered the use of the LMA-
Proseal laparoscopic chol ecystectomy i n obsess pati ents.
93
Thi s surgi cal procedure has l ong been
consi dered the prototypi cal case for contrai ndicated LMA use because of hi gh intraperi toneal
pressures, as wel l as intraoperati ve stomach manipul ation. Laparoscopi c chol ecystectomy was
performed in 46 pati ents, 12 of whom had a body mass i ndex of greater than 30 kg/m
2
. The
median ai rway pressure at whi ch a gas leak occurred was 34 cm H
2
O (range 18 to 45). Four obese
patients crossed over to a control , tracheal tube group. Stomach si ze (e.g., di stensi on) was equal
between groups.
Apart from bei ng successful l y used as a posi ti ve pressure as wel l as spontaneous ventil ati on
ai rway, the LMA-Proseal has a distinct advantage over al l currentl y avai labl e supragl otti c airways.
The presence of the gastri c drain al l ows positi on di agnosi s.
95
Thi s faci l ity, ori ginal l y i ntended by
Dr. Brai n, has been extensively researched by Drs. M. Stix and C. O' Connor. These authors have
devel oped a protocol for

judgi ng LMA-Proseal posi ti on, a task typically difficult for the l ess experienced LMA user. The
protocol of Stix and O' Connor fol lows a simpl e logi c based on the observations of Dr. Brain and
FIGURE 22-13. The LMA-Proseal: A. Anterior view showi ng gastri c drai n passing through the
bowl . B. Lateral vi ew showi ng the ci rcumferenti al and posterior mask cuffs. (In the
photograph, the vi ew of the esophageal lumen is obscured by the airway l umen.) C. The
ai rway lumen and gastric drai n, separated by an i ntegral bi te bl ock, emerge from the patient.
D. A drop of water-sol ubl e l ubri cant has been pl aced i n the proxi mal aperture of the
esophageal l umen to moni tor for gas l eak, whi ch should not be present.
P.607
thei r own observati ons.
Bi te bl ock depth. Based on the successful use of the LMA-Proseal in 147 women and 127 men, a
first approximati on of insertion adequacy can be made from observation of the i ntegral bi te bl ock.
The mi dway poi nt of the bi te bl ock was found to be proximal to the i nci sors (e.g., wi thin the oral
cavi ty) in 78% of women and 92% of men.
96
Though mi d (or greater) bi te bl ock advancement i nto
the esophagus i ndi cated good pl acement, a normal di stri buti on of depths i ndi cate that the bi te
bl ock test affords a first approximati on of LMA-Proseal posi ti on adequacy.
Suprasternal notch test (SSN). When correctl y positi oned, the proximal ori fi ce of the gastri c drai n
tube shoul d be wi thi n the boundari es of the upper esophagus, making i t conti guous wi th the
esophageal l umen.
95
Gentle percussi on over the suprasternal notch resul ts in a bri ef pressure
increase i n the lumen of the gastri c drai n. Thi s can be demonstrated wi th the placement of a seal
of surgi cal jell y, or preferabl y, nontoxi c soap (e.g., chi l dren' s bubbl e-maki ng soap) over the di stal
end of gastri c drai n (Fi g. 22-13D).
97
Inadequate i nserti on depth and glotti c or fol ded posi ti ons wi l l
resul t in a negati ve SSN test.
98

Ai rway seal test. Once the i nserti on depth and esophageal posi ti on of the proxi mal gastri c drai n
orifice i s assured, posi ti ve-pressure breaths are given. If an adequate separati on of the al imentary
and ai rway tracks has been achieved, no insufflated gas should emerge from the distal gastric
drain.
95
The surgi cal jel ly-soap or bubble seal of the distal gastric drai n wi l l ai d i n detecti on of
escapi ng gas.
99

Gastric drain patency. Posteri or fol ding of the di stal aspect of the LMA-Proseal mask has been
descri bed.
100
Fol ding of the mask in the hypopharynx may not be detected duri ng routi ne
ventil ati on. Dr. Bri macombe and col l eagues have stated that one or more of the above-menti oned
tests may gi ve a false-positi ve resul ts.
101
These authors suggest supplementing the LMA-Proseal
positi on testing wi th the insertion of a gastri c tube, thereby assuring gastri c drai n patency.
The i mportance of posi ti on testi ng was hi ghl i ghted i n a report of pul monary aspi ration of gastri c
contents during a cholecystectomy wi th an LMA-Proseal.
102
No position testi ng had been
performed, and though adequate ventil ati on was achieved and wi th ai rway pressures of 27 cm
H
2
O, the LMA-Proseal had been unknowi ngl y pl aced in a fol ded posi ti on. This case i l lustrates the
importance of the LMA-Proseal in modern cli ni cal practice: as of this wri ti ng more than 10
supraglotti c ai rways are i n use in cli nical practi ce. Because many are recent arrival s to the cl i ni cal
arena, there is l i ttl e or no i nformati on avai labl e regardi ng gastri c i nsufflati on with posi ti ve-
pressure ventil ati on and protecti on from gastri c content aspirati on. The LMA-Proseal remai ns the
only devi ce where these questi ons have been repeatedl y investi gated, and posi ti on testi ng i s a
possi bi li ty.
Simil arl y, li ttl e i s known of the resusci tation util i ty of new SGAs. The LMA-Proseal woul d be
expected to functi on simil arl y to the LMA-Classi c in a cannot intubate/cannot venti l ate si tuati on,
and adds gastri c emptying as a resuscitati ve maneuver.
103, 104

Esophageal and gastri c i nsuffl ation have been noted with some proseal LMA pl acements.
105
The
inci dence and cl i ni cal si gnature of thi s air trappi ng are unknown.
The LMA and the Difficult Airway. Apart from its rol e as a routine anestheti c ai rway devi ce, the
LMA has a hi story of being a valuabl e tool i n the care of the pati ent wi th the anti cipated, or the
unanti ci pated, difficult airway. Thi s wil l be considered later i n thi s chapter.
The Laryngeal Tube. The l aryngeal tube (LT) (VBM Modi zi ntechni l e, GmbH, Sul z aN, Germany)
consi sts of a si ngle l umen tube wi th an approximately 130 degree midshaft angl e and two (di stal
and proxi mal ) l ow pressure cuffs (Fi g. 22-14A). An oval aperture between the cuffs serves as a
ventil ati on arti fi ce. The di stal end of the tube i s scaled around the distal cuff. When i nserted
correctl y, the distal cuff seal s the oral and nasal pharynx. Venti lation (spontaneous or posi ti ve
pressure) occurs vi a the mi dcuff ori fi ce. The cuffs are i nfl ated via a common pil ot val ve. The LT i s
reusable, requi res a mouth openi ng of at l east 2.3 cm and is i nserted ei ther bl i ndl y or wi th the ai d
of a l aryngoscope. Six sizes (0 through 5) are sui tabl e for neonates to l arge adul ts. Several
studi es have exami ned the use of the LT i n spontaneous and controll ed venti l ati on, and i n
compari son to the LMA classi c and the LMA-proseal. Gai tini et al used the LT in 175 pati ents
presenting for el ecti ve surgery.
106
Posi ti ve-pressure ventil ati on was successful i n 96.6% of cases.

Ocker et al compared the LT to the LMA cl assic i n 50 pati ents undergoing routi ne surgery. Ti me of
inserti on and adequacy of ventil ati on were si mil ar for both devi ces.
107
Peak ai rway pressure and
ai rway leak pressure were higher with the LT (l eak pressures LT 36 3 cm H
2
O, LMA 22 3 cm
H
2
O).
The Cobra Pharyngeal. Laryngeal Ai rway (Engi neered Medical Systems, Indianapol i s, IN, USA) i s
a di sposable supral aryngeal airway devi ce. It has a si ngl e l umen that termi nates i n a wi dened
di stal end (Fi g. 22-14B). A pharyngeal cuff serves to occl ude the upper ai rway from the oral
cavi ty. A seri es of

sl ots i n the wi dened end serve to hold the epigl ottis out of the barrel . A fi berscope and/or ETT
may be passed through the barrel and the sl ots. Reports have demonstrated the use of the cobra
in airway rescue, as wel l as routi ne anesthetic care with spontaneous as wel l as posi ti ve-pressure
ventil ati on.
108, 109

Tracheal Intubation
Routine Laryngoscopy
Prepari ng for laryngoscopy and the best attempt. Whether l aryngoscopy i s undertaken wi th
the pati ent in an awake or unconscious state, repeated attempts often resul t in edema and
bl eedi ng of the anterior upper ai rway structures (e.g., tongue, vall ecul a, epigl ottis, laryngeal
structures), hi ndering subsequent attempts at vi sual i zati on and causi ng i ncreased airway
obstruction. It i s therefore important to assure that the fi rst attempt at l aryngoscopy i s a best
attempt.
Fi rst, when faced wi th the criti cal ly i ll patient, the most ski l led laryngoscopist avail able shoul d be
positi oned to perform the l aryngoscopy. In less acute si tuati ons, i t i s not i nappropri ate for a
trai nee, cl i ni ci an extender, or other ski l led personnel to assume thi s rol e. Second, the avai l abi l ity
of al l the materi al s needed to perform l aryngoscopy and i ntubation shoul d be assured, as should
the avai l abi l ity of material s needed to manage a fail ed i ntubation. When devices are avail able i n a
vari ety of sizes (e.g., tracheal tubes, LMAs), the operator should have at hand the presumed
correct si ze, as wel l as one si ze smal l er and one si ze larger of each i tem (Tabl e 22-9).
FIGURE 22-14. A. The Laryngeal Tube. B. The Cobra Pharyngeal Laryngeal Ai rway.
P.608
Other devi ces that compl ete the equi pment li st, but may not be uniforml y avai labl e, include: end-
ti dal CO
2
moni toring (e.g., capnography or colorimetric devi ce [e.g., Easy Cap II, Mal l i nckrodt]),
pul se oximetry, transtracheal jet venti lati on catheter, and a high-pressure oxygen source.
The hei ght of the supine pati ent surface should be at the l evel of the l aryngoscopi st' s xyphoi d
carti lage, wi th the bed or operati ng room tabl e i n a non-movabl e mode (e.g., wheel s l ocked). The
cl i ni ci an performing the intubati on must have unobstructed access to the head.
Di rect laryngoscopy. Successful laryngoscopy i nvol ves the di storti on of the normal anatomi c
pl anes of the supral aryngeal airway to produce a l ine of di rect vi sual i zati on from the operator' s
eye to the l arynx: thi s requires the creati on of a new (noni ntrinsi c) vi sual axi s, through maximal
al ignment of the axes of the oral and pharyngeal cavi ties, and di spl acement of the tongue.
Unanti ci pated fai l ure of di rect l aryngoscopy i s pri maril y a problem of tongue di spl acement
(i nabi li ty to al i gn the axes can be anti ci pated by physi cal exam).
3
Some i nvesti gators have
focused the search for the cause of di ffi cul t direct laryngoscopy on the rel ati ve positi on of the
tongue. Chow et al have found that a hypopharyngeal tongue (e.g., the greater mass of the
tongue is withi n the hypopharynx) is accompani ed by a caudad l arynx, whi ch i s in turn determined
by measurement of the mandibular hyoi d di stance (a measure of the cephal ocaudad separati on of
the mandi bl e and hyoi d duri ng fetal devel opment).
110

Benumof el oquently expl ai ns thi s fi ndi ng i n terms of ontogeny and the descent of the larynx to
create the phonics of the human pharyngeal space (antagony recapi tulates phyl ongony). A l ong
descent of the l arynx resul ts i n a large part of the tongue to be i n the hypopharynx.
111
Poor
descent of the l arynx resul ts i n a smal l thyromental di stance (TMD) and can i ndi cate a difficult
intubati on. Chow et al al so noted that the l ong mandibularhyoid distance can be i n part because of
a shortened mandibular ranus. A short ranus results i n the fl oor of the mouth being more rostrad
and less compli ant, and therefore di splacement of the tongue i s more di ffi cul t.
112
If both a small
TMD as wel l as a l arge TMD can both predi ct diffi cult l aryngoscopy, then how can thi s measure be
useful to the ai rway eval uator? As poi nted out by the ASA Diffi cul t Ai rway Algori thm, no one
measure may be adequate to determi ne di ffi cul ty of DL, and mul ti pl e measures must be integrated
to make sensi ble ai rway management decisions.
113

Another mandibul ar di mensi on that has been exami ned is the mandi bul ar depth index (the
posteri or depth of the mandi bl e/mandi bul ar l ength).
114
Ki kkawa et al have noted that a deep or
TABLE 22-9 Equipment for Laryngoscopy
a

Oxygen source and sel f-infl ati ng venti l ati on bag (e.g., ambu bag)
Face mask
b

Oropharyngeal and nasopharyngeal ai rways
b

Tracheal tubes
b

Tracheal tube styl et
Syri nge for tracheal tube cuff i nflation
Sucti on apparatus
Laryngoscope handl e (2), tested for worki ng order and battery freshness
Laryngoscope bl ades: Common blades include the curved (Macintosh) and straight
(Mi ll er)
b

Pi l l ow, towel , bl anket, or foam for head posi ti oni ng
Stethoscope
a
Equi pment that shoul d be immedi atel y avail able in the i deal cl inical setti ng.
b
Presumed si ze as wel l as one l arger and one smal ler shoul d be i mmediatel y avai l abl e.
short mandi ble (higher i ndex) indicates a l arge hypopharyngeal tongue and di ffi cul ty wi th
di spl acement. Though

the mandi bul ar hyoid distance and the mandi bular depth i ndex are di sti nct measures, they
approach the probl em of diffi culty wi th DL si mi larly: anatomic rel ationships of the mandi ble may
predi ct a diffi cult to displ ace hypopharyngeal tongue. They al so hi ghli ght that a si ngle measure
(e.g., thyromental di stance) does not yi eld enough i nformati on to be predi cti ve.
Though congenital, anatomi c vari ati on may occur, pathol ogi c vari ati ons may mimi c the same
probl em of hypopharyngeal tongue mass: Ovassapian et al have identi fi ed hyperpl asi a of the
lymphoi d ti ssue at the base of the tongue as the pri nci pl e cause of unantici pated di ffi cul t
laryngoscopy.
3
Vi sual i zati on of thi s tissue i s currentl y the onl y method of di agnosi s. It i s therefore
typi cal l y di scovered duri ng a fai l ed DL.
Direct l aryngoscopy requires the creati on of a l i ne of sight from the operator' s eye to the
aperture of the larynx. Bannister and MacBeth proposed a three-axi s model to expl ai n the
anatomic rel ationships involved i n thi s operati on.
115
Recentl y, thi s expl anati on has been
chal l enged.
116
Work by Adnet et al noted that whereas extensi on at the atl anto-occi pi tal joint
maxi mall y faci li tated an oral cavity/pharyngeal al i gnment, no signi ficant improvement was
achi eved wi th flexion of the cervi cal spi ne on the thorax. Chow and Wu refi ned thi s approach by
noti ng that l aryngeal axi s al i gnment is unnecessary.
117
The end poi nt of the effort to create an i n-
li ne space for tracheal i ntubati on i s the glotti c aperture: al i gnment of the enti re l arynx is
therefore unnecessary. These authors propose a two-axes/tongue-di spl acement model . This model
does not depend on the al i gnment of al l axes to create an i n-li ne view of the l arynx, but rather
maxi mi zes the spaces between the alveol ar ridge and laryngeal aperture through oral -pharyngeal
al ignment and tongue di spl acement. Thi s concept can be used to understand not only the probl ems
that may hi nder di rect laryngoscopy, but al so why common indexes of airway assessment fai l in
thei r predi cti ve power. Thi s concept has been descri bed previ ousl y and can be vi ewed as
functi onal ai rway assessment (FAA).
118
FAA is a method of examining the functional nature of each
of the anatomi c correl ates of the commonl y used assessment indices. FAA pl aces an emphasi s on
the interdependence of these anatomi c characteri stics rather than on their individual size or
functional integrity. As explai ned by Chow and Wu, when the head and neck are in the neutral
positi on, the oral and pharyngeal axi s are perpendi cul ar to each other.
117
With maximal extension
of a normal atl anto-occi pi tal joint, 35 degree of moti on i s attai ned Fi g. 22-15. Thi s bri ngs the
angle between the oral and pharyngeal axi s to 125 degree. Though an i mprovement, certai nl y not
the 180 degree requi red for creati on of a l ine of sight to the gl otti s. A di fferent space must be
created. Thi s space i s created by di spl acement of the tongue wi th the l aryngoscope. Though
atlanto-occi pi tal extension cannot by i tself all ow di rect laryngeal vi si on, i t does provide anterior
di spl acement of the mass of the tongue and bri ngs upper the al veol ar ri dge i nto i mproved posi ti on
rel ati ve to the tongue and l arynx. The extension of the atl anto-occi pi tal point al so provides an
advantage in mouth openi ng.
26
Calder et al has shown that the maximal mouth openi ng i s 50%
greater i n ful l atlanto-occi pi tal extension as compared to the neutral head positi on. Temporal -
mandi bul ar jaw (TMJ) functi on al so contri butes to the di splacement of the tongue away from the
requi red vi sual axi s. Rotati on and transl ati on of the TMJ resul t in a rel axati on of the tongue
inserti on, as wel l as creation of the aperture wi dth needed for instrumentation.
P.609
Usi ng the FAA approach to ai rway eval uation al so hel ps to expl ai n the val ue of the popul ar yet
hi ghl y criti ci zed Mal lampati and Thyromental distance indices. These two measures have
hi stori cal ly been considered i mportant because they approximate the relative mass of the tongue
(Mall ampati ) and the anteri or-posterior borders of space i n which it wi l l be di spl aced (TMD) by the
laryngoscope. As noted el sewhere, these indi ces have shown to have poor and/or vari abl e
predi cti ve power. Two groups have consi dered the i nterrel ated nature of these measures i n a way
whi ch reveal s why they perform poorl y when consi dered indi vi duall y: Ayoub et al found a hi gh
Mal lampati score to be predi cti ve of a diffi cult DL when the TMD was l ess than 4 cm.
119
When the
TMD was greater than 4 cm, rel ati ve tongue size (as determi ned by the Mal lampati) was not
predi cti ve: Iohon et al found si mi l ar resul ts usi ng a TMD cutoff of 6 cm.
120
The finding that the
predi cti ve power of the Mal l ampati i mproves when the mandi bl e is short i s consi stent wi th the
concept of FAA: When the mandi bul ar space i s restri cted, tongue si ze i s i mportant. When the
space is l arge, a tongue of any nonpathologi c si ze should be accommodated. An excepti on to this
may be hypopharyngeal tongue as descri bed by Chow and Wu, though accordi ng to those authors,
measurement of the mandi bul ar hyoi d distance shoul d hel p i n di agnosi ng thi s.
110

An unforeseen cause of di ffi cul ty i n di rect l aryngoscopy is a pathol ogi c i ncrease i n tongue size.
Ovassapi an et al have identi fi ed l i ngual tonsi l hyperpl asia (LTH) as the most commonly
undi agnosed cause of unantici pated di ffi cul t di rect l aryngoscopy.
3, 121
Ovassapi an et al revi ewed
the cases of unanti cipated difficult di rect laryngoscopy i n their i nstituti on from 1989 to 2000.
Thi rty-three pati ents were identi fi ed. Al l pati ents were found to have LTH on fi beropti c exam.
Devices that ai d i n positi oning the patient i n a sniff posi ti on pi l l ow have become avail able. These
incl ude the Sni ff posi ti on pi l low (Al iMed, Inc. of Dedham, MA) devel oped by Mi chael

Popi tz, and Pi ' s pi l l ow (Dupaco, Oceansi de, CA), whi ch i s comfortable for the awake patient but
easil y reconfi gured after anestheti c inducti on to provi de an i deal posi ti on, has been devel oped by
Dr. Kai duan Pi (Fi g. 22-16).
FIGURE 22-15. A. With the pati ent supi ne, the oral and pharyngeal axes do not overlap. B.
Extensti on at the atl anto-occi pi tal joint maximally overlaps the oral and pharyngeal axes.
P.610
The obese patient may need further positi oning to move the mass of the chest away from the
pl ane across whi ch the l aryngoscope handl e wi ll sweep as it i s mani pulated into the mouth. This
may requi re pl aci ng a wedge-shaped l i ft (e.g., bl ankets, pi l l ows) under the scapul a, shoulders,
and nape of neck, rai si ng the head and neck above the thorax and providi ng a grade to al low
gravity to take the mass away from the airway (Fig. 22-17).
If, during the l aryngoscopy, a satisfactory laryngeal vi ew i s not achi eved, the backward-
upward-ri ghtward pressure (BURP) maneuver may ai d i n i mprovi ng the vi ew. In thi s
maneuver, a second operator displ aces the l arynx (B) backward agai nst the cervi cal vertebrae, (U)
superi orl y as possi bl e, and (R) sl ightly laterall y to the ri ght, usi ng external pressure over the
cricoid carti lage. The BURP maneuver has been shown to i mprove the laryngeal vi ew, decreasi ng
the rate of diffi cult i ntubation in 1,993 pati ents from 4.7 to 1.8%.
122, 123
When a left-handed
operator i s using a left-handed l aryngoscope bl ade, the l ateral external pressure shoul d di spl ace
the larynx to the left. Si mi l arl y, Benumof describes optimal external laryngeal mani pul ati on,
whi ch consists of pressi ng posteri orl y and cephal ad over the thyroi d, hyoi d, and cri coi d, as
improvi ng l aryngeal view by at least one Cormack and Lehane grade.
124, 125

Once al ignment has been achieved, the mouth is opened by one of two techni ques (Fi g. 22-18).
The fi rst accompl ishes hyperextension of the atl anto-occi pi tal joint by the use of the domi nant
hand under the occi put. Thi s maneuver tends to open the mouth, and can be accentuated by usi ng
the fi fth finger of the nondomi nant hand (holdi ng the laryngoscope) to appl y pressure over the
chin i n a caudad di recti on (Fi g. 22-18A). In the second technique, which tends to be more
effecti ve but requires contact of the (gl oved) hand wi th the teeth and/or gum, caudad pressure is
appl i ed wi th the thumb of the dominant hand on the mandi bul ar molars on the pati ent's same si de
whi l e the fi rst fi nger, crossed above or bel ow the thumb, appl i es cephal ad pressure to the
ipsi lateral maxil l ary molars (Fi g. 22-18B). The ul timate goal of both techni ques i s rotati on and
transl ati on of the temporomandibular joint to achieve the wi dest interi ncisor gap. The pati ent,
FIGURE 22-16. A Pi ' s pi l l ow (Dupaco, Oceansi de, CA) pl aces the pati ent i n a comfortable
positi on prior to the i nducti on of anesthesia and (B) in an ideal sniff positi on duri ng ai rway
management. C The Popi tz sni ff posi ti on pi l l ow.
FIGURE 22-17. A. With the morbi dl y obese pati ent, a 10-cm pi ll ow may not provide a
positi on adequate for laryngoscopy. B. A wedge-shaped l i ft i s used to move the mass of the
morbi dly obese pati ent' s chest away from the area of laryngoscopy and to i mprove the
compl i ance of the thoraci c cavi ty.
whether consci ous or not, i s now ready for laryngoscopy.
Though di rect l aryngoscopy remai ns the most uti l ized method for tracheal i ntubation,
126
it is far
from successful i n al l cases nor al ways beni gn when successful . DL may be di ffi cul t or i mpossi ble
8.5% and 1.8%, respecti vel y, of the ti me.
126
Domi no et al ' s anal ysi s of the ASA cl osed cl ai ms
database reveal s that l aryngeal i njury duri ng DL occurs more often i n easy as opposed to
di fficul t l aryngoscopi es.
24
Among the 4,460 cases i n the ASA closed cl ai m database, 87 i nstances
of laryngeal trauma were recorded. Of these, 80% occurred duri ng routine (non-di fficul t) tracheal
intubati on, where no injury was suspected. This has l ed some to questi on whether routi ne tracheal
intubati on i s as safe as assumed.
22

Use of the l aryngoscope blade. Proper use of the l aryngoscope bl ade is vital to the success of thi s
basic ai rway management techni que. Two blade types are commonl y avai lable and each i s appl i ed
in a unique manner (Fi g. 22-19). The curved (Maci ntosh) blade i s used to pul l the epigl ottis out of
the li ne of si ght by tensing the glossoepigl otti c li gament, whereas the strai ght bl ade (Mi l l er)
compresses the epigl ottis against the base of the tongue. Both blades i nclude a fl ange along the
left

si de of thei r length, which is used to sweep the tongue to the l eft si de of the mouth. Blades wi th a
ri ght-si de fl ange are avai l abl e for the l eft-handed practi ti oner, but they are not commonl y found
in practi ce.
FIGURE 22-18. Techni ques of openi ng the mouth in preparati on for l aryngoscopy. A.
Hyperextensi on of the atlanto-occi pi tal joi nt and use of the fi fth fi nger of the domi nant hand.
B. The thumbfi rst fi nger sci ssors technique.
P.611
Histori call y, choice of l aryngoscopi c blade had a theoreti cal bases in airway i nnervati on. The
internal branch of the superi or laryngeal nerve (a branch of the vagus) provi des sensory
innervati on from the l evel of the vocal cords to the undersi de of the epi glotti s. Stimul ati on of
these structures (with the Mi ll er blade) was bel i eved to cause more vagal l y related reacti ons
(l aryngospasm, bradycardi a, hypertension.) The vall ecul a, sti mulated by the curved, Maci ntosh
bl ade, i s innervated by the gl ossopharyngeal nerve.
In most avai labl e systems the flange incorporates the l ight source, either a bul b pl aced near the
di stal bl ade aspect or a ri gi d fiberopti c cabl e that transmits l ight produced wi thi n the handl e. In
ei ther case, these blades must be l ong enough to achi eve thei r respecti ve appl icati ons. Therefore,
bl ade si ze needs to be chosen appropri atel y and, on occasi on, exchanged after a fai l ed attempt.
As a general i zati on, the Maci ntosh bl ade i s regarded as advantageous whenever there i s l ittle
room to pass an endotracheal tube (e.g., smal l mouth), whereas the Mi l l er bl ade is considered
better i n the pati ent who has a smal l mandi bul ar space, large inci sor teeth or a l arge epi glotti s.
127

The strai ght-against-the tongue nature of the Mil l er bl ade affords maxi mal transfer of effort from
the operator' s elbow and shoul der to the di spl acement of the tongue i nto a smal l mandi bular
space.
Wi th the left hand hol ding the l aryngoscope handl e, the bl ade i s inserted into the ri ght side of the
mouth, with care taken not to compress the upper l ip against the teeth. As the blade i s advanced
toward the epi gl ottis, i t is swept l eftward, usi ng the fl ange to displ ace the tongue to the l eft as
the blade compresses i t i nto the mandi bul ar space. Once reaching the base of the tongue (the
Macintosh bl ade ti p i n the val lecul a, or the Mi l l er bl ade compressi ng the epigl ottis against the
base of

the tongue), the operator' s arm and shoul der li ft i n an anteri or and caudad di recti on (Fi g. 22-20).
FIGURE 22-19. Maci ntosh, Mil l er, and Henderson l aryngoscope bl ades wi th smal l and
regul ar-si zed handl es.
P.612
Importantl y, the laryngoscopist must stri ve to avoi d rotati ng the wrist and l aryngoscope handle in
a cephal ad di recti on, bri ngi ng the bl ade agai nst the upper i ncisor teeth. Extendi ng ei ther blade
styl e too deeply can bri ng the ti p of the blade to rest under the l arynx i tsel f, so that forward
pressure l i fts the entire airway from view (Fi g. 22-21).
FIGURE 22-20. A. When a curved laryngoscope bl ade i s used, the ti p of the bl ade is pl aced
in the vall ecul a, the space between the base of the tongue and the pharyngeal surface of the
epi gl ottis. B. The ti p of a strai ght bl ade i s advanced beneath the epigl ottis.
Speci al considerati ons appl y to the techni que of laryngoscopy and intubati on i n the infant and
chil d. Because of the rel atively l arger si ze of the occiput in chi l dren, produci ng an anatomi c
sniffi ng posi tion, elevation of the head (as done i n the adul t) i s not needed.
128
On occasi on, one
may need to el evate the thorax instead. The rel ati vely short neck gi ves the i mpressi on of an
anterior posi ti on of the l arynx. Posteri or cri coi d pressure is often requi red to pl ace the l aryngeal
inlet i nto vi ew. A strai ght bl ade is more hel pful in di spl aci ng the sti ff, omega-shaped, and hi gh
epi gl ottis. Si nce the cricoid carti lage i s the narrowest aspect of the ai rway unti l 6 to 8 years of
age, the intubator must be sensiti ve to resistance to advancement of the ETT that has easi l y
passed the vocal folds. Hyperextensi on at the atl anto-occi pi tal joint, as done i n adul t, may cause
ai rway obstructi on because of the rel ative pl iabi li ty of the trachea. In the chi ld, there i s a hi gher
ri sk of endobronchial intubati on or extubati on wi th head movement owi ng to the short length of
the trachea.
Wi th l aryngoscopy, the view of the l arynx may be compl ete, partial , or i mpossi ble. A l aryngeal
view scori ng system that has won general acceptance was devel oped by Cormack and Lehane, who
descri bed four grades of l aryngeal vi ew.
125
Grade 1 i ncl udes vi sual i zati on of the entire gl ottic
aperture; Grade 2 i ncl udes vi suali zation of only the posteri or aspects of the gl otti c aperture;
Grade 3 is visual izati on of the ti p of the epigl ottis; Grade 4 i s vi suali zation of no more than the
soft pal ate (Fi g. 22-22). A CormachLehane Grade 3 or 4 is expected i n 1.5 to 8.5% of adul t
laryngoscopies.
129

FIGURE 22-21. The sequence of routi ne l aryngoscopy. A. With the mouth maximally opened,
the laryngoscope i s hel d in the l eft hand and the bl ade inserted on the right si de of the
mouth. Usi ng the bl ade flange, the tongue i s swept to the l eft as the wri st pul ls i n a caudad
di recti on. B. Whi le vi sual i zi ng the laryngeal inlet, the tracheal tube i s i nserted.
Thi s system has proved useful not onl y as a means of recording the laryngeal vi ew on i ndividual
patients, but al so as a cli ni cal end poi nt i n the evaluati on of preoperative ai rway assessment
tool s. A modi fi cati on of the Cormack and Lehane score (MCLS) has been proposed by Koh et al ,
who noted that partial vocal cord vi ew (MCLS 2A) was signi fi cantl y easi er to i ntubate than when
only the artynoi ds and epigl otti s were seen (MCLS 2B).
130

Once the larynx is visual ized wi th a l eft si deflanged bl ade, the tracheal tube i s i nserted from the
ri ght-hand si de, care bei ng taken not to obstruct the view of the vocal fol ds. Whenever possi ble,
the action of the endotracheal tube passi ng through the vocal fol ds shoul d be wi tnessed by the
laryngoscopist. The tracheal tube shoul d be i nserted to a depth of at l east 2 cm after the
di sappearance of the tracheal tube cuff past the vocal fol ds to approximate pl acement in the
mi dtrachea. This shoul d present the 21-cm and 23-cm external markings at the teeth for the
typi cal adul t femal e and mal e, respecti vel y.
131
Choi ce of adult tracheal tube si ze may be made by
the general izati on that for women, size 7 to 8 id (i nternal diameter) may be used, and for a man,
si ze 8 to 9 i d. The larger tracheal tubes may be desi rabl e i f pul monary toi l et or diagnosti c or
therapeutic bronchoscopy is to be part of the cl i ni cal course. Pedi atri c l aryngoscope bl ades and
tracheal tube sizes are discussed in detai l elsewhere i n this chapter (Tabl e 22-10).
FIGURE 22-22. The CormackLehane laryngeal vi ew scoring system: (A) Grade 1, (B)
Grade 2, (C) Grade 3, (D) Grade 4.
FIGURE 22-23. Cri coi d pressure (Sel l i ck' s maneuver) i s appl i ed to occl ude the esophagus
and prevent aspi rati on of gastri c contents.
TABLE 22-10 Size and Length of Tracheal Tubes Relative To Airway Anatomy
AGE INTERNAL
DIAMETER
(mm)
DISTANCE
FROM LIPS TO
MIDTRACHEA
a
(cm)
DIAMETER
OF
TRACHEA
(mm)
LENGTH
OF
TRACHEA
(cm)
DISTANCE
FROM LIPS
TO CARINA
(cm)
Premature 2.5 8
An al ternati ve approach to direct l aryngoscopy has been descri bed by Henderson.
132
In thi s
approach to tongue di spl acement, a strai ght-bl aded l aryngoscope i s introduced into the ri ght side
of the mouth. The bl ade is advanced between the tongue and palasti ne tonsil . The blade passes
bel ow the epi gl otti s, whi ch i s then el evated. This approach subjects the tongue to l ess
compressi ve forces. It has been suggested that thi s techni que may i mprove the view of the l arynx
in the presence of l i nguar tonsi l hyperpl asi a (see Fi g. 22-19).
Veri fi cation of successful tracheal tube pl acement i s made by a vari ety of methods. The gol d
standard for confirmation

uof pl acement incl udes visual izati on of placement through the vocal fol ds and sustai ned detecti on
of exhal ed carbon di oxi de as measured wi th capnography or a di sposabl e chemical col orimetric
device such as the Easy Cap II (Mall i nckrodt). Other portabl e techni ques i ncl ude auscultati on over
the chest and abdomen, vi suali zati on of the chest excursion, observati on of condensati on i n the
ETT, use of a sel f-infl ati ng bulb (Tubechek-B, Ambu, Li nthicum, MD), l i ghted styl ets (Trachl i ght,
Laerdal Medi cal , Armonk, NY; SURCH-LITE, Aaron Medi cal Industri es, St. Petersburg, FL),
fi beropti c bronchoscope (FOB) i dentificati on of the tracheal ri ngs, or chest x-ray.
132, 133

NPO Status and the Rapid-Sequence Induction. Induction of anesthesi a i n pati ents who have
Full term 3.0 10
16 mo 3.5 11 5 6 13
612 mo 4.0 12
2 yr 4.5 13
4 yr 5.0 14
6 yr 5.5 15
8 yr 6.5 16 8 8 18
10 yr 7.0 1718
12 yr 7.5 1820
14 yr 8.09.0 2022 20
b
15
c
14
b
12
c
28
b
24
c
a
Add 23 cm for nasal tubes.
b
Mal es.
c
Femal es.
P.613
ful l stomachs or i ncompetent gastroesophageal sphi ncters can resul t i n regurgitati on and
pul monary aspi rati on. Individual s at ri sk i nclude the morbidl y obese, pregnant women, diabeti cs
wi th gastroparesi s, those who requi re emergency operati ons, pati ents wi th gastroesophageal
refl ux di sease, and pati ents who have recently eaten. Individual s experienci ng emoti onal stress
have i ncreased gastri c aci d secreti ons and are al so at an i ncreased ri sk for aspi rati on.
134
A
compl ete di scussi on of the pharmacol ogic therapy for aspi ration prophylaxi s is avai labl e elsewhere
in thi s text.
The techni que of rapi d-sequence i nducti on i s performed to gai n control of the ai rway in the l east
amount of time after the abl ation of protective ai rway reflexes with the i nduction of anesthesi a. In
the rapi d-sequence techni que, the admi ni strati on of an intravenous anestheti c induction agent i s
i mmedi atel y fol l owed by a rapi dly acti ng neuromuscul ar blocki ng drug. Direct l aryngoscopy and
i ntubati on are performed as soon as muscl e rel axati on i s confirmed. Cri coi d pressure (Sell i ck's
maneuver) i s appl i ed by an assistant from the begi nni ng of i nduction unti l confirmati on of
endotracheal tube pl acement. Cri coi d pressure entail s the downward di spl acement of the cri coi d
carti lage agai nst the vertebral bodi es (Fi g. 22-22). In thi s manner, the l umen of the esophagus i s
abl ated, whi le the compl etel y ci rcular nature of the cri coi d carti l age maintai ns the tracheal lumen.
Earl y cadaveri c studi es showed that correctl y appli ed cri coi d pressure was effecti ve i n preventi ng
gastri c fl ui ds, under 100 cm H
2
O pressure, from l eaki ng i nto the pharynx. Unfortunately, the
esophagus i s laterall y displ aced i n a majority of normal pati ents.
135
Because cri coi d pressure
further l ateral i zes the esophagus, the adequacy of esophageal abal ati on has been questi oned.
Cri coi d pressure is contraindi cated wi th active vomi ti ng (ri sk of esophageal rupture), cervi cal
spi ne fracture, and laryngeal fracture. Hi stori cal ly, facemask venti lation is not undertaken for the
40 to 90 seconds of ti me requi red to achi eve adequate neuromuscul ar rel axation. Thi s practi ce is
based on mi ni mal data and has recentl y been questi oned.
If duri ng rapi d-sequence inducti on there are di fficul ties i n securi ng the ai rway and oxyhemoglobi n
desaturation occurs, gentl e posi ti ve-pressure ventil ati on may be used whi le mai ntaini ng cricoi d
pressure. Thi s posi ti ve pressure shoul d requi re <25 cm H
2
O pressure. If more posi ti ve pressure i s
used, there i s a ri sk of gastric distenti on and regurgi tation.
The Intubating Laryngeal Mask Airway (LMA-Fastrach). Bl i nd, fi beropti c ai ded, styl et-gui ded,
and l aryngoscopy-di rected i ntubati on vi a the LMA has been wi del y reported i n adul ts and
chil dren.
79, 136, 137, 138, 139, 140, 141, 142
There are several l imitati ons to thi s procedure including the
maxi mal si ze ETT that can be used, the mi nimal l ength of the ETT requi red to ensure that its cuff
is wi thi n the larynx and not wedged between or above the vocal fol ds, and the diffi culty in
removi ng the LMA after i ntubation.
79, 143
In an effort to overcome these li mitati ons, Brai n
introduced a versi on of the LMA wi th a l arge-diameter (13 mm i d), short-length (14 cm) ri gid
stai nless steel barrel curved to al i gn the mask aperture to the gl otti c vesti bul e (Fi g. 22-
24).
144, 145, 146

The mask i ncorporates a verticall y oriented semi rigi d bar, fi xed at the proxi mal end of the bowl
aperture and posi ti oned to si t beneath the epigl ottis i n the average adul t. A handle at the
proxi mal end of the barrel i s used for inserti on, reposi ti oni ng, and removal . A secondary
advantage of the handl e i s that the operator need never place fi ngers into the patient' s mouth.
Thi s device, the LMA-Fastrach, can accommodate up to an 8.0-mm id cuffed ETT, whi ch can be
i nserted bl i ndl y or over a fi berscope or other styl et device. The LMA-Fastrach is desi gned to be
used wi th a strai ght, armored, si li cone tracheal tube (Euromedics, Malaysi a), al though standard or
Parker Fl ex-ti p (Parker Medical, Engl ewood, Col orado) pol yvi nyl chlori de tracheal tubes have been
used.
147
To date, the LMA-Fastrach has been di stri buted i n adul t si zes with cuffs equi valent to the
si ze 3, 4, and 5 LMAs. Experi ence has suggested that most adul ts between 40 and 70 kg are best
managed wi th a size 4 LMA-Fastrach, larger persons requi ri ng the size 5. Pedi atri c sizes are not
yet available.
The LMA-Fastrach is i ndi cated for routi ne, el ecti ve i ntubation and for anti ci pated and
unanti ci pated di fficul t i ntubati on.

Si nce i t was desi gned to faci l i tate bl i nd tracheal i ntubation, the presence of airway secretions,
bl ood, or edema (e.g., from previ ous i ntubation attempts or trauma) does not i nterfere wi th i ts
use. Because the desi gn of the barrel i s based on the normal adult palate-to-gl otti s rel ati onshi p,
patients who are eval uated as bei ng manageabl e wi th tracheal i ntubati on based on external exam,
but subsequentl y are found to have a high CormackLehane score (because of li ngual tonsi l
hyperplasia or cervi cal spi ne immobi li ty, for exampl e) should be successful ly managed wi th the
LMA-Fastrach.
125
In the l argest trial of the LMA-Fastrach to date, venti lati on was sati sfactory i n
95% and unsatisfactory in 1% of 500 uses, and 96% were i ntubated wi thin three attempts (79.8%
on fi rst, 12.4% on second, 4% on thi rd).
148
Pati ents who are assessed as grossl y abnormal on
preoperati ve ai rway exam may often sti l l be managed wi th the LMA-Fastrach.
149
The LMA-Fastrach
has been demonstrated to be useful as a venti l atory and i ntubati ng devi ce after fai l ed rapi d
FIGURE 22-24. A. The LMA-Fastrach. B. The LMA-Fastrach used for intubati on i n a pati ent
outsi de the operati ng room. C. The LMA C-Trach.
P.614
sequence intubati on.
147

A l arge study has shown the uti li ty of the LMA-Fastrach in anti cipated as well as unanti cipated
di fficul t to intubate pati ents. Ferson et al successfull y intubated 234 pati ents over a 3-year peri od
using the LMA-Fastrach.
150
Studi ed pati ents i ncl uded those wi th normal -appeari ng ai rways on
routine exam who were unexpectedl y diffi cult to manage, pati ents wi th a Cormack and Lehane
laryngeal view grade 4 on l aryngoscopy, pati ents with immobi li zed or traumatized cervical spines
and pati ents wi th ai rway tumors, pri or ai rway surgery, or radiation. Successful bl i nd i ntubati on vi a
the LMA-Fastrach occurred i n 96.99%, the remai ni ng ones faci l itated with supplemental use of a
fiberopti c intubati on scope. [A new desi gn of the LMA-Fastrach, the C-Trach, i ntroduced i n 2004
i ncorporates a fi beropti c cabl e and mini aturized moni tor i nto the LMA-Fastrach desi gn (Fi g 22-
24C)].
Notabl y i n this seri es all pati ents who presented wi th a cannot intubate/cannot ventil ate si tuati on
were successfull y venti lated and i ntubated wi th the LMA-Fastrach, emphasizing i ts

i mportance i n the cannot i ntubate/cannot mask venti l ate and emergency pathways of the ASA
Di ffi cul t Ai rway Al gori thm.
113

Contraindicati ons to the LMA-Fastrach are simil ar to those of the LMA. Si nce the end poi nt of LMA-
Fastrach procedure i s tracheal i ntubation, i t may prove useful for the management of pati ents at
moderate risk for gastroesophageal regurgitati on and aspi rati on, or for hi gh-ri sk pati ents on whom
other techni ques have fai l ed.
The LMA-Fastrach is i nserted with the head i n a neutral posi ti on. It can be used in the unconsci ous
or awake pati ent (wi th the use of topical anestheti cs). The mask of the LMA-Fastrach is tested,
defl ated, and l ubri cated as descri bed for the LMA. It i s i nserted i nto the mouth, wi th the handl e
hel d parall el to the chest, so the mask l ies fl at agai nst the pal ate. Gentl e pressure on the handle
and barrel , toward the chin, reproduces the pal atal pressure described for i nserti on of the LMA. A
smooth backward rotati on of the handl e toward the top of the head seats the ti p of the mask i n
the hypopharynx, posteri or to the cri coi d carti l age. Once seated, the LMA-Fastrach' s mask i s
inflated via the pilot cuff. An ambu bag or anesthesi a ci rcui t i s attached to the proxi mal end of the
LMA-Fastrach barrel and ventil ati on i s attempted. By usi ng the LMA-Fastrach handl e, the positi on
of the devi ce can be opti mi zed by lateral and anteri orposterior mani pul ati on. This i s termed the
Chandy Maneuver (after Dr. Chandy Verghese, Uni ted Ki ngdom). A seemi ngly common cause of
ai rway obstructi on i s the down-fol di ng of the epigl ottis. Thi s can be rel ieved wi th a smooth
rotati onal movement of the i nfl ated LMA-Fastrach out of the ai rway (6 cm al ong the axi s of the
inserti on) whil e the cuff remains i nfl ated, and immedi ate re-pl acement (the up-down maneuver).
After adequate ventil ati on i s achieved, the ETT i s advanced through the barrel. As the ETT exi ts
the bowl aperture of the LMA-Fastrach, the semi ri gi d el evati ng bar i s pushed anteriorl y, carryi ng
the epigl ottis out of the way of the ai rway. If posi tioned correctl y, the ETT can freely enter the
gl otti s.
The second part of the Chandy Maneuver may facil i tate bli nd tracheal i ntubation. In thi s maneuver
the handl e i s used to gentl y li ft (wi thout rotation) the LMA-Fastrach anteriorly, seal ing the bowl
against the larynx.
When bl i nd i ntubati on fail s (esophageal i nserti on or obstruction) several maneuvers are
undertaken.
150
Earl y obstructi on i s typi cal l y a result of a down-fol ded epi glotti s. An up-down
maneuver, as descri bed earl i er, can be empl oyed and tracheal i ntubation attempts repeated. Earl y
resistance (wi thi n 1 cm of the Euromedics ETT exit mark) may al so si gni fy vall ecul ar entrapment
secondary to too l arge an LMA-Fastrach. The operator may remove the LMA-Fastrach and pl ace a
smal l er si ze. Obstructi on at 3 cm past the exit mark may signify entrapment or too smal l a device,
and agai n, a change i s i ndi cated.
When intubation fails despite the Chandy or up-down maneuvers, or a change i n the ILM si ze, the
cl i ni ci an shoul d recal l that the LMA-Fastrach is a venti lation device fi rst! Typi cal ly venti l ati on wi ll
be adequate despi te fail ure to i ntubate. At thi s juncture the cl inici an can (1) continue with short
surgi cal procedures usi ng the LMA-Fastrach as a simpl e SGA (procedures l onger than 15 mi nutes
P.615
may be i l l advi sed because of the pressure exci ted by the LMA-Fastrach on tissues), (2) change to
another LMA devi ce, (3) di agnose the i ntubati on i mpedi ment wi th the ai d of another device (e.g.,
fi beropti c bronchoscope or FAST (Clarus Medical), (4) remove the LMA-Fastrach and conti nue wi th
DL, or an another techni que of tracheal i ntubati on, or (5) i n the resuscitati ve si tuati on, perform a
surgi cal airway whi le conti nui ng venti lation wi th the LMA-Fastrach.

Thi s last procedure may be an underappreci ated faci l i ty of al l LMAs and the SGAs. These devices
may serve as a bri dge whi l e i nvasi ve airway procedures are performed.
Once i ntubation is achi eved and confi rmed (e.g., by auscul tati on or capnography), the ETT ci rcuit
adapter i s removed and the LMA-Fastrach is wi thdrawn over the ETT. Duri ng thi s removal
procedure, the ETT i s stabil i zed by one of two methods. A sil i cone stabi l i zi ng rod (suppl i ed by the
manufacturer) can be hel d agai nst the ETT as the LMA-Fastrach is retreated out of the mouth. The
advantage of thi s technique i s that the operator's hands do not have to enter the oral cavi ty. The
di sadvantage i s that i n the mi dremoval positi on, the operator l oses di rect contact wi th the ETT. In
the second techni que, descri bed by Rosenblatt and Murphy, a Magi l l forceps i s used to hold the
proxi mal ti p of the ETT whi l e the LMA-Fastrach is removed.
147
In the midremoval posi ti on, a fi nger
is pl aced i n the mouth to i dentify and stabil i ze the ETT, whil e the Magi ll forceps i s removed and
the LMA-Fastrach is ful l y retreated. This techni que requires the hand to be pl aced i n the mouth,
but al l ows improved control of the ETT.
Extubation of the Trachea
Though a weal th of l i terature i s focused on the field of tracheal intubati on, few reviews have wel l
contempl ated the area of extubati on after compl etion of surgery, or prolonged venti latory
support.
151
Indeed, the period of extubation may be far more treacherous than that of i ntubati on
(Tabl e 22-11 [see section A]).
P.616
TABLE 22-11 Tracheal Extubation
A. Causes of Ventilatory Compromise during Tracheal Extubation
Resi dual anestheti c
Poor central respi ratory effort
Decreased respi ratory rate
Decreased respi ratory dri ve i n response to CO
2

Decreased respi ratory drive in response to O
2

Reduced tone of upper ai rway musculature
Reduced gag and swal l ow refl ex
Decreased threshol d to l aryngospasm
Surgi cal ai rway compromise
Surgical ai rway edema
Vocal cord paralysi s
Arytenoi d carti l age disl ocati on
Supragl ottic edema with ai rway obstructi on by the epi gl ottis
Retroarytenoi d edema wi th l imi ted vocal fol d abducti on
Subgl ottic edema
Tracheomal aci a (from long-standi ng tracheal intubati on)
Bronchospasm
B. Complications of Tracheal Extubation
Respi ratory dri ve fai l ure
Hypoxi a (e.g., atel ectasi s)
Upper ai rway obstructi on (e.g., edema, resi dual anestheti c)
Vocal fol drel ated obstructi on (e.g., vocal cord paralysi s)
Tracheal obstruction (e.g., subglotti c edema)
Routine Extubation. Extubation of the trachea must not be consi dered a beni gn procedure.
It i s not si mply the el iminati on or reversal of tracheal i ntubation. Extubation is fraught wi th
its own set of potenti al compl icati ons (Tabl e 22-11 [see secti on B]). Appropriatel y trai ned
personnel and equi pment shoul d be immedi atel y avail able at the ti me of extubation. Thi s may
range from a postanesthetic care uni t nurse or respiratory therapist wi th a set of laryngoscopes to
a surgeon prepared to perform an emergency tracheostomy.
Most adult pati ents are extubated after the return of consci ousness and spontaneous respi ration,
the resol uti on of neuromuscular block, and the abi l ity to fol low si mpl e commands (Tabl e 22-12).
The pati ent i s asked to open the mouth and a sucti on catheter i s used to remove excessi ve
secreti ons and/or bl ood. The airway pressure i s al l owed to ri se to 5 to 15 cm of H
2
O to al l ow for a
passi ve cough, and the endotracheal tube i s removed after the cuff (if present) is deflated.
151
If
coughing or straini ng i s contrai ndicated or hazardous (e.g., i ncreased i ntracrani al pressure),
extubati on may be performed whi l e the pati ent i s i n a surgi cal plane of anesthesi a. In pati ents at
ri sk for gastri c contents aspi ration (e.g., ful l stomach) or upper

ai rway obstructi on, the cl inici an needs to assess the rel ative ri sk of each potenti al morbi di ty. For
the latter ri sk, and possibl y the former, a maneuver has been descri bed i n whi ch an LMA is pl aced
posterior to the ETT, whi ch i s then removed. This obvi ates the probl em of upper ai rway
obstruction, and may offer some protecti on agai nst regurgi tati on and aspi rati on.
152, 153, 154
Because
of the ri sks of atel ectasi s and di ffusion hypoxi a, the abil i ty to admini ster oxygen shoul d be
avai labl e at the time of extubati on.
Bronchospasm
Aspi rati on
Hypertensi on
Increased i ntracrani al pressure
Increased pul monary artery pressure
Increased bronchi al stump pressure (e.g., after pul monary resecti on)
Increased ocul ar pressure
Increased abdomi nal wal l pressure (e.g., ri sk of wound dehi scence)
P.617
TABLE 22-12 Criteria For Routine Awake Extubation
Subjective Clinical Criteria:
Fol l ows commands
Clear oropharynx/hypopharynx (e.g., no active bleedi ng, secreti ons cl eared)
Intact gag refl ex
Sustained head l i ft for 5 seconds, sustained hand grasp
Adequate pai n control
Minimal end-expiratory concentrati on of inhal ed anestheti cs
Objective Criteria:
Vi tal capacity: 10 mL/kg
Peak vol untary negative inspiratory pressure: >20 cm H
2
O
Tidal volume >6 cc/kg
Sustained tetani c contraction (5 sec)
Difficult Extubation. The patient who presented as a di fficult airway at the time of anestheti c
i nducti on must be consi dered a difficult airway at the time of extubati on, even when corrective
surgery was performed i n the i nteri m (e.g., uvulopharyngoplasty i n the obstructi ve sleep apnea
patient).
As a cause of venti l atory compromise, l aryngospasm deserves speci al attention because of i t
prevalence in chi l dren and because i t accounts for 23% of al l cri tical postoperative respiratory
events in adul ts.
151
Laryngospasm may be tri ggered by respi ratory secreti ons, vomi tus, or bl ood i n
the ai rway; pai n in any part of the body; and pelvic or abdomi nal vi sceral sti mul ati on. The cause
of ai rway obstructi on duri ng laryngospasm is the contracti on of the l ateral cri coarytenoi ds, the
thyroarytenoi d, and the cricothyroi d muscl es. Management of l aryngospasm consi sts of the
immedi ate removal of the offendi ng stimul us (i f i dentifiabl e), admini stration of oxygen with
conti nuous positi ve airway pressure, and, if other maneuvers are unsuccessful, the use of a smal l
dose of short-acti ng muscl e rel axants.
151

Negati ve-pressure pulmonary edema may result from any airway obstructi on i n a pati ent who
conti nues to have a vol untary respi ratory effort. Negative intrathoraci c pressure is transmitted to
the al veoli , whi ch are unabl e to expand owing to the more proximal obstructi on. Fl ui d i s entrai ned
from the pul monary capi ll ary bed. Negati ve-pressure pulmonary edema is treated as any other
form of noncardi ogeni c edema.
Identi fi cation of pati ents at risk at extubati on. A number of wel l known cl inical si tuati ons may
pl ace pati ents at i ncreased ri sk for compli cati on at the ti me of extubati on. Tabl e 22-13 li sts the
ri sk factors for extubati on compl icati ons. However, the cli ni ci an shoul d evaluate every patient i n
terms of potenti al probl ems, i n the same manner that they are prepared for the unanti cipated
di fficul t i ntubation.
T
1
/T
4
ratio >0.7

Al veolar-Arteri al Pao
2
gradi ent (on FIO
2
of 1.0): <350 mm Hg
a

Dead space to ti dal vol ume rati o:
0.6
a
a
Used duri ng weani ng from mechani cal venti lation in the i ntensi ve care setting.
TABLE 22-13 Clinical Situations Presenting Increased Risk For Complications at
Extubation
151

Paradoxi cal vocal cord moti on
(preexisting)
Poorl y understood mechani sm
Thyroi d surgery 4.3% recurrent l aryngeal nerve injury
Local edema
Tracheomal aci a (from l ong-standi ng goiter)
Laryngoscopy (di agnosti c) Edema, l aryngospasm, especi al l y with biopsy
Uvulopal atopl asty Pal atal and oropharyngeal edema
Obstructive sl eep apnea syndrome (uncorrected)
Caroti d endarterectomy Wound hematoma, gl otti c edema, nerve
pal si es
Maxi l lofacial trauma Laryngeal fracture
Reduced l evel of consci ousness
Requirements for mandi bul ar/maxi ll ary wi res
Cervi cal vertebrae decompressi on Supragl otti c and hypopharyngeal edema
Parki nson' s di sease
Rheumatoi d arthri ti s
Generali zed edema Laryngotracheal narrowi ng
Angi oneurotic edema Laryngotracheal narrowi ng
Anaphyl axi s Laryngotracheal narrowi ng
Hypopharyngeal i nfecti ons Laryngotracheal narrowi ng
Hypoventi lati on syndromes
a
Hypoxemi c syndromes
b
Inadequate airway protecti ve refl exes Aspi ration ri sk
a
Resi dual anestheti c or preoperati ve medi cations (i ncludi ng al cohol and i ll i ci t drugs),
central sl eep apnea, carotid endarterectomy, pol i omyel iti s, Gui ll ain-Barr syndrome,
myastheni a gravi s, botul i sm, thoracic skel etal deformi ty, severe pain (wi th
Approach to the di ffi cul t extubati on. When there i s a suspici on that a patient may have di fficul ty
with oxygenation or venti lation after tracheal extubation, the cli ni cian may choose from a number
of management strategies. These may range from the preparati on of standby rei ntubati on
equipment to the active establi shment of a route or guide for rei ntubation and/or oxygenati on.
When the patient' s i ntubation is wi thout diffi culty and there is no substantial reason to bel ieve
that an i nterim i nsul t to the ai rway has occurred, extubati on may be accompl i shed i n a routi ne
fashi on, wi th a hei ghtened state of readi ness for rei ntubati on. When there has been diffi culty wi th
intubati on or there i s a cl ini cal suspici on that rei ntubati on wi ll be di fficul t, extubation over a
gui ding stylet may be a successful techni que. Any number of devi ces can be used as a styl et
(Tabl e 22-14).
A popular test to predict airway patency after extubation is the detecti on of a l eak on defl ati on of
the ETT cuff. A recent i nvesti gati on has cast doubt on the rel i abi l ity of this test as a predi ctor of
ai rway incompetence: though the absence of an ai rway l eak on cuff defl ati on was not predi cti ve of
subsequent venti latory fai l ure after extubati on, no pati ent wi th a posi ti ve l eak test (l eak around
the ETT cuff) devel oped probl ems after extubati on.
155

Another techni que may be the use of an FOB to vi ew the tracheal structures duri ng the removal of
the ETT. If extubati on i s tolerated, the FOB can be sl owl y wi thdrawn i nto the subgl otti c regi on. If
secretions do not obstruct the objecti ve l ens, the vocal folds and other structures may be
visual i zed and eval uated.
di aphragmati c spl i nting), morbi d obesi ty, severe chroni c obstructi ve pulmonary disease.
b
Hypoventi lati on, venti lationperfusi on mismatch, i ntracardi ac or i ntrapulmonary
shunti ng, increased oxygen consumption, severe anemia, i mpai red al veolar oxygen
di ffusion.
TABLE 22-14 Devices Used as Extubating Stylets
DEVICE ADVANTAGE DISADVANTAGE
Fi beropti c bronchoscope Visual ize structures
Oxygen can be i nsuffl ated
through worki ng channel
ETT cannot be
exchanged
Eschmann catheter or
si mi l ar devi ce
Inexpensi ve, semi ri gi d Cannot vi sual i ze or
oxygenate
Exchange/venti latory
catheter
Oxygen can be i nsuffl ated
through central lumen
Cannot vi sual i ze, may
be too fl exi ble
A number of obturators are avai lable for use in tri al extubati on (where they may be l eft in pl ace i n
the ai rway for extended peri ods) or endotracheal tube exchange (e.g., fai l ure of the ETT cuff).
156

It i s beyond the scope of thi s text to

descri be all the commercial ly avai l abl e catheters. The Cook Airway Exchange Catheters (Cook
Cri tical Care, Bloomington, IN) are manufactured with external di ameters of 2.7, 3.7, 4.7, and
6.33 mm (Fi g. 22-25A). The small est diameter catheter (whi ch can fi t wi thin a 3.0-mm id ETT) is
45 cm l ong, whereas the others are 83 cm i n length. They all have a central l umen and rounded,
atraumati c ends. The catheters are graduated from the di stal end. The proximal end is fitted wi th
ei ther a 15-mm or a Luer-lock Rapi -Fi t adapter, whi ch can be qui ckl y removed and repl aced for
ETT removal or change. Wi th these adapters an oxygen source can be used to provide insufflated
or jet-ventil ated oxygen i f the pati ent fail s extubati on and/or i f rei ntubati on over the catheter
fai l s.
The Cardi omed endotracheal ventil ati on catheter (Gromley, Ontari o, Canada) desi gned by Ri chard
Cooper, MD, a Canadian anesthesi ol ogist, i s 85 cm i n length, and has i nner and outer di ameters of
3 and 4 mm, respectivel y. An integral Luer-lock fi tti ng adapter i s found at the proximal end,
whereas the bl unted distal end i ncorporates ei ght hel i cal ly arranged side hol es i n addi ti on to the
di stal end hole (Fi g. 22-25B). The arrangement of these holes i s meant to center the catheter
during oxygen insufflation, and prevent traumatic whi ppi ng within the trachea. The use of thi s
catheter for ETT exchange, tracheal reintubati on, oxygen i nsufflation, jet ventil ati on, and end-
ti dal CO
2
detecti on after extubati on has been documented by the inventor.
151

THE DIFFICULT AIRWAY
The Di f f i cul t Ai r way Al gor i t hm
In 1993, the ASA' s Task Force on the Di ffi cul t Airway first published an al gori thm that has
become a stapl e of management for cl i ni cians. This al gorithm was rei ssued i n 2003.
113, 157

The

most dramati c change in the ASA Di ffi cul t Ai rway Algori thm (ASA-DAA) was the reposi tioni ng of
the LMA from the emergency to the routine management pathway (Fi g. 22-26). The ASA defi nes
P.618
FIGURE 22-25. A. The Cook ai rway exchange catheter fi tted wi th a Rapifit Luer-lock adapter
(Cook Cri ti cal Care, Bloomi ngton, IN). A 15-mm Rapi fi t adapter for attachment to an
anesthesia ci rcui t or ambu bag is al so avail able. B. The Cardiomed endotracheal venti lation
catheter.
P.619
the diffi cult ai rway as the si tuati on i n whi ch the conventi onall y trained anesthesi ol ogist
experi ences difficulty with mask venti l ati on or both. Based on avai l able data, the i nci dence of
fai l ed i ntubati on i s 0.05 to 0.35%, whereas the inci dence of fai led intubati on/i nabi li ty to perform
mask venti lation is 0.01 to 0.03%.
158, 159

The ASA al gori thm stands as a model for the approach to the di ffi cul t ai rway for nurse
anesthetists, emergency medi cine physi cians, and prehospi tal personnel, as well as for
anesthesiol ogi sts. Al though the algori thm largel y speaks for itself, i ts sal i ent features are
di scussed here. One statement i n thi s document summari zes the di ffi cul ty of wri ti ng and
recommendi ng practi ces i n the di ffi cul t ai rway management: The difficult ai rway represents a
compl ex i nteracti on between patient factors, the cl inical setti ng and the ski l ls of the
practi ti oner.
113

Entry i nto the al gori thm begins wi th the eval uati on of the ai rway. Al though there i s some debate
as to the value of particular eval uation methods and i ndi ces, cl ini ci ans must use al l avai l abl e data
and their own cl i ni cal experi ence to reach a general i mpressi on as to the di ffi cul ty of the pati ent' s
ai rway in terms of laryngoscopy and intubati on, supragl ottic ventil ati on techni ques, aspi ration
ri sk, or apnea tol erance.
Thi s eval uati on shoul d di rect the cl i ni ci an to enter the ASA al gori thm at one of i ts two root poi nts:
Aawake i ntubati on, or Bintubati on attempts after the i nduction of general anesthesi a (see Fi g.
22-26). Thi s hi ghl ights the mi snomer of the al gori thm: i t i s not onl y for diffi cult ai rways, but is
rel evant to

al l instances where the ai rway is managed. Box B descri bes the approach taken i n the majori ty of
tracheal i ntubati ons (and i s appl icable to facemask and SGA-managed pati ents). The deci si on to
FIGURE 22-26. The Ameri can Soci ety of Anesthesiologi sts Di ffi cul t Airway Al gori thm.
(Adapted from Practi ce gui deli nes for the management of the di ffi cul t ai rway: An updated
report by the Ameri can Soci ety of Anesthesi ol ogi sts Task Force on Management of the
Difficult Ai rway. Anesthesiol ogy 98:1269, 2003.)
P.620
enter the al gori thm vi a box A or B i s a premanagement one. Box A i s chosen when di ffi cul ty is
anti ci pated, whi l e box B i s for the si tuati on when no di ffi cul ty i s anti cipated. Thi s deci si on can be
refi ned i n l i ght of the prol iferati on of SGAs. Takenaka et al , have questi oned the need to enter the
ASA-DAA box A when SGAs are deemed usabl e despi te an anti ci pated di ffi cul t tracheal i ntubati on
by DL.
160
Thi s has been further del i neated i nto a preoperati ve deci si on tree by Rosenbl att.
161

Fi gure 22-27 outl i nes the Ai rway Approach Algorithm (AAA), whi ch i s a si mpl e, one-pathway
al gori thm for enteri ng into the ASA-DAA. Branch choi ce, l i ke the earl ier-noted statement from the
ASA practi ce gui del i nes, i s hi ghl y dependent on the cl i ni ci an' s ski l l and experi ence. Detai l s of the
AAA can be found el sewhere and are summari zed here:
161

1. Is airway control necessary? No matter how routi ne sedati on or general anesthesi a become
to potenti al l y make a pati ent apneic, should al ways be consi dered seriousl y and al ternati ves
should be consi dered.
2. Wi l l DL be (at al l ) di ffi cul t? If there i s no indi cation that DL wi l l be di ffi cul t (based on
physi cal exam and hi story), the cl i ni ci an may proceed with any technique (i nducti on, DL,
LMA, etc.) as cl i ni cal ly appropri ate. This i s the essence of box B of the ASA-DAA.
3. Can SGA ventil ati on be used? If the cl inici an feel s that there i s a physi cal reason that SGA
ventil ati on (by facemask, LMA, or other devi ce) wi l l be di ffi cul t, the juncture of possibl e
cannot i ntubate/cannot venti late (CNI/CNV) has been reached. Because thi s i s a
preoperati ve al gori thm, box A of the ASA-DAA may be the root entry poi nt.
4. Is there an aspi ration ri sk? As di scussed earl i er, the pati ent at ri sk for aspi ration is not a
candi date for elective SGA use. A juncture of cannot i ntubate/shoul d not venti l ate has
been reached and box A of the ASA-DAA i s chosen.
5. Wi l l the pati ent tol erate an apnei c peri od? Questi on 3 from thi s li st is di fficul t to answer and
is highly dependent on the skil l s and experi ence of the cl i ni ci an. Shoul d i ntubati on fai l, and
SGA venti lation not be adequate, the patient' s abil i ty to sustai n oxygen saturation wi ll
FIGURE 22-27. The Ai rway Approach Al gori thm: A decisi on tree approach to entry i nto the
Ameri can Soci ety of Anesthesi ologi sts Di ffi cul t Airway Al gori thm (see Fi g. 22-26). (From
Rosenbl att W. The ai rway approach al gorithm. J Cli n Anesthesi a 16:312, 2004.)
di ctate their abil i ty to tolerate an apnei c peri od. Factors such as age, obesity, pul monary
status, abnormal oxygen consumpti on (e.g., fever), and choi ce of induction agents wi l l
infl uence thi s. These factors have been di scussed i n detai l el sewhere.
161
To il l ustrate the
cl i ni cal appl i cati on of the AAA, the path through thi s algori thm wi l l be traced for the cl i ni cal
scenari os at the end of thi s chapter.
The excepti on to the AAA i s the pati ent who i s unabl e to cooperate owi ng to mental retardati on,
intoxi cation, anxi ety, depressed level of consciousness, or age. This patient may sti l l enter box A,
but awake intubati on may need to be modi fi ed i n favor of techni ques whi ch mai ntai n spontaneous
ventil ati on (e.g., i nhalati on i nducti on).
Preparati on of the patient for awake i ntubation is di scussed l ater. In most instances, awake
intubati on i s successful i f approached wi th care and pati ence. When awake intubati on fai ls, the
cl i ni ci an has a number of opti ons. Fi rst, one can consi der cancel l ati on of the surgi cal case. In this
si tuati on, speci al i zed equi pment or personnel can be assembled for a return to the operati ng
room. Where cancel lation is not an option, regi onal anesthetic techni ques can be consi dered, or, i f
demanded by the si tuati on, a surgi cal ai rway (e.g., tracheostomy) may be cal led for.
The deci si on to proceed wi th regi onal anesthesi a because the ai rway has been assessed or proven
to be di ffi cul t to manage must be consi dered i n terms of ri sks and benefi ts (Tabl e 22-15). The
ASA-DAA trul y becomes useful i n the unanti ci pated di ffi cult airway (box B, unable to intubate by
DL after the i nducti on of anesthesi a). When inducti on agents (with or wi thout muscl e relaxants)
have been admi nistered and the ai rway cannot be control l ed, vi tal management deci si ons must be
made rapi dl y. Typi cal l y, the cl i ni cian has attempted di rect l aryngoscopy and i ntubati on after
successful or fail ed anesthesi a mask venti l ati on (unless a rapid-sequence inducti on i s bei ng
performed). Even if the pati ent' s oxygen saturation remai ns adequate throughout these efforts,
the number of laryngoscopy attempts shoul d be l i mi ted to three. As discussed earli er, significant
soft ti ssue trauma can resul t from multi ple laryngoscopies, thereby worsening the si tuati on. First,
mask ventilation shoul d be i nsti tuted. If facemask venti l ati on i s adequate, the ASA-DAA
nonemergency pathway i s entered. The cl i ni ci an may then turn to the most convenient and/or
appropriate techni que for establ i shi ng tracheal intubati on, i f needed. Thi s mi ght i ncl ude, but is not
li mi ted to, bl i nd oral or nasal intubati on; intubati on faci l i tated by a fi beropti c bronchoscope, LMA,
LMA-Fastrach, bougi e, l i ghted styl et, or a retrograde wi re; or a surgical ai rway. (The most wi dely
appl ied of these procedures, as well as new techniques, i s di scussed withi n the cli nical scenarios
in a later secti on of thi s chapter.) When mask venti lation fail s, the al gori thm suggests supragl ottic
ventil ati on via any LMA. If successful, the nonemergency pathway of the ASA-DAA has agai n been
entered and al ternati ve techni ques of tracheal i ntubati on may be uti l i zed, i f needed (e.g., perhaps
LMA venti lation is adequate for the cl ini cal si tuati on).
TABLE 22-15 Factors To Consider in Proceeding With Regional Anesthesia (RA) After
The Patient Has Been Judged To Have a Difficult Airway
MAY CONSIDER RA SHOULD NOT CONSIDER RA
Superfici al surgery Cavity-invading surgery
Mi nimal sedati on needed Significant sedation needed
Anestheti c may be
provi ded wi th l ocal
infi ltration
Extensive neuroaxial l ocal anesthetic admi ni strati on wi ll be
requi red, or risk of intravascul ar i njecti on/absorpti on i s
hi gh
Shoul d LMA venti l ati on fai l to sustai n the pati ent, the emergency pathway i s entered. The ASA-
DAA suggests use of an Esophageal -Tracheal Combi tube, ri gi d bronchoscopy, transtracheal
oxygenati on, or a surgi cal ai rway.
At any juncture, the deci sion to awaken the pati ent shoul d be consi dered based on the adequacy
of venti lati on, the ri sk of aspirati on, and the ri sk of proceeding wi th i ntubati on attempts or the
surgi cal procedure.

The repositi oning of the LMA wi thin the al gorithm (in i ts 2003 republi cati on) was based on more
than 12 years of cl inical use i n the Uni ted States (and more than 20 years' experi ence worl dwi de).
Rel ati vel y few cases of LMA fai lure i n the face of the CNI/CNV situation have been
reported.
10, 162, 163, 164, 165, 166, 167, 168
Three broad categori es account for these fail ures: acute oral
pharyngeal angl e, obstructi on at the level of the hypopharynx, obstructi on below the vocal folds.
Conversel y many cases of LMA rescue of the fai led ai rway have been reported. Though control
studi es are l acki ng, Parmet et al noted that al l cases of CNI/CNV (with the excepti on of an
iatrogeni c subglotti c obstructi on) occurri ng i n a 2-year peri od i n a si ngl e hospital were rescued
with an LMA.
162

Awake Airway Management
Awake ai rway management remai ns a mai nstay of the ASA' s Diffi cul t Ai rway Al gori thm.
Awake i ntubati on provi des many advantages over the anestheti c state, incl udi ng mai ntenance
of spontaneous venti lation in the event that the airway cannot be secured rapi dl y, i ncreased size
and patency of the pharynx, rel ati ve forward pl acement of the base of the tongue, posteri or
pl acement of the l arynx, and patency of the retropalatal space.
169, 170
The effect of sedati ves and
general anestheti cs on ai rway patency may be secondary to di rect effects on motoneurons and on
the reticular activating system.
171
The sl eep apnea patient may be parti cul arl y prone to
obstruction wi th mi ni mal sedati on. Addi ti onall y, the awake state confers some maintenance of
upper and l ower esophageal sphincter tone, thus reducing the ri sk of reflux. In the event that
refl ux occurs, the pati ent can cl ose the gl otti s and/or expel aspi rated forei gn bodi es by cough to
the extent that these reflexes have not been obtunded by l ocal anesthesia.
172
Lastl y, pati ents at
ri sk for neurol ogic sequel ae (e.g., pati ents wi th unstable cervi cal spi ne pathol ogy) may undergo
sensory-motor moni tori ng after tracheal i ntubation. In an emergent si tuati on, there may be
cauti ons (e.g., cardi ovascul ar stimul ati on i n the presence of cardiac ischemia or i schemi c ri sk,
bronchospasm, i ncreased i ntraocular pressure, increased i ntracranial pressure) but no absolute
contrai ndi cations to awake intubati on.
173
Contraindi cations to el ecti ve awake intubati on i ncl ude
patient refusal or i nabi li ty to cooperate (e.g., chil d, profound mental retardati on, dementi a,
intoxi cation) or al l ergy to l ocal anestheti cs.
Once the cl i ni ci an has deci ded to proceed wi th awake airway management, the pati ent must be
prepared both physi cal l y and psychol ogi cal l y. Most adul t patients wil l appreciate an expl anati on of
Access to the airway i s
good
Access to the airway i s poor
Surgery can be halted at
any time
Surgery cannot be stopped once started
P.621
the need for an awake ai rway exam and wi ll be more cooperative once they real ize the i mportance
of, and rati onal e for any uncomfortabl e procedures. Once the ai rway has been prepared, patients
wil l real i ze that they shoul d experience no further discomfort duri ng the intubati on.
Apart from appropri ate expl anati on, medi cati on can also be used to al l ay anxi ety. If sedati ves are
to be used, the cl i ni ci an must keep i n mi nd that produci ng obstructi on or apnea in the di ffi cul t
ai rway pati ent can be devastati ng and an overl y sedated patient may not be able to protect the
ai rway from regurgi tated gastri c contents, or cooperate wi th procedures. Smal l doses of
benzodiazepi nes (diazepam, mi dazol am, l orazapam) are commonl y used to al l evi ate anxi ety
wi thout produci ng si gnificant respi ratory depressi on. These drugs may be given in iv or oral forms
(when avai labl e) and may be reversed with speci fic antagoni sts (e.g., fl umazeni l). Opi oi d receptor
agoni sts (e.g., fentanyl, al fentani l , remi fentani l ) can al so be used i n smal l , titrated doses for their
sedati ve and anti tussi ve effects, al though caution must be exerci sed. A specifi c antagoni st (e.g.,
naloxone) shoul d always be i mmedi ately avai l able. Ketami ne and droperi dol and the new agent,
dexmetomodi ne, have also been popul ar among cl i ni cians.
Admi ni strati on of antisi al agogues i s i mportant to the success of awake intubati on techni ques. As
wil l be di scussed bel ow, cleari ng of ai rway secreti ons is essenti al to the use of indi rect optical
i nstruments (e.g., fi beropti c bronchoscope, ri gi d fi beropti c l aryngoscope) because smal l amounts
of any l i qui d can obscure the objecti ve l ens. The commonl y used drugs atropi ne (0.5 to 1 mg i m or
iv) and glycopyrrolate (0.2 to 0.4 mg i m or iv) have other si gnifi cant effects: by reduci ng sali va
producti on, these drugs i ncrease the effecti veness of topi cal l y appl ied l ocal anestheti cs by
removi ng a barri er to mucosal contact and reduci ng drug di luti on. Vasoconstri cti on of the nasal
passages i s needed if there is to be instrumentati on of thi s part of the airway. If the pati ent i s at
ri sk for gastri c regurgi tation and aspi rati on, prophyl acti c measures shoul d be undertaken. It i s
al so prudent to suppl y suppl emental oxygen to the pati ent by nasal cannul a (whi ch can be pl aced
over the nose or mouth).
Local anesthetics are a cornerstone of awake airway control techni ques. The ai rway, from the base
of the tongue to the bronchi , comprises an undeni abl y sensi ti ve series of ti ssues. Topical
anesthesia and injected nerve block techni ques have been devel oped to bl unt the protecti ve
ai rway refl exes as wel l as to provi de anal gesia. As i s wel l known to the anestheti c practi ti oner,
local anestheti cs are both effecti ve and potential ly dangerous drugs. The cl i ni cian should have a
thorough understandi ng of the mechani sm of acti on, metabol ism, toxi citi es, and acceptable
cumul ati ve doses of the drugs that he or she chooses to empl oy i n the airway. Because much of
the agent used wi ll be wi thin the tracheal bronchi al tree and wi l l travel to the alveol i, there wil l
be si gni fi cant and rapi d i ntravascular absorpti on.
Despi te the avai l abi l ity of myri ad l ocal anestheti cs, onl y those most commonl y used i n ai rway
preparati on wi l l be di scussed here.
Among otol aryngol ogi sts, cocai ne i s a popular topi cal agent. Not only i s it a highly effecti ve local
anesthetic, but al so it i s the onl y l ocal anestheti c that i s a potent vasoconstrictor. It is commonl y
avai labl e in a 4% sol ution. The total dose appli ed to the mucosa should not exceed 200 mg i n the
adult. Cocai ne should not be used i n patients wi th a known cocai ne hypersensiti vi ty, hypertension,
ischemi c heart di sease, preecl ampsi a, or those taki ng monoamine oxi dase i nhibi tors.
174
Si nce
cocai ne i s metabol i zed by pseudocholi nesterase, it i s contrai ndi cated i n pati ents defici ent i n thi s
enzyme.
Lidocai ne, an amide local anestheti c, i s avai lable i n a wi de vari ety of preparati ons and doses
(Tabl e 22-16). Topi cal ly appl i ed, peak onset i s wi thi n 15 mi nutes. Toxi c pl asma level s are not
impossibl e to achi eve but are not commonly reported i n ai rway management.
TABLE 22-16 Available Lidocaine Preparations
PREPARATION DOSES
Tetracai ne is an amide l ocal anestheti c wi th a l onger durati on of action than ei ther cocai ne or
li docaine. Soluti ons of 0.5%, 1%, and 2% are avai l abl e. Absorption of this drug from the
respiratory and GI tracts is rapid, and toxi ci ty after nebul i zed appl i cati on has been reported wi th
doses as l ow as 40 mg, al though the acceptabl e safe dose in adul ts i s 100 mg.
175

Benzocai ne is popul ar among some cl ini ci ans because of i ts very rapi d onset (<1 mi nute) and
short durati on (~10 mi nutes). It i s avail able i n 10%, 15%, and 20% sol uti ons. It has been
combi ned with tetracai ne (Hurri cai ne, Beutl ich Pharmaceuticals) to prolong the durati on of
acti on. A 0.5-second aerosol administrati on of Hurri cai ne del i vers 30 mg of benzocaine, the toxic
dose being 100 mg. Another common preparation is Cetacai ne spray, whi ch combi nes benzocai ne
with tetracai ne, butyl ami nobenzoate, benzalkonium chlori de, and cetyl di methyl ethyl ammonium
bromi de. Benzocaine may produce methemogl obi nemia, which is treated by the admi ni strati on of
methyl ene bl ue.
There are three anatomic areas to whi ch the cl ini ci an di rects local anestheti c therapy: the nasal
cavi ty/nasopharynx, the pharynx/base of tongue, and the hypopharynx/l arynx/trachea. The nasal
cavi ty i s innervated by the greater and l esser palanti ne nerves (i nnervati ng the nasal turbi nates
and most of the nasal septum) and the anteri or ethmoi d nerve (innervati ng the nares and anteri or
third of the nasal septum). The two palanti ne nerves ari se from the sphenopal antine gangl ion,
l ocated posteri or to the mi ddl e turbi nate. Two techni ques for nerve bl ock have been descri bed.
The gangl ion can be approached through a noni nvasi ve nasal approach: cotton-ti pped appl i cators
soaked in l ocal anestheti c are passed along the upper border of the middl e turbi nate unti l the
posterior wall of the nasopharynx is reached. They are l eft in pl ace for 5 to 10 mi nutes. In the
oral approach, a needl e is i ntroduced into the greater pal antine foramen, which can be pal pated i n
the posteri or l ateral aspect of the hard pal ate, 1 cm medi al to the second and thi rd maxi l l ary
mol ars. Anestheti c sol ution (1 to 2 mL) i s i njected wi th a spi nal needl e i nserted i n a
superi or/posterior directi on at a depth of 2 to 3 cm. Care must be taken not to inject i nto the
sphenopal anti ne artery. The anteri or ethmoi d nerve can be bl ocked by cotton-ti pped appl i cators
soaked in l ocal anestheti c pl aced al ong the dorsal surface of the nose unti l the anteri or cri bri form
pl ate is reached. The appl i cator i s left i n place for 5 to 10 mi nutes.
The oropharynx is i nnervated by branches of the vagus, faci al , and gl ossopharyngeal nerves. The
gl ossopharyngeal nerve (GPN) travels anteri orl y al ong the lateral surface of the pharynx, i ts three
branches suppl yi ng sensory innervati on to the posteri or thi rd of the tongue, the val l ecul a, the
anterior surface of the epi gl otti s (li ngual branch), the wal l s of the pharynx (pharyngeal branch),
and the tonsi l s (tonsil l ar branch). A wi de variety of techni ques may be used to anesthetize thi s
part of the ai rway. The si mpl est techniques involve aerosoli zed l ocal anestheti c sol ution, or a
vol untary swi sh and swal l ow. As long as the cl i ni ci an has devel oped a plan to anestheti ze al l
rel evant structures, has al lowed enough ti me for drying agents to work, and remains conti nual l y
cogni zant of the total dose of l ocal anestheti cs admi ni stered, most pati ents wi ll be adequatel y
Injectable/topi cal sol uti on 1%, 2%, 4%
Viscous solution 1%, 2%
Oi ntment 1%, 5%
Aerosol 10%
P.622
anesthetized i n thi s way.
Some pati ents may requi re a GPN bl ock, especi al l y when topi cal techni ques do not adequatel y
bl ock the gag reflex. The branches of thi s nerve are most easil y accessed as they transverse the
pal atoglossal folds. These fol ds are seen as soft tissue ri dges, whi ch extend from the posteri or
aspect of the soft palate to the base of the tongue, bi l ateral ly (Fi g. 22-28).
A noni nvasi ve techni que employs anestheti c-soaked cotton-ti p appl i cators, whi ch are posi ti oned
against the inferi or-most aspect of the folds and left in place for 5 to 10 mi nutes. When the
noni nvasive techni que proves inadequate, l ocal anestheti c can be injected. Standi ng on the side
contral ateral to the nerve to be bl ocked, the operator di spl aces the extended tongue to

the contral ateral side and a 25-G spi nal needl e is i nserted i nto the membrane near the fl oor of the
mouth. An aspiration test is performed. If air i s aspi rated, the needl e has passed through-and-
through the membrane. If bl ood i s aspi rated, the needle is redi rected more medial ly. The l i ngual
branch i s most readil y blocked i n thi s manner, but retrograde tracki ng of the injectate has al so
been demonstrated.
172
Though provi di ng a rel i abl e block, thi s techni que i s reported to be pai nful
and may resul t i n a bothersome and persistent hematoma.
176
A posteri or approach to the GPN has
been descri bed i n the otol aryngol ogi c l iterature (for tonsi ll ectomy). It may be di ffi cul t to vi suali ze
the si te of needl e i nsertion, whi ch is behi nd the pal atopharyngeal arch where the nerve i s i n cl ose
proxi mi ty to the caroti d artery. Because of the ri sk for arterial injecti on and bleedi ng, the
techni que wi l l not be descri bed here; however, the reader is referred to a more authoritati ve
text.
177

The i nternal branch of the superi or l aryngeal nerve (SLN), which is a branch of the vagus nerve,
provi des sensory innervati on to the base of the tongue, epi glotti s, aryepi glotti c folds, and
arytenoi ds. The branch origi nates from the SLN l ateral to the cornu of the hyoi d bone. It then
pierces the thyrohyoid membrane and travels under the mucosa i n the pyriform recess. The
remai ni ng porti on of the SLN, the external branch, suppl i es motor i nnervati on to the cri cothyroid
muscl e. Several bl ocks of thi s nerve have been descri bed. In many instances topi cal appl i cation of
anesthetics i n the oral cavi ty wi ll provi de adequate anal gesi a. An external bl ock i s performed wi th
the pati ent supi ne wi th the head extended and the cl i ni ci an standing on the si de i psi l ateral to the
FIGURE 22-28. The pal atogl ossal arch (arrow) i s a soft ti ssue fol d that i s a conti nuati on of
the posteri or edge of the soft pal ate to the base of the tongue. A l ocal anestheti csoaked
swab pl aced i n the gutter al ong the base of the tongue i s l eft in contact with the fol d for 5 to
10 mi nutes.
P.623
nerve to be bl ocked. Beneath the angle of the mandi ble the cli ni cian identi fi es the superior cornu
of the hyoi d bone (Fi g. 22-29). Usi ng one hand, medi al l y di rected pressure i s appl i ed to the
contral ateral hyoi d cornu, di spl aci ng the i psi l ateral hyoi d cornu toward the cl i ni cian. Caution must
be taken to l ocate the carotid artery and displ ace i t if necessary. The needle can be i nserted
di rectl y over the hyoi d cornu and then wal ked off the cartil age in an anteri or-caudad di recti on
unti l it can be passed through the membrane to a depth of 1 to 2 cm (Fi g. 22-29A). Before the
injecti on of l ocal anesthetic, an aspi rati on test shoul d be performed to ensure that one has not
entered the pharynx or a vascul ar structure. Local anesthetic wi th epi nephri ne (1.5 to 2 mL) i s
injected i n the space between the thyrohyoi d membrane and the pharyngeal mucosa. The superi or
laryngeal nerve can al so be blocked wi th a noninvasi ve bl ock i nternal techni que. The patient i s
asked to open the mouth wi dely, and the tongue i s grasped usi ng a gauze pad or tongue bl ade. A
ri ght-angle forceps (e.g., Jackson-Krause forceps) wi th anestheti c-soaked cotton swabs i s sl i d
over the l ateral tongue and into the pyriform si nuses bi laterall y. The cotton swabs are hel d i n
pl ace for 5 mi nutes.
Sensory i nnervation of the vocal fol ds and the trachea is provided by the recurrent l aryngeal
nerve. Transtracheal i njecti on of l ocal anesthetic can easily be performed to produce adequate
anal gesi a, and the techni que i s descri bed i n detai l bel ow (see Retrograde Intubati on secti on, Case
2) (Fi g. 22-29B). Li docai ne, 4 mL of 2% or 4% sol ution, is i njected.
An effecti ve and noninvasi ve technique of tracheal and vocal cord topi cal analgesia uti l izes the
worki ng channel of the fiberopti c bronchoscope. A disadvantage of this techni que is that sol utions
leavi ng the worki ng channel can obscure the objecti ve l ens. Thi s can be overcome by use of an
epi dural catheter, inserted through the worki ng channel , as descri bed by Ovassapi an.
178
Not onl y
does thi s prevent the obscuring of the vi ew, but al so i t all ows speci fi c ai mi ng of the anestheti c
stream.
Cl i ni cal Di f f i cul t Ai r way Scenar i os
The cli nici an approachi ng the pati ent wi th a di ffi cul t ai rway has a vast armamentari um of
techni ques and i nstruments that can be appl i ed to securi ng and mai ntai ning oxygenati on and
ventil ati on.
179
Al though thi s array can be confusi ng, textbook authors cannot di ctate speci fi c
approaches in every si tuati on; moreover, the vari abil i ty of patient presentati on makes speci fi c
FIGURE 22-29. When a superi or laryngeal nerve bl ock i s performed, pressure i s appl i ed to
the contral ateral greater cornu of the hyoi d to faci li tate i dentificati on of anatomi c landmarks.
The needl e i s inserted at the l evel of the thyrohyoi d membrane just i nferi or to the greater
cornu of the thyroi d cartil age. A. Superior laryngeal nerve bl ock. B. Transtracheal aspirati on
and injecti on of l ocal anestheti c (note bubbl e of aspi rated tracheal ai r).
recommendations di ffi cul t. Thus, to di scuss management, the foll owing secti on presents a number
of bri ef cl inical scenari os and the author' s own approach. The major alternati ve ai rway
management techni ques are di scussed in thi s manner. All of the cl i ni cal cases descri bed herei n
have been managed by the author or a col league. Other techni ques that mi ght be appl i ed i n each
si tuati on are al so di scussed, together wi th the author' s own deci si on tree regardi ng thei r
appl icabil i ty. In these cases, as in actual practi ce, the fi rst techni que appl i ed may not have

been the best one. The pri ncipl e of fl exi bil i ty (and a keen eye to the need to change course
qui ckly) i s emphasi zed repeatedl y. In vi ew of the criti cal i mportance of the act of ai rway control ,
the cl i ni cian must be prepared to al ter hi s or her approach as the situation demands. Tabl e 22-17
shows the author' s route through the AAA (Fi gure 22-27) with each case.
When DL and tracheal i ntubati on fail , the cl i ni ci an has a l arge armamentari um of tool s to turn to.
Because successful DL is dependent on sufficient ti ssue di stortion (to create a l ine of sight),
techniques that do not require simil ar anatomi c al ignment may be successful after fail ed DL.
Fi beropti c, SGA, styl et-assi sted (e.g., l i ghted styl et) and retrograde techni ques may provide a
successful al ternati ve. But these techniques al so call on alternati ve ski l l sets. In a di ffi cul t or even
criti cal situation it i s unli kel y that turni ng to an unpracticed techni que wil l be hel pful.
180

Unfortunatel y, cl i ni ci ans rarely empl oy alternati ve techni ques unti l a diffi cult si tuati on ari ses.
Heidegger et al i ntroduced a simpl e al gori thm for i ncorporati ng fl exi ble fiberopti c-ai ded tracheal
intubati on i nto dai l y practice as a routine alternati ve to DL.
180
Thei r i nci dence of di ffi cul t
intubati on was 6 i n 1,324 cases, or 0.049%, markedly lower than the 0.3% reported previousl y.
181

Case 1: Flexible Fiberoptic-Aided Intubation
A 50-year-old man with symptomatic cervical vertebrae disk herni ati on presents for disk resection
and spi nal fi xation. He has a hi story of tobacco use, alcohol consumpti on, and gastroesophageal
P.624
TABLE 22-17 The Airway Approach Algorithm as Applied to the Clinical Cases
Presented in This Chapter
CASE
a
REQUIRE
CONTROL?
b
DL
Difficult?
b
SGA
POSSIBLE?
b
ASPIRATION
RISK?
b
APNEA
b
BOX
b
1 Yes Yes Yes Yes A
2 Yes Yes ? A
3 Yes No B
4 Yes No B
5 Yes Yes Yes No B
a
Refer to cl i ni cal cases.
b
Refer to Fi gure 22-7.
refl ux. In the preoperati ve hol di ng area 0.4 mg of gl ycopyrrol ate i s admi ni stered. Fifteen mi nutes
later, when the pati ent states that hi s oral secretions are mi ni mi zed, topi cal anesthesi a is
administered to the ai rway. The pati ent recei ves 4 mg of intravenous midazol am. An intubati ng
oral airway i s pl aced wi thout el iciting a gag reflex and a flexibl e fi beropti c bronchoscope i s
advanced i nto the airway. The vocal l i gaments are vi suali zed, and 4 mL of 4% l idocai ne soluti on
are injected through the fi berscope' s worki ng channel , bei ng seen to bathe the laryngeal and
subl aryngeal structures. The distal end of the fi berscope i s advanced i nto the l arynx, and a 7.0-id
endotracheal tube, whi ch had been threaded onto the fi berscope' s inserti on shaft, i s advanced into
the trachea. The fiberscope is removed whi le the structures of the cari na, trachea, and, fi nall y,
the tracheal tube are observed. The anesthesi a circui t is attached to the tracheal tube and a
steady output of carbon di oxi de i s detected by capnography. A bri ef sensory and motor neurologi c
exam i s performed by the attendi ng surgeon and general anesthesi a i s i nduced.
Use of the Fiberoptic Bronchoscope in Airway Management. The FOB i s a ubi qui tous
i nstrument i n anesthesi a, bei ng avai l abl e to 99% of surveyed acti ve ASA members.
179
The
techni que of fi beropti c-ai ded i ntubati on was fi rst performed usi ng a chol edochoscope i n a pati ent
with Sti l l 's di sease (i di opathi c, adult onset arthriti s).
182
By the late 1980s i t was recognized that
the use of the flexi bl e FOB represented such a signifi cant advancement i n the management of the
patient wi th a diffi cult ai rway that experts stated that no anesthesi ol ogist could afford not to be
faci le wi th thi s technique.
183
It i s now general l y accepted that for a vari ety of cli nical si tuati ons,
the FOB is a cri tical tool i n the armamentari um of the anesthesi ol ogi st deal ing wi th the awake or
unconsci ous pati ent who i s, or appears to be, diffi cult to intubate.
184
The FOB has proven to be
the most versati le tool avai l abl e i n this regard.
178

There is no true or firm indication for FOB-ai ded i ntubati on, as there mi ght be wi th di rect
l aryngoscopy (e.g., rapi d-sequence induction for the ful l -stomach pati ent). There are,
however, many cl i ni cal si tuati ons where the FOB can be of unparal l eled ai d i n securing the airway,
especial ly i f the cl inici an has made an effort to master the necessary skil l s by usi ng i t i n routi ne
intubati ons.
178, 180
These i nclude antici pated di fficult intubation because of hi stori cal or physical
exam fi ndi ngs, unanti ci pated di ffi cul t i ntubati on (where other techniques have fai l ed), l ower and
upper ai rway obstructi on, unstabl e or fi xed cervical spi ne disease, mass effect i n the upper or
lower ai rways, dental risk or damage, and awake intubati on.
178
Unl i ke the other devi ces used to
intubate the trachea, the FOB can also serve to vi suali ze structures below the level of the vocal
fol ds. For exampl e, i t can identi fy the pl acement of the tracheal tube or aid i n pl acement of a
doubl e l umen tracheal tube. It may be hel pful in di agnosi s within the trachea and bronchial tree,
or i n pulmonary toi let (Fi g. 22-30).
FIGURE 22-30. The fi beropti c bronchoscope may be useful for di agnosi s and therapy bel ow
the level of the vocal l igaments i ncl udi ng bronchi al segments exam and toi l et (see Fi g. 22-
30). A. Laryngeal web. B. Bronchial tumor.
Contraindicati ons to FOB-ai ded i ntubati on are rel ati ve and revolve about the l i mi tati ons of the
device (Tabl e 22-18).
Because the optical el ements are smal l (the objective l ens is typicall y 2 mm in di ameter or
smal l er), mi nute amounts of airway secreti ons, blood, or traumati c debri s can hi nder vi suali zation.
Care must be taken to remove these obstacles from the ai rway beforehand: appli cati on of
intramuscul ar or i ntravenous anti sial agogues (e.g., gl ycopyrrol ate, 0.2 to 0.4 mg; atropine, 0.5 to
1 mg) will produce a drying effect within 15 minutes, but cauti on should be taken i n patients who
may not be able to tol erate an i ncrease in heart rate. Vasoconstri cti on of the nose usi ng topi cal
oxymetazol ine, phenyl ephrine, or cocai ne reduces the chances of bl eedi ng should this route be
chosen. If an awake intubati on i s pl anned usi ng the FOB, the pati ent must be abl e to cooperatea
qui et ai rway, wi th l i ttle moti on of the head, neck, tongue, and l arynx, i s vi tal to success. Fi nal ly,
because FOB-ai ded i ntubati on of the trachea can require significant time, especi al l y i f the cl i ni cian
is not facil e wi th the devi ce, hypoxi a or i mpendi ng hypoxi a i s a contrai ndicati on, and a more rapi d
method of securi ng an ai rway (e.g., LMA or surgi cal airway) shoul d be consi dered.
Elements of the Fiberoptic Bronchoscope. The FOB i s a fragi le device with optical and
nonopti cal el ements. The

fundamental el ement consists of a gl ass-fi ber bundl e. Each fi ber i s 8 to 12 microns i n diameter
and is coated wi th a secondary glass l ayer, turned the cl addi ng. The cl addi ng ai ds in mai ntai ning
the image within each fiber as the l i ght i s refl ected off the si dewal l 10,000 ti mes per meter as i t
moves from the objective l ens to the eyepiece l ens i n the operator' s handl e. The typical intubati ng
FOB has 10,000 to 30,000 such fi bers encased i n a 60-cm, water-impermeabl e insertion cord, wi th
graduati on marks every 10 cm. Though the fi bers are al lowed to rotate over each other throughout
the length of the cord, they are fused together at the two ends i n a coherent pattern; that i s, the
arrangement of the fi bers at the eyepi ece end i s identi cal to the arrangement at the objecti ve
lens, where a diopter ring all ows focusi ng. Therefore, one might envi sion that the i mage before
the objective lens (i .e., the objecti ve) is di vi ded i nto 10,000 i ndi vi dual and uni que pictures, whi ch
i ndependentl y travel down an unwi el dy cord, to be reassembl ed i n front of the eyepiece l ens.
Broken fi bers, whi ch may occur because of bending of the insertion cord, entrapping the cord i n
other equi pment, and droppi ng the FOB, are readi ly apparent and are general ly no more than a
nui sance unti l the number of broken fi bers i nterferes wi th the visual fi el d.
The i nserti on cord al so contains a working channel : a l umen, up to 2 mm i n di ameter, whi ch
travel s from the di stal ti p to the handl e. It can be used for appl yi ng sucti on, or oxygen, and
TABLE 22-18 Contraindications To Fiberoptic Bronchoscopy
Hypoxi a
Heavy airway secretions not reli eved with sucti on or anti sial agogues
Bl eedi ng from the upper or l ower ai rway not rel i eved wi th suction
Local anesthetic all ergy (for awake attempts)
Inabi l ity to cooperate (for awake attempts)
P.625
insti ll i ng l avaging fl ui ds or drugs (e.g., l ocal anestheti cs). There i s one report of gastri c rupture
attri buted to the i nsuffl ati on of oxygen through the worki ng channel when the FOB was wi thin the
esophagus.
185
In general, FOBs <2 mm in external di ameter (e.g., pedi atri c) do not have a
worki ng channel .
Two wi res travel ing from a lever i n the handl e down the l ength of the i nserti on cord control
movement of the distal tip in the sagittal pl ane. The entire i nserti on cord i s protected by a metal
wrap unti l the l evel of the distal ti p, which is hinged for movement. Coronal pl ane movement i s
accompl i shed by a combined use of the control l ever and rotation of the enti re FOB from handl e to
di stal end. Because the fi bers are abl e to move over one another, except for where they are fused
at the extreme ends of the optic cord, rotational control i s maxi mi zed by reducing any curves i n
the FOB shaft (Fi g. 22-31).
The fi nal el ement of the FOB i s the l i ght source. Ill umi nati on of the objecti ve i s provi ded by one or
two noncoherent bundl es of gl ass fibers that transmi t li ght from the handl e to the distal tip. The
l i ght i s provi ded ei ther by a uni versal cord that emerges from the handl e and i s i nserted i nto a
medical -grade endoscopic l i ght source, or may be provi ded by a battery-operated li ght source on
the handl e.
Preparation of the Fiberoptic Bronchoscope. When approachi ng the FOB-ai ded i ntubati on, one
must ensure that the device i s i n worki ng order. A series of i nspecti ons are made, as li sted in
Tabl e 22-19.
FIGURE 22-31. Handl i ng of the fi beropti c bronchoscope. A. The handle is held in the
nondomi nant hand wi th the ti p of thumb over the sagi ttal plane control l ever. The i ndex
finger can be used to control the working channel (e.g., sucti on, oxygen i nsuffl ati on). The
domi nant hand i s used for fi ne mani pul ati on at the di stal end. B. The operator' s two hands
should be kept maxi mall y apart so as to keep the insertion shaft as strai ght as possi ble,
maximizing coronal plane rotational control. C. Curves i ntroduced along the shaft reduce
coronal pl ane rotational control .
TABLE 22-19 Preparation of the Fiberoptic Bronchoscope
PROCEDURE FINDING SIGNIFICANCE AND ACTION
Use of the Fiberoptic Bronchoscope. The FOB is held in the nondominant hand, the thumb over
the control l ever and the index finger poi sed over the working channel valve (see Fi g. 22-31). The
domi nant hand wil l be used to steady and hol d the i nserti on cord as i t i s mani pul ated i n the
patient. Many operators are tempted to swi tch hands, but the thumb of the nondomi nant hand
shoul d be capabl e of control ling the gross movement of the control l ever. Any experi enced
endoscopi st wil l recogni ze that the fi ne control required to hol d the shaft of the endoscope steady,
advance the objecti ve end i nto the ai rway, and make di recti onal adjustments is where the art of
endoscopy l i es.

Inspect passive
angul ati on:

Allow FOB to hang
from the hand.
Observer devi ati ons from
plum.
Angul ati on may si gni fy
damage to the i nsertion shaft.
If lever controls are
operative, the FOB may be
usabl e.
Excessi ve angul ati on or
curvature may make
mani pul ati on di ffi cul t,
di sori enting the operator, so
the scope shoul d not be used.
Acti ve angul ati on:
The control l ever i s
used to mani pul ate
the distal ti p
Does the l ever control
move the tip in the sagittal
pl ane smoothly and to the
extent stated by the
manufacturer?
There may be a damaged or
entrapped control wi re. The
devi ce shoul d be repai red by
the manufacturer.
Appl y sucti on to the
worki ng channel .
No or mi ni mal sucti on at
di stal aperture.
Caking of secreti ons wi thi n
channel may requi re cl eani ng
by the manufacturer.
Crimping of insertion cord
requi res repair.
Pi cture cl ari ty:
Observe pri nted
wri ti ng a few
mi ll i meters i n front of
the objective lens.
Foggy or di rty pi cture. The objecti ve l ens and
eyepiece l ens can be cleaned
with a li nt-free cl oth.
Use a commerci al defogger.
Pri or to placing i n the pati ent,
warm water may prevent
further foggi ng by equal i zi ng
the l ens and pati ent
temperatures.
Suction or oxygen
insufflation.
If these are unsuccessful , the
FOB may need cl eani ng by the
manufacturer.

The i nserti on shaft is l ubri cated wi th a water-solubl e lubri cant, and i t is threaded through the
lumen of an ETT, the objective end emergi ng from the mai n ETT ori fi ce. A cli ni cal l y appropri ate
ETT shoul d be chosen, but the larger the rati o between the i nternal di ameter of the ETT and the
external diameter of the i nsertion shaft, the greater the ri sk of hangup on ai rway structures, as
occurs i n 20 to 30% of attempts (Fi g. 22-32).
178

Hangup occurs when a cl eft exi sts between these two devi ces because of the di fferential sizes.
Hangup may i nvol ve entrapment of the epi glotti s, corni culate/arytenoi d cartil ages, the
aryepigl otti c fol ds, or the vocal folds, and can occur wi th any number of stylet-gui ded techniques
(e.g., fi beropti c, retrograde wi re, l ighted styl et) though i t i s most thoroughl y descri bed wi th
fi beropti c ai ded i ntubati on.
186, 187
The ori entati on of the tracheal tube bevel i s important i n thi s
regard. In orotracheal intubati on, the bevel cl eft i s l i kel y to entrap the right arytenoid carti l age
when the ETT is i n its typical concavi ty anteri or posi ti on. Rotation of the ETT countercl ockwi se 90
P.626
P.627
FIGURE 22-32. The si ze di screpancy between the fi beropti c bronchoscope and the tracheal
tube that has been threaded onto i t can create a cl eft that can entrap anterior anatomi c
structures, hi nderi ng advancement of the tracheal tube i nto the l arynx (hangup).
pl aces the bevel faci ng positi vel y and i mproves passage. During nasotraceheal i ntubati on, the
epi gl ottis may be entrapped, and a bevel -up posi ti on (rotati on of the ETT 90 cl ockwise) may
faci li tate passage.
188

The type of tracheal tube may also affect passage. It has been suggested that the Parker Flex-ti p
(Parker Medi cal , Ci nci nnati , OH) may pass the ai rway structures more easi l y than a standard ETT
bevel.
189
The use of soft-ti pped ETTs, asking the patient to i nspi re deepl y duri ng the ETT
advancement, and the doubl e setup ETT, whi ch uses a smal l ETT (e.g., 5.0 id) wi thi n a cl i ni cal ly
adequate ETT (e.g., 7.5 i d) to overcome the cl efts caused by si ze di fferenti al s have been
descri bed.
186, 190

The cli nici an chooses the route of i ntubation, either oral or nasal , based on cl i ni cal requi rements,
surgi cal needs, operator experi ence, and other i ntubation techniques avai l abl e shoul d FOB-ai ded
intubati on fail . Thi s last factor i s important because shoul d an attempt at nasal i ntubation fai l ,
there may be si gni fi cant bl eedi ng hi nderi ng other i ndi rect vi sual ization techni ques. The nasal
route i s considered easi er by many cli nici ans. The differences between oral and nasal FOB-ai ded
i ntubati on are di scussed i n Tabl e 22-20.
A vari ety of i ntubating oral ai rways (IOA) are commerci al l y avai l abl e. Thei r chi ef function is to
provide a clear visual path from the oral aperture to the pharynx, keep the bronchoscope i n the
mi dli ne, prevent the pati ent from bi ti ng the i nsertion cord, and provi de a clear ai rway for the
spontaneousl y or mask-ventil ated patient. The common characteri sti c of all IOAs is a channel
al ong the l ength of the airway l arge enough to al l ow the passage of the endotracheal tube. The
Ovassapi an airway (Fi g. 22-33) provi des two sets of semici rcul ar, i ncompl ete flexibl e fl anges that
stabi l ize the ETT (up to si ze 9.0 i d) i n the mi dli ne but al l ow i ts removal from the ai rway after
i ntubati on has been accompl i shed so that the IOA can be removed from

the mouth. The fl at li ngual surface of the ai rway gi ves i t good lateral and rotati onal stabi li ty. The
Patil -Syracuse endoscopic airway and the Luomanen oral ai rway (see Fi g. 22-33) were al so
desi gned for fi beropti c-ai ded i ntubati on. Each has a central groove, open at the li ngual (Pati l -
Syracuse) or palatal (Luomanen) aspect, whi ch al lows easy removal of the ETT. The fl at l ingual
surface provi des good stabi li ty. Though this style of IOA provides superb access to the pharynx, it
is l arger than other ai rways and is often uncomfortabl e for the pati ent. The Wil l iams ai rway (see
Fi g. 22-33) and the Berman ai rway were both desi gned for bl i nd oral i ntubati on. It i s often
TABLE 22-20 Techniques of Nasal and Oral Fob-Aided Intubation
NASAL ORAL
Preparati on Antisi al agogues, topical decongestant,
serial dil ati ons wi th soft and l ubri cated
nasal trumpets
a
Antisi al agogue, intubati ng
oral airway (IOA)
ETT Softened by pl aci ng i n warm water. May
be kept either on proxi mal i nserti on cord
(near handl e) or i nserted
b
into the nose
so that i t i s fel t to turn the bend from
the nasal cavity i nto the nasopharynx
Kept either on proximal
inserti on cord (near
handl e) or i nserted 4-5 cm
into the IOA
Structures
seen
Fl oor of nose, nasal turbinates, superior
aspect of the soft pal ate, nasopharyngeal
posterior wall , base of tongue, epigl ottis
(di stal ti p),
c
arytenoid carti lages, vocal
fol ds, tracheal ri ngs, cari na
IOA (anteri or or
anterior/posteri or
dependi ng on IOA)
Soft palate/uvula
Epi glotti s (di stal ti p),
c

arytenoi d carti lages, vocal
folds, tracheal rings,
cari na
a
Although phenyl ephrine and cocaine have been used to decongest the nose, evidence
suggests that oxymetazol i ne may be the best agent.
b
The bevel of the ETT shoul d foll ow al ong the nasal septum, away from the turbi nates. If
the ETT wil l not turn i nto the nasopharynx, i t may be rotated 90 in a cl ockwi se or
countercl ockwi se di rection and readvanced.
c
An obstructi ng base of tongue or epigl ottis can be moved by extensi on at the atl anto-
occi pi tal joint, jaw thrust, chi n l i ft, or having an assi stant pull the tongue forward.
P.628
di fficul t to mani pul ate the ti p of the fiberscope when it is within these narrow airways. Both are
mol ded pl asti c with a compl ete ci rcular internal l umen which gui des the ETT toward the l arynx.
These ai rways have a small profil e and are often better tol erated by the awake pati ent, but tend
to be l ess stabl e on the tongue. Because the internal l umen i s a compl ete ci rcl e, the Wi ll i ams
airway must be retreated off the ETT if it is goi ng to be removed after i ntubati on. Thi s may pose
di fficul ty i f the ETT i n use has a fused ci rcui t adapter. The Berman ai rway sol ves thi s problem by
bei ng spl i t al ong the l ength of one si de. The pl asti c of the opposi te si de i s thi n and mal leabl e. If
the interi ncisor gap i s adequate, the airway can be opened l ateral l y to al l ow removal from the
ETT.
After successful navi gation through the supragl otti c ai rway, the endoscopist vi sual i zes the vocal
fol ds. If gl ottic cl osure, gag, or coughing occur as the FOB distal tip sti mulates the structures of
the larynx, the operator can choose to appl y local anestheti c through the worki ng channel ,
administer more sedation, or wi thdraw the scope and rei nforce preparatory procedures. The
cl i ni ci an might al so deci de to advance the FOB i nto the l arynx wi thout further preparati on. The
acti ons taken must be dictated by the indi vi dual cl i ni cal situation; i n the elective scenario, for
example, there may be time for reinforced airway anal gesi a, whereas i n the face of i mpendi ng
respiratory arrest pati ent di scomfort may need to be tol erated. Once the larynx is entered, the
operator may choose a structure, such as the tracheal cari na, to serve as an i dentifyi ng l andmark
as the ETT is advanced. Si mpl y because the FOB has entered the trachea, there i s no guarantee
that the i ntubation wi ll be successful . As noted earl ier, 20 to 30% of ETT advancements are
accompani ed by hangup. Therefore, a pati ent with a criti cal airway shoul d not be i nduced wi th a
general anestheti c wi th the assumption that the ETT wi l l be easy to pass.
Once the ETT enters the trachea, the cl i ni ci an may choose to vi ew the ETT and a chosen anatomi c
landmark si multaneously (e.g., the tracheal carina) to assure correct ETT pl acement before the
FOB i s wi thdrawn.
There have been a number of variations and adjuncts to FOB-ai ded i ntubati on. The reader i s
referred to the pri mary l i terature l isted i n Tabl e 22-21, which is not meant to be exhausti ve.
FIGURE 22-33. Left. Wil l iams ai rway. Middle. Luomanen ai rway.Right. Ovassapi an
fi beropti c i ntubati ng ai rway.
TABLE 22-21 Aids to Fiberoptic-Aided Intubation
TECHNIQUE ADVANTAGE
Al though FOB-ai ded i ntubati on i s a versati l e and vital techni que, there are several pi tfall s, most of
whi ch have been di scussed. Tabl e 22-22 li sts the most common reasons for fail ure of FOB-ai ded
intubati on.
Fl exi ble fi beropti c-ai ded i ntubati on i s a technol ogy-intense techni que. Apart from the del i cate
fiberopti c device, there are cameras, recorders, l i ght sources, and a vari ety of di sposabl e adjuncts
that are typicall y requi red. Dedi cated wheel ed carts, desi gned carry requi red as wel l as opti onal
equipment i n a functi onal arrangement, are avai l abl e (Fi g. 22-34). The cli nici an cal l ed to manage
the pati ent outsi de the operati ng theater may benefi t from portabl e arrangements (Fi g. 22-35).
Endoscopy mask Control ventil ati on mai ntained duri ng or between
attempts at FOB-ai ded i ntubati on
Laryngeal mask Excell ent view of the l arynx and abi li ty to venti late
duri ng or between attempts at FOB-ai ded i ntubati on
Fi beropti c-ai ded retrograde
intubati on
Guidi ng of the FOB wi th a wire known to be enteri ng
the trachea
Retrograde fi beropti c
intubati on
Changi ng a tracheostomy to an oral or nasal tracheal
tube when antegrade i ntubati on i s di ffi cul t or
i mpossi bl e
FOB-ai ded i ntubati on with the
ai d of a ri gi d l aryngoscope
Helpful wi th an obstructing mass or l arge epigl ottis
TABLE 22-22 Common Reasons For Failure During Fiberoptic-Aided Intubation
Lack of experi ence: Not practi ci ng on routi ne intubati ons
Fai lure to adequatel y dry the ai rway: Underdose or rushed techni que
Fai lure to adequatel y anestheti ze the ai rway of the awake pati ent: Secreti ons not dri ed;
rushed technique
Nasal cavi ty bl eeding: Inadequate vasoconstriction; rushed technique; forcibl e ETT
inserti on
Obstructing base of tongue or epi glotti s: Poor choi ce of i ntubati ng ai rway; require chi n
lift/jaw thrust
Inadequate sedation of the awake pati ent
Hangup: ETT too large
Foggi ng of the FOB: Sucti on or oxygen not attached to worki ng channel ; col d
bronchoscope
FIGURE 22-34. The Di fficul t Ai rway SmartKart (Sei tz Techni cal Products, Avondal e, PA) i s
desi gned to transport several fiberscopes as wel l as other diffi cult ai rway equi pment,
accessories, and the electroni cs requi red for video vi ewi ng through i ndirect optical devices.
Rigid Fiberoptic Intubation Devices. Ri gi d fi beropti c devi ces al l ow indi rect views of the l arynx
and act as an ETT gui de for intubati on. More than one-third of all anesthesiol ogi sts have access to
these devi ces.
179
The most commonl y avai l abl e of these devi ces i ncl ude the Bul l ard (ACMI, Santa

Barbara, CA, USA) and WuScope (Pentax Preci si on Instruments, Orangeburg, NY) laryngoscopes
(Fi g. 22-36). Although these laryngoscopes may be used in routi ne cl ini cal si tuati ons, they are
parti cul arl y useful when movement of the pati ent' s head and neck i s i mpossi ble or contrai ndi cated
(e.g., atlanto-occi pi tal joint disease and the spine-i njured pati ent). They are al so appl i cabl e when
there i s a li mi ted oral aperture (0.64 cm i n the case of the Bul lard). These devices consi st of a
ri gid, stainless-steel laryngoscope-l i ke bl ade that encases a fi beropti c cabl e wi th a proxi mal
eyepiece and di stal objective lens. The bl ades have an anatomic curve to match the neutral
positi on of the human oral cavi ty-pharynx-hypopharynx rel ati onshi p. Al ignment of the oral ,
pharyngeal , and tracheal axes is not required. Ill umi nati on i s provi ded by a second fi beropti c
cable transmi tti ng li ght from a battery or free-standi ng l i ght source.
FIGURE 22-35. The Medi pack (Karl Storz Endoscopy, Cul ver City, CA) i ncorporates a l i ght
source, fi berscope camera receiver, and vi deo screen i n one package.
P.629
The Bul lard scope, whi ch comes i n adul t and pedi atric si zes, has been the best i nvesti gated. It
features a fi xed fi beropti c cabl e l ocated on the posteri or aspect of the bl ade. The eyepi ece lens
has an adjustabl e diopter. A worki ng channel al so runs the length of the bl ade. Once the l arynx i s
visual i zed, the ETT i s advanced usi ng a detachabl e styl et, al though other techni ques have been
descri bed.
191
The advantages of the Bul lard scope over tradi ti onal laryngoscope blades in
managi ng the spi ne-i njured pati ent and the obese pati ent have been i nvesti gated.
192, 193, 194

Adequate exposure wi th the Bul lard l aryngoscope may be achi eved after fail ed DL.
195

The Upsher scope i s avai l abl e i n an adul t size as of this writing. Instead of a styl et, the ETT is
hel d and advanced through a C-shaped l umen i n the bl ade. There i s no worki ng channel in thi s
scope. The eyepi ece is focusabl e.
The Wu scope differs from the other devi ces i n that a fl exi bl e fi beropti c endoscope is fitted into a
passage wi thi n a three-part stai nless steel handl e and bl ade. A second, larger l umen accepts the
ETT. A worki ng channel i s posi ti oned alongsi de the endoscope l umen. Two adul t sizes are
manufactured. Once the l arynx i s vi sual i zed and the ETT advanced i nto the trachea, the two
stai nless-steel pi eces of the l aryngoscope bl ade are disassembl ed and removed from the mouth.
FIGURE 22-36. The Bul l ard l aryngoscope, battery handl e, and styl et.
Unl i ke the other two devi ces, the Wu scope can al so be used for nasal i ntubati on by assembl i ng
only the anteri or blade porti on and the handl e. An ETT, previ ousl y pl aced in the pharynx vi a the
nares, can be fi tted i nto the anteri or porti on of the bl ade.
A new generati on of fi beropti c devi ces i s focused on si mpli city and portabi li ty, by i ncorporati ng
optical and l ight source el ements i nto a single styl et-li ke stai nl ess steel sheath. The l ack of a
tongue displ aci ng bl ade and a sucti on/oxygen channel are potenti al di sadvantages. The Bonfi l s
Intubati on Fi berscope (Karl Storz Endoscopy, Tuttingen, Germany) (Fi g. 22-37A) i s a l ong, rigi d
tubul ar devi ce wi th conventi onal opti cal and li ght transmitting fi beroptic el ements.
196
A proxi mal
end eyepi ece (wi th adjustable di opter) can be used wi th the naked eye or fi tted with a standard
endoscopy camera. A cabl e (or battery powered attachment) bri ngs i l lumi nation from an external
l i ght source. The di stal end has a 40 angul ati on. Suction may be appl i ed through a worki ng
channel . The techni que of use repl icates the paragl ossal approach of l aryngoscopy di scussed
previ ously in thi s chapter. The Shi kani Seei ng Opti cal Styl et (Clarus Medical, LLC, Mi nneapol is,
MN) (SOS) has a si mi lar configuration to the Bonfi ls wi th the excepti on that the di stal one-half of
the styl et is mal l eabl e (Fi g. 22-37B). The l i ght source may be sel f-contai ned (a propri etary
powered handl e or a green l i ne

[Rusch Medi cal , Dul uth, Georgi a] laryngoscope handl e) or cabl ed. Unl i ke the Bofi l s, a mi dli ne
approach i s recommended. Studi es have i nvestigated the use of the SOS as a substi tute for the
laryngoscope in routi ne anesthetic cases.
197
The hypotheti cal benefit of thi s practi ce i s the
reduction of unanti cipated diffi cult i ntubations and the mai ntenance of al ternative techni que ski l ls
by i ncorporati ng this or si mi l ar devi ces i nto dai l y practi ce.
180

Glidescope (Fig. 22-38)
New innovati ons i n video del ivery have given rise to the next generation of vi deo-assi sted
laryngoscopy tool s. The Gl idescope (Saturn Bi omedical Systems, Burnaby, BC, Canada) provi des
an electroni cal ly projected image on a vi deo moni tor emanati ng from a video chi p set at the di stal
end of a conventional -li ke l aryngoscope bl ade, but wi th a more acute (60) angul ati on.
198

Il l umi nation is l i kewi se generated at the distal aspect. Thi s confi guration affords several
advantages: (1) It may be handl ed wi th a ski ll set si mi l ar to that used with conventional DL. (2)
The operator' s point of si ght (e.g., the vi deo apparatus) i s posi ti oned cl ose to the di stal blade
aspect (thereby el i mi nating fragil e fi beroptic elements). The operator therefore sees at a
positi on behi nd the tongue, and displ acement as wi th conventi onal DL, i s not necessary in most
cases. Si mil arl y, li ngual tonsi l hyperplasia shoul d not affect the vi sual axi s as it does wi th
P.630
FIGURE 22-37. Opti cal styl ets. A. The objecti ve end of the Bonfil s (Karl Storz Endoscopy,
Cul ver Ci ty, CA). B. The Shikani Seeing Opti cal Styl et (Cl arus Medi cal , Mi nneapol is, MN).
conventi onal DL.
3
(3) The vi deo i mage of the ai rway i s displ ayed on a l ightwei ght portabl e screen.
The vi deo displ ay al l ows for visual izati on by more than one i ndi vi dual (e.g., ai d, mentor, student).
(4) Less stress is i mposed on the airway by vi rtue of reduced compressi ve force directed to the
tongue. (5) An external l i ght source i s not needed. At the time of thi s wri ting, no control led tri al
information is avail able on thi s devi ce.
Video-Macintosh Laryngoscope (Fig. 22-39)
The Vi deo-Macintosh (VM) (Karl -Storz Endovision, Cul ver City, Cal i forni a) consi sts of a
conventi onal -appeari ng l aryngoscope handl e and bl ade. A stai nless-steel shaft bui lt i nto the bl ade
flange accepts a short, fi beroptic cabl e containi ng both l i ght source and opti cal cables. This
fi beropti c cabl e enters the handle where the camera el ements are housed. Two larger (and l ess
fragi le) cabl es exi t proxi mal handl e and connect to standard l i ght- and vi deo-processi ng devi ces
from the same manufacturer. The vi deo i mage i s di spl ayed on a standard NTSC moni tor. Though
the image projected from the VM cl osel y resembl es that seen wi th the naked eye (1) ETT
pl acement i s faci l itated because the operator need not mai ntain an unobstructed li ne of si ght (hi s
eye usi ng the video monitor), (2) external laryngeal mani pul ati on can be observed by a second
operator, and (3) use of the VM is i denti cal standard DL, maki ng the

video facil i ty uni quel y val uable during supervised i nstruction. Though l arge control l ed tri al s have
not been publ i shed at the ti me of this wri ti ng, the VM wi l l li kel y have a significant advantage i n
teaching and some di ffi cul t laryngoscopies.
FIGURE 22-38. A. The Gl i de Scope. B. Gli de Scope screen i n use duri ng l aryngoscopy
(photograph courtesy of Dr. Ri chard Cooper).
P.631
Case 2: Retrograde Wire Intubation
A 65-year-ol d femal e wi th a 60-pack/year history of smoki ng and advanced rheumatoi d arthriti s
presents to the emergency department (ED) in respi ratory di stress. Her oxygen saturati on wi th a
nonrebreather oxygen mask i s 85%. She has a l i mi ted oral aperture (~2.5 cm) and a thyromental
di stance of 6 cm. Al though the cri cothyroid membrane can be palpated, there i s l imited access to
it and the tracheal ri ngs owi ng to a signi ficant cervi cal kyphosis. The sputum i s noted to be bl ood-
ti nged and contai ns thi ckened bronchi al secreti ons. Awake bl i nd nasal i ntubati on i s attempted
twi ce by the emergency medi cine physi cians, i s unsuccessful , and resul ts i n epistaxi s. Retrograde
intubati on of the airway i s performed wi th the pati ent i n a sitting posi tion. After i ni tial local
anesthetic i nfil trati on of the skin over the membrane, on 18 G angiocatheter is advanced over the
mi d-cricothyroi d membrane at an angl e of 45 to the chest. After the free aspirati on of ai r i s
noted, the Teflon sheath of the catheter is advanced i nto the trachea. A 0.035-inch radi ol ogic
gui dewire 110 inches i n l ength is advanced vi a the catheter unti l the proxi mal end emerges from
the mouth. A 7.0 ETT is pl aced over the wi re and i s gui ded into the trachea. The wi re is removed
by pushi ng i t i nto the percutaneous puncture si te and retrieving i t from the proxi mal end of the
tracheal tube. Breath sounds are auscultated over the l ung fi el ds as venti lation is assi sted with
positi ve pressure. Once improved oxygen saturati on i s noted, the pati ent receives sedation with
intravenous mi dazolam (i n divi ded doses, ti trati ng to the sedati ve effect).
Use of the Retrograde Wire Intubation in Airway Management. Retrograde wire i ntubation
(RWI) i nvol ves the antegrade pul l ing or guidi ng of an ETT into the trachea usi ng a wire or
catheter, whi ch has been passed i nto the trachea vi a a percutaneous puncture through the
cricothyroid membrane or the cricotracheal membrane and bl i ndl y passed retrograde i nto the
l arynx, hypopharynx, pharynx and out of the mouth or nose. Retrograde i ntubati on was fi rst
descri bed i n 1960 by Butl er and Ci ri l lo, with the pl acement a red rubber urethral catheter vi a a
previ ous tracheostomy up through the l arynx and out of the mouth.
199
The percutaneous techni que
used today was fi rst described by Waters i n 1963, usi ng an epi dural catheter.
200
In 1993 the
techni que was i ncl uded i n the ASA' s Di ffi cul t Ai rway Al gori thm.
157
The basic equi pment used i n the
retrograde intubati on techni que i s l isted i n Tabl e 22-23.
FIGURE 22-39. The Vi deo Maci ntosh (Karl Storz Endoscopy, Cul ver Ci ty, CA).
TABLE 22-23 Equipment for Retrograde Wire Intubation
Retrograde wi re i ntubati on has been descri bed i n a number of cl i ni cal si tuati ons as a pri mary
intubati on techni que (elective or urgent) and after fai led attempts at di rect l aryngoscopy,
fi beropti c-ai ded i ntubati on, and LMA-gui ded i ntubati on.
201
The most common indicati ons are
inabi l ity to vi suali ze the vocal folds owi ng to blood, secreti ons, or anatomic variations; unstable
cervi cal spi ne, upper airway mali gnancy; and mandi bul ar fracture. Contrai ndicati ons i nclude l ack
of access to the cri cothyroid membrane or the cricotracheal l igament

(because of severe neck deformi ty, obesi ty, mass), l aryngotracheal disease (stenosis, mal i gnancy,
infecti on), coagul opathy, and ski n i nfecti on.
The anatomi c rel ati onshi ps to be considered i n RWI have been descri bed el sewhere i n thi s chapter.
Typi cal l y, the procedure requires 5 mi nutes to perform.
202
Because most cli nici ans are not faci l e
wi th the techni que, i t may take several minutes in i nexperienced hands; therefore, RWI i s
rel ati vely contrai ndicated i n the hypoxi c pati ent. RWI has been used i n elective and emergent
si tuati ons, i n adul ts and i nfants, i n the operati ng room, ED, and the prehospi tal environment.
Compli cati ons reported wi th RWI are li sted i n Tabl e 22-24.
In the current patient (as in Case 1), RWI was chosen i n a setti ng where the pati ent was not
apnei c and was therefore supporti ng her own venti lation and oxygenation, al beit poorl y. The two
cases di ffer i n impendi ng respi ratory fai lure (Case 2) versus FOB-ai ded i ntubati on undertaken i n
an stable si tuati on (Case 1). In many situations, where awake intubati on i s an obvious ini ti al
approach to securi ng the ai rway, there i s l ittle ti me for pati ent preparati on (e.g., the
18 G or l arger angiocatheter
Luer-lock syri nge, 3 mL or l arger
Guidewire:
Preferabl y J-type end
Length: at l east 2.5 times the l ength of a standard ETT (typi cal l y 110 to 120 cm)
Diameter: capabl e of passi ng vi a angi ocatheter bei ng chosen
Other: Scal pel bl ade, nerve hook, Magi l l forceps, 30 si l k suture, epi dural catheter
P.632
TABLE 22-24 Complications Associated with Retrograde Wire Intubation
201

Bl eedi ng (11)
Subcutaneous emphysema (4)
Pneumomediasti num (1)
Breath-holdi ng (1)
Catheter traveli ng caudad (2)
Tri gemi nal nerve trauma (1)
Pneumothorax (1)
administrati on of anti sialagogues, topi cal anestheti cs, and/or sedation). In this regard, RWI does
not requi re a cl ear vi sual fi eld or si gnifi cant pati ent cooperati on and can often be performed wi th
li ttl e analgesi a of the airway. The techni que of RWI di ffers greatl y from other methods of tracheal
intubati on fami l iar to the anesthesiol ogi st. Preferabl y RWI shoul d be l earned on a
si mulator/mannequin model before bei ng attempted i n a pati ent. In addi ti on, unl ess RWI i s
practi ced often, it may be ti me-consuming. For thi s reason, RWI may be a poor choice for rescue
of an acutel y compromised ai rway.
Performing Retrograde Wire Intubation (Fig. 22-40). RWI i s general l y performed wi th the
patient in a supi ne positi on, although the si tti ng posi tion is often used for pati ents in respi ratory
di stress. Extensi on of the head or the neck di splaces the cri coi d and tracheal carti lages anteriorly
and displ aces the sternoclei domastoi d muscl es laterall y, though, as i n Case 2, this may not al ways
be possibl e. The skin shoul d be prepared. If the pati ent i s consci ous, a l ocal anestheti c skin wheel
is made over the puncture si te. Local anesthesia of the ai rway shoul d be admini stered to prevent
di scomfort and airway refl exes as ti me permi ts. In general , topi cal anesthesi a of the trachea,
l arynx, pharynx, and nasal passages i s desi rabl e. Transl aryngeal anesthesi a is a parti cularly
convenient technique si nce a percutaneous entry of the trachea i s requi red duri ng the RWI.
Structures above and below the vocal fol ds are anesthetized duri ng the ensui ng pati ent cough i f a
local anestheti cfil l ed syri nge is used to facil i tate the recogni ti on of appropri ate pl acement

(wi th tracheal ai r bubbl es) and then i s injected to provi de airway anesthesia (see Fi g. 22-29B).
203

As noted earl i er, the CTM and CTL are both potenti al si tes for translaryngeal puncture. Al though
the CTM has the advantage of being di rectl y anteri or to the large posterior surface of the cricoid
carti lage, thereby protecting the esophagus from a puncturi ng needl e, i t pl aces the needl e i n cl ose
proxi mi ty (0.9 to 1.5 cm) to the vocal folds and hence al lows for a somewhat smal l er margi n of
P.633
FIGURE 22-40. The sequence of retrograde wi re intubati on after the cricothyroi d or
cricotracheal li gament i s i dentified and a percutaneous puncture i s performed wi th air
aspi rati on (see Fi g. 22-29B). (A) The retrograde devi ce (twi sted wi re, Cook Cri ti cal Care) i s
advanced until (B) i t emerges from the mouth or nose. (C) The wi re i s cl amped at the
entrance site and the endotracheal tube i s advanced over the wi re in an antegrade fashion.
(D) The wire i s removed, leavi ng the tracheal tube i n place.
error at the ti me of the intubati on.
Although classi cal l y performed wi th a Tuohy needl e and epi dural catheter, the advent of small er
di ameter, stiffer wi res wi th atraumatic J ti ps has made the gui dewi re modi fi cati on popul ar.
These gui dewi res are typi cal ly 0.032 to 0.038 i nches i n di ameter, bei ng abl e to pass through an
18-G intravenous catheter. The typi cal l ength is between 110 and 120 cm. The only requirement
for l ength i s that the wi re be more than twice as long as the tracheal tube to be used, so that no
matter where in i ts course al ong the wi re the tracheal tube should be, both ends of the wi re are
al ways accessi ble to the operator. Ki ts that conveni ently i ncorporate al l the necessary equi pment
are avai l abl e (Cook Cri tical Care, Bloomi ngton, IN).
The needl e/catheter approaches the trachea at 90 to the coronal and sagi ttal planes i f possi bl e
(as it was not i n Case 2). In thi s ori entati on, the needl e i s li kel y to i mpact the posterior aspect of
the cri coi d carti l age i f advanced too far, and not puncture the esophagus. Additi onal l y, thi s angl e
wil l hel p to avoi d trauma to the near-lyi ng vocal folds.
After the percutaneous puncture is made and the trachea identi fi ed by free air aspi rati on, the
catheter i s angled cephal ad and the wi re is advanced (J-ti p) into the trachea until i t emerges from
the mouth or nose. The wire may need to be retri eved from the mouth with a sweepi ng finger,
Magi ll forceps, or nerve hook. Any obstructi on to advancement of the wire shoul d prompt re-
eval uation of the angl e of the catheter

and the posi ti on of the head and neck (e.g., catheter di rected posteri or and/or caudad, neck
flexed). Coughi ng typi cal l y heral ds caudad travel i ng of the wi re. If the wi re i s retracted and found
to be bent, i t i s prudent to procure a new one. When compl ai nts of pai n are encountered above
the level of the larynx, i t i s typi cal ly a resul t of the wi re passing i nto an i nadequatel y prepared
nasal cavi ty. Options i ncl ude retracting the wi re modestly and aski ng the patient to open the
mouth and maxi mall y protrude the tongue duri ng the readvancement, reachi ng into the
oropharynx to retri eve the wi re, or pati ently repreparing the nasal passages. Once the wi re is
sati sfactori ly retrieved, placement of the tracheal tube may be performed usi ng the wi re i n a
number of fashions, dependi ng on the operator's preference and previ ous experience. Tabl e 22-25
li sts common techniques, together wi th thei r advantages and di sadvantages. Detai l s of these
techniques have been descri bed el sewhere.
204

P.634
TABLE 22-25 Techniques of ETT Advancement Over a Retrograde Wire
TECHNIQUE ADVANTAGE DISADVANTAGE
Wi re travels through entire
main lumen of the ETT
Standard
technique
Margin of error
a
equals
di stance from vocal fol ds to
puncture si te
No stylet after removal of wi re
Rai lroading
b
can occur
Wi re placed into ETT l umen vi a
Murphy eye
Increased margin
of error
Cannot use stylet (below)
Decreased rai l roadi ng
Wi re enters di stal end of ETT
and exi ts via Murphy eye
Decreased
rail roading
Margin of error equal s di stance
from vocal fol ds to puncture
si te
In the case reported, other techni ques may have been considered. Al though i ndi rect vi sual devi ces
(fl exi bl e fi beropti c bronchoscope, ri gi d fi beropti c l aryngoscope) may have al so been hel pful in thi s
case, three el ements worked against thei r use: (1) ti ssue trauma from repeated attempts at bl ind
nasal intubati on produced a bl oody ai rway, frustrati ng the use of these devi ces; (2) the patient
was unable to cooperate owing to her respiratory distress; (3) because of the i mpendi ng
respiratory fail ure, there was li ttl e time for adequate ai rway analgesi a. A coughi ng, gaggi ng,
conscious pati ent makes fiberopti c techni ques nearl y i mpossi bl e. Strai ni ng and coughi ng duri ng
fiberopti c intubati on attempts have resul ted i n Mal l ory-Wei ss tears of the esophagus, resul ting i n
si gni fi cant hemorrhage.
Bl ind nasal i ntubation was the fi rst technique attempted i n thi s pati ent. Unti l recentl y, bl i nd nasal
intubati on has been a stapl e of airway control , especi all y in the emergency department, where i t
has been l argel y suppl anted by rapi d-sequence intubati on.
205
Thi s techni que requi res si gni fi cant
anal gesi a of the nasal passages i n the awake pati ent. Success i s far more l i kel y i n the
Cannot use stylet (below)
ETT exchange styl et is
pl aced over wi re, pri or to
pl acement of ETT
Decreased
rail roading
Cost
Can use styl et to vastl y i ncrease margin of error
once wire i s removed
Fi beropti c bronchoscope i s
pl aced over wi re pri or to
pl acement of ETT
Decreased
rail roading
Cost
Can use styl et to vastl y i ncrease margin of error
once wire i s removed
Vi sual i zati on
Silk suture No rai l roadi ng May be di ffi cul t to place sil k
suture
Margin of error i ssues reduced
Smal l ETT Reduced
rail roading
May not be cl i ni cal ly adequate
a
Margi n of error refers to the di stance bel ow the vocal fol ds that the endotracheal tube
extends at the time that the gui dewi re i s removed. If thi s distance is not adequate,
there i s a ri sk of i mmediate extubati on.
b
Rai lroadi ng refers to the di fferenti al si ze of the gui dewi re and the tracheal tube. A large
di screpancy i n si ze al l ows for a cl eft, which may entrap the epigl ottis, arytenoi d
carti l ages, aryepi gl otti c folds, or vocal folds, hinderi ng intubati on attempts.
spontaneousl y breathing pati ent. Wi th the head i n the Magi l l posi ti on, the ETT i s advanced i nto the
nares, nasal passage (keepi ng the ETT bevel al ongsi de the nasal septum), and i nto the pharynx.
Breath sounds are auscul tated from the ETT, and i ts positi on adjusted to keep them maxi mized.
The pati ent' s head and l arynx can be mani pul ated external ly as necessary.
Case 3: Esophageal Tracheal Combitube
A 55-year-ol d mal e wi th a hi story of ci rrhosi s and esophageal vari ces requi res ai rway control as a
resul t of acute, recurrent upper gastrointestinal bl eedi ng. Apart from fresh bl ood i n the ai rway,
physi cal exam of hi s external airway i s consi stent wi th a routi ne l aryngoscopy. Furthermore, he
had been i ntubated for si mi l ar events i n the past. After a rapid-sequence induction, the l arynx
cannot be visual ized on three laryngoscopies owi ng to fresh blood emanati ng from the esophagus.
On al l three attempts, the ETT i s advanced bl i ndl y, and the absence of breath sounds over the
thorax together wi th the presence of copi ous bl ood i n the ETT l eads to the di agnosi s of esophageal
intubati on. A l arge adul t-si zed esophageal tracheal Combi tube (Tyco Heal thcare, Mansfiel d, NY) is
requested, bl i ndl y i nserted i nto the ai rway, and the pharyngeal and distal cuffs are i nflated.
Ventil ati on through the pharyngeal perforations l umen (bl ue) produces bi lateral breath sounds to
auscul tati on, and the oxygen saturati on increases to >90%. Copious bl ood i s sucti oned from the
esophageal l umen. The pati ent i s transported to the angi ography suite where his esophageal
vari ces are embol i zed. The esophageal tracheal Combi tube is removed and the pati ent i s i ntubated
with direct l aryngoscopy.
History of the Tracheal Esophageal Combitube. The tracheal esophageal Combi tube was
developed from the concept of the esophageal obturator (ESO) airway, whi ch was i ntroduced i n
1968.
206
The ESO consi sted of a tracheal -li ke tube,

34 cm i n l ength, wi th an i nflatabl e cuff at i ts seal ed, di stal end. It was i nserted bl i ndl y i nto the
esophagus, so that the cuff lay at a l evel caudad and posterior to the tracheal carina. Sixteen
holes communicati ng wi th the central l umen were posi ti oned so as to be i n the hypopharynx when
inserted to the proper depth. A facemask at the proxi mal end was used to seal the ai rway.
Ventil ati on was achieved by applying posi ti ve pressure to the proximal open aperture, where it
emerged from the facemask. Unfortunately, significant probl ems/compl icati ons became apparent
as the ESO came into common practi ce.
These shortcomi ngs of the ESO were addressed by Dr. Mi chael Frass, a cri ti cal care physi cian in
Vienna, Austri a, i n 1986.
207
The facemask of the ESO was replaced by an oropharyngeal ball oon,
seali ng the upper airway and anchori ng the device agai nst the hard pal ate. As wi th the ESO,
perforations at the hypopharyngeal l evel al l owed egress of ai r near the level of the larynx. A
second l umen, patent from proxi mal to di stal end, wi thout perforati ons was substi tuted for the
bl i nd esophageal tube of the ESO. As wi th the ESO, a cuff at the di stal aspect of the esophageal
lumen occludes the esophagus. This desi gn, named the Tracheal Esophageal Combi tube, i s
functi onal i f i ntroduced into the esophagus (ventil ati on bei ng achi eved through the esophageal
lumen, vi a the hypopharyngeal perforati ons) or i n the trachea (ventil ati on bei ng achi eved through
the tracheal lumen, vi a the di stal aperture). In ei ther case, the proximal ball oon seal s both the
oral and nasal passages, and the distal conventi onal tracheal tube cuff isolates the respiratory
system from the gastrointestinal system. The devi ce i s avai l abl e i n two si zes: the 41Fr size is used
for l arger adults (hei ght >5.5 feet) and the 37Fr size i s used for adul ts 4 to 6 feet tall (Fi g. 22-
41). Though a si ngl e-use devi ce, Combitube reprocessi ng and reuse has been reported.
208

P.635
Use of the Esophageal Tracheal Combitube. The esophageal tracheal Combi tube i s i nserted
bl i ndl y. The operator li fts the lower jaw and tongue anteri orly wi th one hand, and the
esophageal tracheal Combi tube i s i nserted with a downward, caudad-curved moti on until the
proxi mal depth i ndi cator (two bl ack ri ngs pri nted on the doubl e l umen tube) come to rest at the
level of the teeth. The oropharyngeal bal loon i s infl ated wi th 100 mL of ai r through a bl ue pl asti c
pi l ot bal loon (85 mL i n the small adul t size) whi l e the di stal cuff i s i nfl ated with 5 to 15 mL (vi a a
whi te pil ot bal loon). An ambu bag or anesthesi a ci rcuit i s attached to the proximal end of the
esophageal lumen (constructed of bl ue pol yvi nyl chlori de), and venti l ati on i s confi rmed by
auscul tati on or other means. Because 90% of esophageal tracheal Combi tube placements resul t i n
an esophageal positi on, venti l ati on occurs vi a thi s l umen' s hypopharyngeal perforations. If no
breath sounds are auscul tated and/or gastri c infl ati on i s noted, the esophageal tracheal Combi tube
has been posi ti oned i n the trachea. Wi thout repositi oning, venti l ati on i s changed to the di stal end
of tracheal l umen (clear pol yvi nyl chl oride). If no maneuver i mproves venti lation, the devi ce is
most l ikely i n the esophagus, but has been advanced too deepl y, wi th the oropharyngeal cuff
obstructing the ai rway.
209
In thi s case, the cuffs shoul d be defl ated, the devi ce wi thdrawn 2 cm,
and the venti l ati on sequence repeated.
Advantages of the esophageal tracheal Combi tube i ncl ude rapi d ai rway control , ai rway protection
from regurgi tati on, ease of use by the inexperi enced operator, no requi rement to visual ize the
l arynx, and bei ng abl e to mai ntain the neck in a neutral positi on, though cervi cal spi ne movement
may be greater than that seen with the LMA, LMA-Fastrach, and fl exi bl e fi berscope.
210
It has been
shown to be useful in the patient with massi ve upper gastroi ntesti nal bl eedi ng or vomi ting, and as
a rescue devi ce i n fail ed rapi d-sequence i nducti on or unanti ci pated di ffi cul t i ntubati on. It is al so
useful i n the morbi dl y obese, in acute bronchospasm, duri ng cardi opul monary resusci tati on, and
for prol onged venti l ati on after airway
rescue.
129, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 211, 212, 213, 214, 215, 216, 217
Several seri es have
demonstrated the effectiveness esophageal tracheal Combitube in prehospi tal management of the
ai rway.
218, 219, 220
Urtubia et al have used the esophageal tracheal Combitube for el ecti ve surgery
with a hi gh success and low compl i cati on rate.
221

Techni ques for exchange of the esophageal tracheal Combi tube (after pati ent stabil i zati on) for an
endotracheal tube have been descri bed.
222

Contraindicati ons to use of the esophageal tracheal Combi tube use include esophageal obstruction
or other abnormal i ty, i ngesti on of causti c agents, upper ai rway forei gn body or mass, l ower ai rway
obstruction, hei ght l ess than 4 feet, and an i ntact gag refl ex. Since the esophageal tracheal
FIGURE 22-41. A. The esophageal tracheal Combi tube. B. The fi beropti c port of the Easy
Tube.
Combitube includes l atex i n i ts construction, i t should not be used in pati ents wi th l atex al l ergy.
Compli cati ons associ ated wi th the esophageal tracheal Combitube have i ncl uded l acerati ons to the
pyri form sinus and esophageal wal l resul ti ng i n subcutaneous emphysema, pneumomedi asti num,
pneumoperitoneum, and esophageal rupture.
223, 224, 225

A devi ce si mi l ar to the esophageal tracheal Combi tube has been avai l abl e i n many parts of the
worl d si nce 2003.
226
The Easy Tube (EzT) (Rusch Internati onal , Kernen, German) i s di stributed i n
two si zes, 41ch for pati ents above 130 cm i n hei ght and 28ch for pati ents 90 to 130 cm i n hei ght.
Unl i ke the Combitube, the distal lumen of the EzT i s desi gned to resembl e an ETT (incl uding a
Murphy eye). The pharyngeal aperture i s desi gned to all ow easy passage of a fiberscope (or
sucti on catheter) (Fi g. 22-41B). The EzT was desi gned for routi ne anestheti cs as wel l as
emergency and cannot intubate/cannot ventil ate si tuati ons. Contrai ndi cati ons to EzT use are
identi cal to those for the Combi tube. Though i t may be i nserted bl i ndl y, i t i s desi gned to be used
with a laryngoscope (much li ke a standard ETT). Unl i ke the Combi tube, i t i s latex free.
Case 4: Failed Rapid-Sequence Induction and the LMA
A 39-year-ol d mal e presents for el ecti ve uvul opharyngopal atoplasty. He has no previ ous surgi cal
hi story. Hi s maxi mal inci sor gap i s 5 cm, thyromental di stance i s 7 cm, and hi s oropharyngeal
view i s a SamsoonYoung Cl ass 2. There i s no l imitati on i n head and neck fl exi on and extensi on.
During a sl eep apnea study, he had 15 apnei c events each hour. The patient has a si gnifi cant
hi story of gastroesophageal refl ux, and rapi d-sequence i nducti on i s pl anned. After the
administrati on of pentothal, succi nylchol ine, and cricoi d pressure (Sel l ick maneuver), di rect
laryngoscopy wi th a Maci ntosh number 3 laryngoscope bl ade reveals a l arge epi gl otti s obscuring
the vi ew of the vocal folds (CormackLehane Grade 3).
125
Si gni fi cant hyperpl asi a of the base of
the tongue, which prevents i ts ful l di spl acement, i s al so noted. The BURP maneuver does not
improve the view.
122
A Maci ntosh 4 and Mi l ler 3 bl ades are used and do not improve the view.
Oxygen saturati on, whi ch was 100% pri or to i nduction, i s now 92%, and facemask ventil ati on i s
initi ated wi th the Sel l i ck maneuver in place. Compl ete obstruction to venti l ati on i s encountered,
despi te chin and/or jaw l ift, two-person venti lation, and a reducti on i n the degree of cri coi d
pressure. The oxygen saturati on fall s to 85% and a si ze 5 LMA (whi ch had been prepared pri or to
the induction of anesthesi a) i s inserted wi th the techni que as descri bed by the i nventor.
Immedi ately, a clear ai rway is establ i shed, and the Sell i ck pressure remai ns i n place. A second
dose of pentothal i s admini stered, and the pati ent i s i ntubated by the bl i nd passage of a 7.0-id
ETT vi a the LMA. The LMA is then removed using a Cook airway exchange catheter (Cook Cri ti cal
Care, Bl oomington, IN) as a styl et, and the surgi cal case proceeds.
The LMA in the Failed Airway. One clear advantage of LMA use is i n the fail ed ai rway. There
have been many reported (and unreported) cases of fai l ed i ntubati on and fai l ure to ventil ate by
facemask i n whi ch the ai rway was rescued wi th an LMA.
227, 228
Parmet et al estimate that
1:800,000 fail ed airway patients cannot be managed wi th an LMA, provi ding an 80-fol d i ncrease i n
margi n of safety over the oft-noted 1:10,000 patients who cannot be venti lated by mask nor
i ntubated by tradi ti onal means.
162
Likewi se, a weal th of li terature descri bes the use of the LMA i n
el ecti ve di fficul t airway management in awake and unconsci ous pati ents, i n anti ci pated and
unanti ci pated si tuati ons, in cervical spi ne i njury, and in pedi atri c dysmorphi c
syndromes.
103, 104, 162, 229, 230
The characteri sti cs of the LMA that underli e i ts superi ority as a tool in
the diffi cult ai rway armamentari um are that i t is wel l tol erated by the patient, si mul ati ng the
natural distension of the hypopharyngeal tissues by food, and that i ts inserti on fol l ows an intri nsic
pathway, requi ri ng no ti ssue di storti on (as wi th l aryngoscopy), whi ch may not be possi ble i n al l
patients. Fi nal ly, i t is a bl i nd techni que not hi ndered by bl ood, secreti ons, debri s, and edema from
previ ous attempts at l aryngoscopy.
229
Because the LMA' s ease of i nserti on i s not dependent on
anatomy that can be assessed on routi ne physical exam, typi cal airway assessment measures do
not appl y to i ts appl i cati on.
230
The major di sadvantage of the LMA i n resusci tati on i s the lack of
mechani cal protection from regurgi tation and aspi rati on. Lower rates of regurgi tation during CPR
(3.5%) than with the bag-val ve mask venti lation (12.4%) have been shown.
52, 231, 232, 233
Even in
the face of regurgi tati on, pul monary aspi rati on i s a rare event wi th the LMA.
234
Unfortunately, the
P.636
use of the Sel li ck maneuver may prevent proper seating of the LMA in a mi nori ty of
instances.
235, 236, 237
Thi s may requi re the bri ef removal of the cri coi d pressure unti l the LMA has
been properl y seated. Cri coi d pressure i s effecti ve wi th an LMA i n si tu. Had it been avail able, the
Fastrack-LMA woul d also have been an i deal devi ce in thi s case scenario.
Case 5: Deviation from the Difficult Airway Algorithm
Thi rteen hours after admi ssi on to the i ntensive care unit, a 76-year-ol d femal e who had sustai ned
trauma to the face, head, and neck in a motor vehi cle accident i s noted to have progressive
decl ine i n her level of consciousness and respi ratory effort. On examinati on, there appears to be
an adequate i nteri nci sor gap and thyromental di stance. The oropharyngeal vi ew and range of
moti on of the head and neck cannot be eval uated. Owi ng to the i nabi l ity to ful ly evaluate the
ai rway wi th respect to ease of i ntubati on, an awake procedure is chosen. Fi beropti c devi ces are
not considered usable because of the presence of fresh and cl otted bl ood i n the mouth as a resul t
of conti nued epistaxis. Other ai rway techni ques that requi re si gni fi cant pati ent preparation are not
consi dered because of the rapi d progression of the pati ent' s respiratory fail ure. Addi tional ly, the
presence of fresh bl ood i n the oral and pharyngeal cavi ties wi l l hi nder adequate dryi ng and
anal gesi a. Bl i nd nasal intubati on i s consi dered contrai ndi cated based upon the obvious faci al
trauma and the ri sk of cri bri form pl ate di srupti on. Neither equi pment for retrograde intubati on nor
the tracheal esophageal Combi tube is readi l y avai l abl e. A l i ghted styl et i ntubati on gui de i s
avai labl e, but no cl i ni ci an present is experi enced wi th thi s technique. Al though the mental status
change i s bel i eved to refl ect an i ntracranial process (e.g., intracrani al hypertensi on), the ri sk of
compl ete l oss of the ai rway i s judged to be the primary cl i ni cal hazard. Awake di rect l aryngoscopy
is attempted wi th manual in-li ne stabi l izati on of the neck. After cl eari ng fresh bl ood from the
pharynx with a Yankauer suction catheter, a CormackLehane Grade 3 l aryngeal vi ew i s obtained;
but because of pati ent resi stance (bi ti ng on the l aryngoscope and movement), tracheal i ntubati on
is not achieved. The deci si on i s made to proceed wi th rapi d-sequence i nducti on and intubati on,
with preparations made for an emergency tracheostomy. After surgi cal preparation of the neck and
preoxygenation, intravenous succinyl chol i ne and etomi date are administered, direct l aryngoscopy
is undertaken, the l arynx i s easil y vi sual i zed, and the trachea i s i ntubated.
Muscle Relaxants and Direct Laryngoscopy. In the case descri bed, the use of muscl e rel axants
si gni fi cantl y improved the abi l ity to vi suali ze the l arynx.
238, 239, 240
In a recent study, the use of
muscle rel axants duri ng a di rect l aryngoscopy increased the success rate of intubati on and was
associated wi th fewer i nci dents of ai rway trauma, intubati on attempts, esophageal intubati ons,
aspirati on, and even death.
241
Intubati ng condi tions wi th and wi thout muscl e rel axati on have been
investi gated i n few wel l -control led trial s because the superi or i ntubati ng condi tions achi eved wi th
muscle rel axants has discouraged i ncl usion of control groups.
242
The effects of muscle rel axation
acti ons that improve l aryngoscopi c vi ew i ncl ude al l owing complete temporomandi bul ar joi nt
rel axation and openi ng, anteri or movement of the epigl otti s, and wi deni ng of the l aryngeal
vesti bul e and laryngeal si nus.
243, 244
In additi on, the finding that laryngoscopic sti mulation of the
pharyngeal

muscul ature causes the upper ai rway l umen to appear smal l i s offset by the use of relaxants.
Leaving the Algorithm. The si tuati on descri bed i n Case 5 is unusual i n that rapi d-sequence
i nducti on was attempted because the cl i ni cal si tuati on had devi ated from the ASA Di ffi cul t Ai rway
Algori thm owing to the progressi ve nature of the ai rway compromi se. The si tuati on was more akin
to the crash airway descri bed by Wal l s et al .
205
In thi s case, the i nstituti on of muscl e rel axati on,
whi ch might be consi dered contrai ndi cated i n the apparentl y di ffi cult-to-intubate pati ent, al lowed
for ful l visual i zati on of the l arynx. Knowing that fai l ure to i ntubate i n thi s case woul d result i n
probabl e l oss of the airway, the cl i ni ci an was prepared for cricothyroi dotomy. Although the ASA's
Difficult Ai rway Al gorithm i s a valuabl e tool i n the process of approachi ng the diffi cult ai rway, the
cl i ni ci an must al ways be prepared for the case that does not fit the mold. As stated earl i er,
adaptabi li ty i n a rapidl y changing cli ni cal si tuati on i s cri tical to the success of airway
management. Al so of interest i n thi s case was the avai labi li ty of a l i ghted styl et for use in si mi lar
di fficul t ai rway scenari os. Al though this device may have been useful i n the current case, no
P.637
cl i ni ci an present was famil i ar with its operati on. A criti cal si tuati on i s not an occasi on for tryi ng an
unfamil i ar technology.
Ot her Devi ces
An ever-increasi ng number of ai rway management devi ces are commerci al l y avail able. Although
encycl opedic coverage of these tool s i s beyond the scope of thi s chapter, a revi ew of the more
establ i shed equi pment fol l ows.
Lighted Stylets
These devices rel y on transil l uminati on of the ai rway. A l ight source introduced i nto the trachea
wil l produce a wel l -ci rcumscri bed glow of the ti ssues over the l arynx and trachea. The same l ight
pl aced in the esophagus wi ll produce no or a diffuse l i ght. A number of devi ces have become
avai labl e, including di sposabl e, partl y di sposabl e, and ful l y reusabl e systems. Although there are
many reports of successful i ntubati on using these devi ces, some common probl ems have been
noted: In general , the operati ng theater l i ghts must be di mmed to best appreci ate the
ci rcumscri bed glow; a styl et tip successful ly placed i n the trachea, but not poi nting i n an anteri or
direction, may give a false-negati ve i mpressi on; it is often difficult to remove the semi ri gid styl et
from the ETT after i ntubati on.
Airway Bougie
These encompass a series of soli d or holl ow, semi mall eable styl ets that may be bl indl y
mani pul ated i n to the trachea. An ETT i s then threaded over the bougi e and i nto the trachea.
These bougies are generall y low i n cost and highly portabl e. The Eschmann i ntroducer (Eschmann
Heal th Care, Kent, England) was i ntroduced i n 1949. It i s 60 cm l ong, 15Fr-gauge, and angl ed 40
degrees 3.5 cm from i ts di stal end (Fi g. 22-42). It i s constructed from a woven pol yester base,
whi ch i s mal leable. It can be very hel pful when the l arynx cannot be vi suali zed with laryngoscopy.
The i ntroducer (al so known as the gum el asti c bougi e) can be mani pul ated under the epi gl otti s, i ts
angled segment directed anteri orl y toward the l arynx. Once i t has entered the l arynx and trachea,
a di sti nctive cl i cking feel i s el ici ted as the ti p passes over the cartil aginous structures. A si mi l ar
device, the Frova Intubati ng Introducer (Cook Criti cal Care, Bl oomi ngton, IN), is a di sposabl e
device, with an opti onal stiffeni ng styl et and a holl ow bore. The i nternal l umen al lows for the
insufflation of oxygen, the detection of carbon di oxide, and the use of a sel f-infl ati ng bulb to
detect i nadvertent esophageal pl acement.
245

FIGURE 22-42. Frova Intubati ng Introducer (Cook Cri ti cal Care, Bl oomi ngton, IN)
Mi ni mal l y I nvasi ve Tr anst r acheal P r ocedur es
When access to the airway from the mouth or nose fai ls or is unavai l abl e (e.g., maxi l lofaci al,
pharyngeal , or laryngeal trauma, pathology, or deformi ty), emergency access vi a the extrathoraci c
trachea i s a feasi ble route to the ai rway. The clini ci an must be fami li ar with these al ternative
techniques of oxygenation and venti lation. The decisi on to proceed with an i nvasive procedure can
be difficult, and most cli nici ans wi ll hesi tate at potential ly grave ri sk to the patient. One shoul d
consi der becoming faci l e wi th at l east one of these techniques in el ective situations (such as
transtracheal aspi rati on for ai rway analgesi a or elective retrograde i ntubation or, consi der, for
example, assisting a surgical coll eague on a tracheostomy). Al though tracheostomy and
cricothyroi dotomy are beyond the scope of this chapter, percutaneous techni ques wi l l be
consi dered.
Cri cothyroidotomy, cri cothyrotomy, coniotomy, and mi ni tracheostomy are synonyms for
establ i shing an ai r passage through the cri cothyroi d membrane. The anatomy of thi s structure and
those surrounding i t was di scussed earl i er i n thi s chapter. Although cri cothyrotomy i s the
procedure of choi ce in an emergency si tuati on, i t may al so appl y to an el ective situation when
there i s li mited access to the trachea (e.g., severe cervi cal kyphoscoli osi s). Cricothyrotomy i s
contrai ndi cated in neonates and chi l dren under 6 years of age, and i n pati ents wi th l aryngeal
fractures.
Percutaneous Transtracheal Jet Ventilation
Percutaneous transtracheal jet venti lation (TTJV), as a form of cricothyroi dotomy, i s the most
famil i ar to anesthesi ol ogi sts.
246
The ASA Di ffi cul t Airway Al gori thm l i sts transtracheal jet
ventil ati on as an opti on i n the cannot mask venti late/cannot intubate si tuati on. TTJV i s a si mpl e
and rel ati vel y safe means to sustain the pati ent's l i fe i n this cri tical si tuati on.
247
An intravenous
catheter of 12-, 14-, or 16-gauge, attached to a 5-mL or larger empty or parti al l y fl ui d-fi l l ed
(sal i ne or local anestheti c) syri nge should be used to enter the airway. The pati ent i s posi ti oned
supine, wi th the head mi dl ine or extended on the neck and thorax (if not contrai ndi cated by the
cl i ni cal situation). After aseptic preparati on, l ocal anesthetic i s i njected over the cricothyroi d
membrane (if the pati ent i s awake and time permits). The ri ght-handed cli nici an stands on the
ri ght side of the pati ent, facing the head. The cl inici an can use hi s or her nondomi nant hand to
stabi l ize the l arynx. The catheter-needle is advanced at ri ght angl es to all pl anes in the caudad
third of the membrane. From the moment of ski n puncture there shoul d be constant aspi rati on on
the syri nge pl unger. Free aspi ration of

ai r confirms entrance i nto the trachea. Unless there i s significant pul monary fl ui d (e.g., bl ood,
aspirated gastric contents, or water from drowni ng), the aspi ration of tracheal air shoul d be
incontroverti bl e. The needle-catheter assembl y should be advanced sl ightly, and subsequently the
catheter advanced ful l y i nto the ai rway al one. Al though this techni que has been descri bed wi th
common angi ocatheters, dedi cated devi ces made of ki nk-resi stant material s and wi th accessory
ports are avai labl e (Fi g. 22-43).
P.638
Once the catheter has been successful ly pl aced i n the ai rway, an oxygen source is attached. The
cl i ni ci an may have several opti ons i n this regard. If a hi gh-pressure system i s avai l abl efor
example, a metered and adjustabl e oxygen source with a hand-control led val ve (Fi g. 22-44) and a
Luer-lock connector25 to 30 psi of oxygen (central hospi tal suppl y or regul ated cyl i nder) can be
del i vered directl y through the catheter, wi th i nsuffl ations of 1 to 1.5 seconds at a rate of 12
insuffl ati ons per mi nute. If a 16-gauge catheter has been placed, thi s system wil l deli ver a tidal
vol ume of 400 to 700 mL. Low-pressure systems cannot provi de enough fl ow to expand the chest
adequatel y for oxygenati on and venti l ati on (e.g., ambu bag: 6 psi , common gas outl et: 20 psi).
Low-pressure oxygen flow meters can be used for TTJV. These systems are capabl e of del i veri ng a
bri ef (0.5 second) 30 psi burst pressure, whi ch qui ckl y decays to 5 psi or l ess.
248
If this oxygen
source is to be used an I:E rati o of 1:1 with a rate of 30 to 60 breaths per mi nute shoul d be used
to assure adequate burst pressures.
FIGURE 22-43. The Cook Cri ti cal Care transtracheal ventil ati on catheter and Enk Fl ow
Modul ator (Cook Criti cal Care, Bloomi ngton, IN).
FIGURE 22-44. System for regul ati on of a hi gh-pressure oxygen source for transtracheal jet
ventil ati on.
The Mual lem Jet Venti l ator (Dr. Mual lem Lebanon) automates respi ratory cycles duri ng jet
ventil ati on. Thi s device was devel oped pri mari l y for use during bronchoscopy but coul d be
appl icable to TTJV.
249

Speci al i zed percutaneous cri cothyroi dotomy systems have been devel oped that i mprove the ease
of this techni que. These devi ces general l y provi de a l arge-bore access that is adequate for
oxygenati on and ventil ati on wi th l ow-pressure systems. The Mel ker emergency cri cothyroi dotomy
catheter set (Cook Cri ti cal Care, Bl oomington, IN) uses a Seldi ngercatheter-over-a-wire
technique fami li ar to most anesthesi a practi tioners (Fi g. 22-45). The set comes i n a variety of
cannul a si zes (3.5-, 4-, and 6-mm internal diameter cuffed and uncuffed). Preparation and
positi oning of the patient are the same as with needl e cri cothyroi dotomy. A 1- to 1.5-cm verti cal
inci sion of the ski n onl y is made over the lower third of the cricothyroi d membrane. Aiming 45
caudad, a percutaneous puncture of the subcutaneous tissue and cri cothyroi d membrane is made
with the provi ded 18-gauge needl e-catheter assembl y and syri nge. After ai r is aspirated, the
catheter i s advanced i nto the trachea. The provi ded gui dewi re is i nserted through the catheter and
into the trachea. The catheter i s removed and the tracheal cannul a, fi tted i nternal l y with a curved
di l ator, is threaded onto the wire. The dil ator is advanced through the membrane usi ng firm
pressure. Si gni fi cant resi stance to its advancement may indicate that the ski n inci sion needs to be
extended. Once the cannula-di l ator has been full y inserted, the dil ator and wi re are removed. The
15-mm ci rcuit adapter end of the cannul a is now attached to an ambu bag or anesthesi a ci rcuit.
Other percutaneous systems i ncl ude Nu-Trake (Wei ss Emergency Airway System; Internati onal
Medi cal Devi ces) and the Qui ckTrach transtracheal catheter (VBM Medi zi ntechnik GMBH).
Nonneedl e puncture techniques are beyond the current di scussi on.
CONCLUSION
Apart from moni tori ng, the management of the routine patient ai rway i s the most common task
of the anesthesi ol ogisteven duri ng the admini stration of regi onal anesthesia, the ai rway must be
moni tored and possi bl y supported. Unfortunately, routi ne tasks often become negl ected tasks in
terms of the care and vigi l ance that i s afforded each event. But the consequences

of a l ost ai rway are so devastating that the cl i ni cian can never afford a l ackadaisi cal approach.
Al though the ASA' s Task Force on the Di ffi cul t Ai rway has gi ven the medi cal communi ty an
immensel y val uable tool i n the approach to the pati ent with the di ffi cul t ai rway, the Task Force' s
FIGURE 22-45. The Mel ker cri cothyroi dotomy cannul a and curved di alator (Cook Cri tical
Care, Bl oomi ngton, IN). The guidewire i s not shown.
P.639
al gori thm must be vi ewed as a starting poi nt onl y. Judgment, experi ence, the cl inical si tuati on,
and avai l abl e resources al l affect the appropri ateness of the chosen pathway through, or
di vergence from, the al gorithm. The cl i ni cian need not be expert in all the equi pment and
techniques currently avai l abl e. Rather, a broad range of approaches shoul d be mastered, so that
the fail ure of one does not present a road block to success.
Simil arl y, the medi cal manufacturi ng communi ty, and the far-si ghted cl i ni cians who suppl y i t wi th
concepts for airway management products, has suppl i ed a vast array of devices. Many represent
redundancy i n concept, and each has its supporters and detractors. No one devi ce can be
consi dered superior to another when considered i n i sol ati on. It i s the cl i ni cian and hi s or her
resources (both equi pment and personnel ) and judgment that determi ne the effecti veness of any
technique. In the management of the di fficul t airway, fl exi bil i ty, and not ri gi di ty, prevai l s.
250, 251

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without paral ysi s. Am J Emerg Med 17:141, 1999
243. Sosis M: Modified rapid sequence induction I. Anesthesi ology 70:1031, 1989
244. Sivarajan M, Joy JV: Effects of general anesthesi a and paralysi s on upper ai rway changes
due to head posi ti on i n humans. Anesthesiol ogy 85:787, 1996
245. Tuzzo DM, Frova G. Appl icati on of the sel f-infl ati ng bul b to a hol l ow i ntubati ng
introducer. Mi nerva Anestesi ol ogica 67:127, 2001
246. Benumof JL, Gaughan SD: Concerns regardi ng barotrauma during jet venti l ati on (l etter).
247. Benumof JL: Transtracheal jet ventil ati on vi a percutaneous catheter and hi gh-pressure
source. In Benumof JL (ed): Airway Management: Pri nci pl es and Practice. St Louis, Mosby
Year Book, 1996
248. Gaughn SD, Gzaki GT, Benumof JL: Compari son i n a lung model of low and hi gh flow
regul ators for transtracheal jet venti l ati on. Anesthesi ology 77:189, 1992
249. Mual l em MK: Muall em Jet Venti l ator. Mi ddl e East J Anesth 15:575, 2000
250. Dunn SM, Robbi ns L, Connel ly NR: The LMA ProSeal
TM
may not be the best opti on for
di fficul t to intubate/venti late pati ents. Anesth Anal g 99:310, 2004
251. Rosenbl att WH: In response. Anesth Analg 99:311, 2004
> Tabl e of Contents > Secti on IV - Prepari ng for Anesthesi a > Chapter 23 - Pati ent Posi ti oni ng
Chapter 23
Patient Positioning
Mark A. Warner
KEY POINTS
Sedated or anestheti zed patients shoul d not be pl aced in posi tions that are not
comfortable whi l e they are awake.
El evated l ower-extremi ty posi tions (e.g., l i thotomy) may reduce perfusion
pressure i n the el evated extremiti es and increase the opportuni ty for devel opi ng
compartment syndromes, especi al l y when the extremi ties are el evated for
prolonged peri ods.
Paddi ng provi ded by any number of di fferent material s (e.g., gel or foam pads,
bl ankets) shoul d be used to wi del y di sperse poi nt pressure on body parts or
ti ssues.
Brachi al pl exus neuropathy associ ated wi th sternotomy in anestheti zed patients
undergoi ng cardi ac procedures may mi mi c as peri pheral ulnar neuropathy.
The etiology of ul nar neuropathy is not al ways cl ear. Most commonl y i t develops
postoperativel y in men 40 to 70 years of age who undergo abdominal or pelvic
procedures. There are anatomic and neurophysi ologic reasons for men compared
to women to devel op thi s problem.
Excessi ve fl exi on or extensi on of the spi ne in anestheti zed pati ents who are
pl aced in uni que surgical posi ti ons may contri bute to spi nal cord i schemia and
catastrophi c neurol ogi c damage.
Peri operative vi sion loss occurs most frequentl y i n anestheti zed pati ents
undergoi ng cardiac surgi cal procedures. Pati ents undergoi ng extensive spi ne
procedures whil e posi tioned prone al so have a hi gh frequency of vi sion loss,
pri mari l y from posteri or i schemi c optic neuropathy.
Neuropathies that result in motor functi on l oss as wel l as sensory l oss compared
to those with isolated sensory l oss general ly are associated wi th more prolonged
or permanent nerve dysfuncti on.
Posi ti oni ng a pati ent for a surgi cal procedure i s frequentl y a compromi se between what the
anesthetized pati ent can tol erate, both structural ly and physiol ogi cal ly, and what the surgi cal
team requi res for access to thei r anatomi c targets.
1, 2
Physi ol ogic i nstabi l ity resul ti ng from disease
or injury may be magnified by rapi dl y movi ng a seriousl y i l l pati ent from bed to transport cart,
through corri dors and el evators, and onto the operati ng tabl e. Induction of anesthesi a and
positi oning may need to be delayed unti l that pati ent i s hemodynamicall y stabl e, or establ i shment
of the intended surgical posture may need to be modi fi ed to match the pati ent's tolerance. Thi s
chapter presents the physi ologi c signi fi cance of vari ous positi ons in whi ch a pati ent may be pl aced
duri ng an operati on, bri efly describes the techniques of establi shi ng the posi ti ons, and di scusses
the potenti al compli cati ons of each posture.
It i s very i mportant for cl ini ci ans to understand the physi ol ogi c and potenti al pathologi c
consequences of pati ent posi tioni ng. Al though consi derable information is avai labl e on the
physi ol ogi c effects of vari ous posi ti ons, there is a pauci ty of informati on on the compl icati ons of
positi oning. Until recentl y, there have been few studies, ei ther retrospecti ve or prospecti ve, that
provi ded epidemi ologi c evidence of the frequency and natural hi story of many of the peri operative
positi oning compli cati ons. Why? In decades preceding the 1990s, catastrophi c peri operati ve
outcomes, such as death or hypoxic brai n i njury from either the del ivery of i nadequate oxygen or
fai l ure adequately to ventil ate patients, were i nfrequent but potenti al l y avoidabl e consequences of
the deli very of anesthesia. The development of pul se oximetry and end-ti dal respi ratory
moni tori ng in the 1980s, the subsequent acceptance of moni toring standards of care by the
anesthesia communi ty, the i ntroducti on of improved drugs, and i mproved physici an educati on
contri buted to a dramati c decl i ne i n the frequency of these major events. Less catastrophic, yet
stil l disabli ng, peri operati ve compl icati ons, such as those possi bl y related to posi ti oni ng,
consequentl y became a hi gher priori ty for study.

In the 1990s and more recently, a number of studies of l arge surgi cal popul ati ons provi ded new
information on the frequency and natural hi story of rare peri operati ve events such as neuropathi es
and vi si on l oss. These studi es occasi onal l y provided suffi cient data to all ow speculation on
potential mechani sms of i njury. Based on the fi ndings of these studi es, investi gators are seeki ng
to confi rm mechani sms of i njury and the effi cacy of novel i nterventions to decrease the frequency
of, or to prevent, these perioperative events. For now, however, the mechanism and even the
onset of many potenti al posi ti oni ng-rel ated compli cati ons often are unknown.
The l ack of sol id sci enti fi c i nformati on on basic mechanisms of posi ti oni ng-rel ated compli cati ons
often leads to medi col egal entangl ements. Attempts to determine the etiol ogy of compl i cations
al l eged to be caused by patient posi ti oni ng are often unconscionabl y bi ased. Notations on
anesthesia and operati ng room records may be absent or uni nformati ve. On some occasi ons,
medi col egal concl usi ons have been shaped by assumpti ons and asserti ons made by peopl e havi ng
no understandi ng of the case i n questi on and no personal famili ari ty wi th proceedi ngs i n an
operating room. Careful, but l aconic, descriptive notations about posi ti ons used duri ng anesthesi a
and surgery, as wel l as brief comments about speci al protective measures such as eye care and
pressure-poi nt padding, are useful i nformati on to incl ude on the anesthesi a record. In potential ly
compl i cated or contenti ous ci rcumstances, a brief resume in the progress notes i s advi sabl e. Onl y
in thi s manner can subsequent i nqui ri es be properl y answered on behal f of either the pati ent or
the anesthesi ol ogi st. When credibl e, expanded knowl edge that further del i neates mechanisms of
positi oning-rel ated compli cati ons is avail able, these i ssues and the care of pati ents wi ll be
improved.
DORSAL DECUBITUS POSITIONS
P hysi ol ogy
Circulatory
In the horizontal supi ne posi tion (Fi g. 23-1A), the infl uence of gravi ty on the vascul ar system i s
minimal. Intravascular pressures from head to foot vary l i ttl e from mean pressures at the level of
P.644
the heart; therefore, al most no perfusion gradient exists between the heart and arteries i n ei ther
the head or the l ower extremi ties. Si mi l arl y, venous gradi ents from the peri phery to the ri ght
atri um consi st pri nci pal l y of the cycli c i ntrathoraci c pressure changes that occur with respi rati on.
FIGURE 23-1. A. Supi ne adult wi th mi ni mal gradi ents in the hori zontal vascular axis.
If the pati ent i n the dorsal decubitus positi on i s ti l ted head hi gh or head l ow, the effects of gravi ty
on bl ood fl ow i n the head or the feet can become qui te si gni fi cant as the gradi ent to or from the
heart i ncreases. Pressures have been shown to change by 2 mm Hg for each 2.5 cm that a gi ven
poi nt varies i n vertical hei ght above or below the reference point at the heart.
3

When the lower extremi ties are bel ow the l evel of the heart, bl ood pool s i n di stensi bl e dependent
vessel s, causi ng a reducti on i n effecti ve ci rculating vol ume, cardiac output, and systemic
perfusi on. If the head i s hi gh and bl ood pressure measured at the l evel of the heart is l ow, the
bl ood pressure i n the brai n i s decreased further accordi ng to the magni tude of the head elevation.
If the head i s ti l ted down (Fi g. 23-1B), pressure in the cerebral vei ns increases i n proporti on to
the gradi ent upward to the heart. Many alert pati ents so posi ti oned compl ai n of a rapidl y
occurri ng, poundi ng vascul ar headache. Congestion develops i n the nasal mucosa and
conjunctivae. In the presence of an intracranial pathol ogi c process, such as a head i njury or a
stroke, el evati ons of cerebral venous pressure resul ti ng from head-down til t can provoke or
intensi fy cerebral edema and dangerousl y raise intracrani al pressure. Head-down til t also
increases cerebrospinal fl uid pressure in the cranial vaul t, addi ng its effect to the total i ntracrani al
pressure el evati on. Fi nal ly, venous congesti on and resul tant edema may cause a compartment
syndrome in areas within the head as vessel s and nerves are squeezed as they traverse smal l
bony spaces.
West et al
4
have i denti fi ed three separate perfusion zones in the pulmonary ci rculation, based on
the interrel ati onshi p among pressures i n the al veoli , arteri oles, and venules.
In zone 1, al veolar pressure exceeds ei ther arterial or venous pressure and perfusi on of the l ung
uni t i s prevented. Although i t i s rarely present i n a normal l ung, zone 1 can be produced by
pul monary hypotension, excessi ve posi ti ve end-expi ratory pressure (PEEP), or overdistention of
al veolar units from l arge tidal volumes duri ng positi ve-pressure ventil ati on.
In zone 2, arterial pressure exceeds al veol ar pressure, whereas al veolar pressure remai ns higher
than venous pressure. This relationship is found in nondependent portions of the lung, and
perfusi on i s the result of a fl uctuati ng bal ance between arteri al and al veolar pressures.
In zone 3, hydrostati c forces i n the dependent porti on of the l ung produce venous congesti on, and
perfusi on i s determi ned by the di fference between arteri al pressure and venous pressure.
In the dorsal recumbent positi ons, the pul monary ci rcul ati on tends to be most congested al ong the
dorsal body wal l and l east congested substernall y. When the pati ent i s ti lted head hi gh, zone 3
moves toward the lung bases as better venti l atory mechani cs i mprove gas exchange. If the ti l t i s
head down, zone 3 shi fts cephal ad into the poorl y ventil ated l ung api ces, and abnormal
ventil ati onperfusi on rati os can be expected to i ntensi fy.
Respiratory
In the supi ne posi ti on, mobi l e abdomi nal viscera gravitate toward the dorsal body wal l and press
the dorsal parts of the di aphragm cephal ad. The displ acement lengthens muscl e fi bers i n that
porti on of the di aphragm and increases the strength and effectiveness of its contractions duri ng
spontaneous venti lation. The benefit i s i mproved aeration of the congested, compacted, and less
Pul monary blood volume is greatest dorsal ly. Vi scera di splace the dorsal di aphragm cephal ad.
Cerebral circul ati on i s sl i ghtly above heart l evel if the head i s on a smal l pi ll ow. B. Head-
down ti l t ai ds bl ood return from lower extremi ties but encourages refl ex vasodi l ati on,
congests vessel s in the poorl y ventil ated l ung apices, and i ncreases intracranial blood
volume. C. El evati on of the head shifts abdomi nal vi scera away from the di aphragm and
improves venti lation of the lung bases. Accordi ng to the gradi ent above the heart, pressure
in arteri es of the head and neck decreases; pressure i n accompanyi ng veins may become
subatmospheri c.
compl i ant l ung bases. Wi th head-up ti lt (Fi g. 23-1C), the visceral weight shifts away from the
di aphragm and ventil ati on i s enhanced. In the head-down posi tion, the vi sceral mass, i ts wei ght
potential ly i ncreased by the presence of abdomi nal fat, fl ui d, or tumors, can cause significant
respiratory embarrassment by impeding caudad excursi ons of the contracti ng diaphragm and
preventi ng adequate expansion of the l ung bases.
In the supi ne posi ti on, gravi ty-i nduced vascul ar congestion forces the dorsal porti ons of the l ung
to functi on as a zone 3.
4
Consequentl y, the compl i ance of the area i s reduced, and passi ve
ventil ati on tends to distri bute gas preferential ly to more easi ly di stensi bl e substernal uni ts where
pul monary blood volume i s l ess. To prevent development of a cl i ni cal ly significant venti l ati on
perfusi on i mbal ance during use of control led ventil ati on, ti dal vol umes must be used that are
greater than the average amount that is sufficient for the spontaneously breathi ng, consci ous
patient.
5

Var i at i ons of t he Dor sal Decubi t us P osi t i on
Supine
Horizontal. In the tradi ti onal hori zontal supi ne posi tion (dubbed lyi ng at attenti on), the pati ent
li es on hi s or her back wi th a smal l pi ll ow beneath the head (see Fi g. 23-1A). The arms are either
comfortabl y padded and restrai ned

al ongsi de the trunk or abducted on wel l padded arm boards. Ei ther arm (or both) may be extended
ventral ly and the flexed forearm secured to an el evated frame i n such a way that perfusion of the
hand i s not compromi sed, no skin-to-metal contact exists to cause el ectri cal burns i f a cautery i s
used, and the brachial neurovascul ar bundl e i s nei ther stretched nor compressed at the axi ll a (see
the left arm arrangement in Fi g. 23-13). The l umbar spine may need padded support to prevent a
postoperative backache (see Compli cati ons of the Dorsal Decubi tus Posi ti ons section). Bony
contact points at the occi put, elbows, and heel s shoul d be padded.
Although the horizontal supi ne posture has a l ong history of wi despread use, i t does not pl ace hi p
and knee joi nts i n neutral posi ti ons and is poorl y tol erated for any l ength of ti me by an
immobil i zed, awake pati ent.
Contoured. A contoured supi ne posture (Fi g. 23-2C) has been termed the lawn chai r posi tion.
6
It
is establ ished by arrangi ng the surface of the operati ng table so that the

trunkthigh hi nge is angulated approximatel y 15 degrees and the thi ghknee hinge i s angul ated a
si mi l ar amount i n the opposite di recti on. Al ternati vely, a rol led towel or bl anket can be pl aced
beneath the pati ent' s knees to keep them flexed. The pati ent of average height then l i es
comfortabl y wi th hi ps and knees fl exed gentl y. Quite often a person who has been required to l i e
moti onl ess on a ri gi d horizontal tabl e and then i s changed to the contoured supi ne posi ti on offers
an al most involuntary expressi on of rel i ef and appreci ati on.
P.645
P.646
As i n the horizontal supi ne position, the pati ent shoul d have a pad or pi l l ow beneath the occi put,
el bows, and heel s. Arms can be posi ti oned as descri bed for the horizontal supi ne posture.
Frog-Leg. On occasi on, a surgeon may wi sh to have access to the peri neum. Pl aci ng the pati ent
supine wi th the knees bent and the soles of the feet together separates the thi ghs suffici ently to
permi t access to the peri neum and vagi na for the surgeon standing at the pati ent's fl ank. If the
patient' s skel eton i s sti ff, l ateral spread of the knees may seri ousl y stress the hi ps or stretch
branches of the obturator nerves;
7
a pad of suffi cient si ze shoul d be used to support each knee
(1) to mini mi ze the opportunity for postoperati ve hi p and back pai n and (2) to prevent a
di sl ocated hip or fracture of an osteoporotic femur duri ng the operati on.
Lateral Uterine or Abdominal Mass Displacement. With a patient in the supi ne posi ti on, a
mobi l e abdominal mass, such as a very large tumor or a pregnant uterus, can rest on the great
vessels of the abdomen and compromise circul ati on. Thi s i s known as the aortocaval syndrome or
the supine hypotensive syndrome. A si gni fi cant degree of perfusi on can be restored if the
compressi ve mass is rol l ed toward the l eft hemi abdomen by leftward tilt of the tabl e top or by a
FIGURE 23-2. Establ ishment of the contoured supi ne (lawn chair) positi on. A. Tradi ti onal
fl at supi ne tabl e top. B. Thi ghs fl exed on trunk. C. Knees gentl y fl exed i n fi nal body posi ti on.
D. Trunk section level ed to stabil i ze fl oor-supported arm board. (Reproduced wi th permi ssi on
from Fi gure 5-3 (p. 42) of Marti n JT, Warner MA [eds]: Positi oni ng i n Anesthesi a and
Surgery, 3rd ed. Phi ladelphi a, WB Saunders, 1997.)
wedge under the ri ght hi p.
8

Lithotomy
Standard. In the standard l ithotomy posi ti on (Fi g. 23-3), the pati ent l ies supi ne with arms
crossed on the trunk or wi th one or both arms extended laterall y to l ess than 90 degrees on arm
boards. Each lower extremi ty i s fl exed at the hi p and knee, and both li mbs are si mul taneously
el evated and separated so that the perineum becomes accessi bl e to the surgeon. For many
gynecol ogi c and urol ogi c procedures, the pati ent' s thighs are fl exed approxi matel y 90 degrees on
the trunk and the knees are bent suffi cientl y to mai ntai n the l ower l egs nearl y paral l el to the
floor. More acute fl exi on of the knees or hips can threaten to angulate and compress major
vessel s at ei ther joi nt. In additi on, hi p fl exi on to greater than 90 degrees on the trunk has been
shown to increase stretch of the i ngui nal li gaments.
7
Branches of the l ateral femoral cutaneous
nerves often pass directl y through these l i gaments and can be i mpi nged and become ischemic
within the stretched li gament.
Numerous devices are avail able to hol d legs that are el evated during del ivery or operati on. Each
should be fi tted to the stature of the indi vi dual pati ent. Care shoul d be taken to ensure that
angul ati ons or edges of the padded hol der do not compress the popl iteal space or the upper dorsal
thigh. Compartment syndromes of one or both lower extremi ties have resul ted from prol onged use
of the li thotomy posi tion with some types of support devices.
9

When the legs are to be l owered to the origi nal supi ne positi on at the end of the procedure, they
shoul d fi rst be brought together at the knees and ankl es in the sagi ttal pl ane and then l owered
sl owly together to the table top. Thi s mi ni mi zes torsion stress on the l umbar spi ne that woul d
occur if each leg were lowered independentl y. It al so permi ts gradual accommodati on to the
increase i n ci rculatory capacitance, thereby avoi di ng sudden hypotensi on.
10

Low. For most urol ogi c procedures and for many procedures that require simul taneous access to
the abdomen and peri neum, the degree of thi gh elevati on i n the l i thotomy posi ti on i s only
approxi mately 30 to 45 degrees (Fi g. 23-4). Thi s reduces perfusi on gradi ents to and from the
lower extremi ties and i mproves access to a peri neal surgi cal si te for members of the operating
FIGURE 23-3. Standard l ithotomy posi ti on with candy cane extremi ty support. Thi ghs are
flexed approximatel y 90 degrees on abdomen; knees are fl exed enough to bri ng l ower l egs
grossl y paral lel to the torso secti on of the table top. Arms are retained on boards, crossed on
the abdomen, or snugged at the si des of pati ent. (Modi fi ed wi th permission from Figures 6-5
and 6-14 of Marti n JT, Warner MA [eds]: Posi ti oni ng i n Anesthesia and Surgery, 3rd ed.
Phi ladelphi a, WB Saunders, 1997.)
team who may need to stand at the lateral aspect of ei ther leg.
High. Some surgeons prefer to i mprove access to the peri neum by suspendi ng the pati ent' s feet
from hi gh pol es. The effect i s to have the patient' s l egs al most ful ly extended on the thighs (Fi g.
23-5) and the thi ghs fl exed 90 degrees or more on the trunk. The posture produces a si gni fi cant
uphi l l gradient for arterial perfusion into the feet, requi ring careful avoi dance of systemi c
hypotensi on. Less mobi le pati ents may tol erate thi s posture poorl y because of angul ati on and
compressi on of the contents of the femoral canal by the i ngui nal l igament (see Fi g. 23-5A), or
stretch of the sci atic nerve (see Fi g. 23-5B), or both.
FIGURE 23-4. Low l ithotomy posi tion for perineal access, transurethral i nstrumentati on, or
combi ned abdomi noperi neal procedures. (Modified with permi ssion from Fi gure 8-4, (p. 99) of
Marti n JT, Warner MA [eds]: Positi oni ng i n Anesthesi a and Surgery, 3rd ed. Phil adelphia, WB
Saunders, 1997.)
Exaggerated. Transperi neal access to the retropubic area requi res that the pati ent' s pel vi s
be fl exed ventral l y on the spi ne, the thi ghs almost forci bl y fl exed on the trunk, and the l ower
legs aimed skyward so as to be out of the way (Fi g. 23-6). The result pl aces the l ong axi s of the
symphysi s pubi s al most paral l el to the floor. Thi s exaggerated l i thotomy posi ti on stresses the
lumbar spi ne, produces a si gni fi cant uphi l l gradient for perfusi on of the feet, and may restri ct
ventil ati on because of abdomi nal compressi on by bul ky thi ghs. It can be tol erated under
anesthesia but can rarel y be assumed by an awake pati ent.

Control of ventil ati on i s usual l y necessary. If painful l umbar spi ne di sease exi sts, an al ternati ve
surgi cal posi tion may need to be chosen beforehand to avoi d severely accentuati ng the l umbar
di stress after surgery. Thi s posi ti on has been associated wi th a very high frequency of lower
extremi ty compartment syndrome.
11
Mai ntenance of adequate perfusi on pressure i n the l egs i s
important.
FIGURE 23-5. Hi gh l i thotomy posi ti on. Note potenti al for angul ati on and
compressi on/obstructi on of contents of femoral canal A, insert) or stretch of sci ati c nerve
(B). (A reproduced with permi ssi on from McLeskey CH [ed]: Geriatri c Anesthesi ology.
Bal timore, Wil l iams & Wi lkins, 1997. B reproduced wi th permi ssi on from Fi gure 6-11 and 6-
12, (pp. 61 & 63) of Marti n JT, Warner MA [eds]: Posi ti oni ng i n Anesthesia and Surgery, 3rd
ed. Phi l adel phi a, WB Saunders, 1997.)
P.647
Tilted. Frequentl y, some degree of head-down til t i s added to one of the l i thotomy positi ons. If
the ti l t i s great enough, and parti cularly i n the i nstance of the exaggerated li thotomy posi ti on, the
patient may sl ide cephal ad. Care must be taken to avoid this si tuati on; there are several
anecdotes from medi col egal acti ons i nvol vi ng patients who sl i d off operati ng tabl es with resul ting
head injuri es.
Dependi ng on the degree of head depressi on, the additi on of til t to the l ithotomy posi tion
combi nes the worst features of both the li thotomy and the head-down postures. The wei ght of
abdomi nal vi scera on the di aphragm adds to whatever abdomi nal compressi on i s produced by the
flexed thi ghs of an obese pati ent or of one pl aced in an exaggerated li thotomy posi tion.
Ventil ati on shoul d be assi sted or controll ed. Because el evati on of the l ower extremi ties above the
heart produces an uphi ll perfusi on gradi ent, systemic hypotensi on and compressi ve l eg wrappi ng
may l i mi t perfusi on to the peri phery, a factor i n the development of compartment syndromes in
the l egs of l i thotomi zed pati ents.
9
Thi s perfusion gradient often is unpredi ctabl e and exaggerated,
potential ly i ncreasi ng the ri sk of compartment syndrome.
12, 13

Head-Down Tilt. Someti me during the mid 1800s, Bardenhauer, an innovative German surgeon in
Col ogne, began to elevate the hi ps of pati ents to gravitate the vi scera cephal ad and hel p expose
lesions deep wi thin the pel vi s.
14
Others may have used the posture at about the same time. That
uni que maneuver, ti l ti ng a patient 30 to 45 degrees head down (Fi g. 23-7), was adopted and
popul ari zed by Fri edri ch Trendel enburg of Bonn and Leipzig before 1870 (thus the often-used term
Trendel enburg positi on). However, its publ i cati on apparentl y awai ted an articl e by Meyer, an
FIGURE 23-6. The exaggerated l i thotomy posi ti on. Shoul der braces, usual l y needed to
stabi l ize the torso, are pl aced over the acromi oclavicular area to minimize compression of the
brachial pl exus and adjacent vessel s. (Reprinted with permission from Figure 6-7 (p. 54) of
Marti n JT, Warner MA [eds]: Positi oning i n Anesthesi a and Surgery, 3rd ed. Phi l adel phi a, WB
Saunders, 1997.)
Ameri can pupi l of Trendel enburg, i n 1885.
15

Rei ch and associates,
16
studying wel l -instrumented, anesthetized pati ents, have compared
ci rculatory variabl es i n the l evel supine posi tion with those recorded after 3 mi nutes of marked
(60-degree) el evation of the lower extremiti es or after 3 minutes of 20 degrees of head-down til t.
They found that head-down til t onl y minimal l y i ncreased cardiac output and mean arteri al
pressure, whereas l eg rai si ng sl i ghtl y increased

mean arteri al pressure without affecting cardiac output. In each posture, there was evidence of
deteri orati ng pul monary functi on and ri ght ventricular stress. They urged cauti on i n the use of
ei ther maneuver in pati ents wi th pul monary di sease or ri ght ventricul ar compromi se.
Cephalad di splacement of the di aphragm and obstructi on of i ts caudad i nspi ratory stroke
accompany a head-down posi tion because of gravi ty-shifted abdomi nal vi scera. Consequentl y, the
work of spontaneous venti lation is i ncreased for an anestheti zed pati ent i n a posture that already
worsens the venti l ati onperfusi on rati o by gravi tati onal accumulation of blood in the poorl y
ventil ated l ung api ces. Duri ng control led ventil ati on, hi gher inspiratory pressures are needed to
expand the l ung.
Intracranial vascular congestion and increased i ntracranial pressure can be expected to resul t
from head-down til t. For pati ents wi th known or suspected i ntracrani al disease, the positi on
should be used onl y i n those rare instances in which a surgi cal l y useful al ternate posture cannot
be found. Mai ntenance of the positi on shoul d then be as bri ef as possi bl e, and the need for
postoperative neurologic i ntensi ve care shoul d be anti ci pated.
Steep head-down til t posi ti ons (e.g., 30 to 45 degrees of head-down ti l t) may require some means
of preventi ng the pati ent from sli di ng cephal ad out of posi ti on. The use of anklets and bent knees
FIGURE 23-7. Head-down tilt. Foreground fi gure shows tradi tional steep (30- to 45-degree)
ti l t descri bed by Trendel enburg. Leg restrai nts and knee fl exi on stabil i ze the patient,
avoi ding the need for wri stl ets or shoulder braces that threaten the brachial pl exus. Upper
figure shows 10 to 15 degrees of head-down til t, which is more common i n modern surgi cal
procedures. (Repri nted wi th permi ssi on from Marti n JT, Warner MA [eds]: Posi ti oni ng i n
Anesthesi a and Surgery, 3rd ed. Phi l adel phi a, WB Saunders, 1997.)
P.648
is a sati sfactory method of retai ning the til ted pati ent i n positi on (see Fi g. 23-7) if the anklets are
not excessi vel y ti ght and if the flexed knee joints are placed suffi ci entl y caudad of the legthigh
hi nge of the table top so that the adjacent fi rm edge of the depressed l eg secti on of the tabl e
cannot i ndent either proxi mal cal f. Shoul d i ndentati on occur, compressi ve i schemi a and phl ebiti s
or a compartment syndrome may resul t.
Histori call y, shoul der braces also have been used to prevent cephal ad sli di ng i n steep head-down
ti l t positi ons. These braces are best tol erated i f placed over the acromi ocl avicular joi nts, but care
must be taken to see that the shoul der is not forced suffi ci entl y caudad to trap and compress the
subcl avi an neurovascul ar bundl e between the cl avi cl e and the fi rst ri b. If the braces are pl aced
medial ly agai nst the root of the neck, they may easi ly compress neurovascul ar structures that
emerge from the area of the scalene muscul ature. For these and other reasons, the use of
shoulder braces has waned i n popul ari ty.
Compl i cat i ons of t he Dor sal Decubi t us P osi t i ons
Postural Hypotension
Depending on the resil i ence of the pati ent' s vasocompensatory mechani sms, postural hypotensi on
may be seen when a head-el evated posi ti on i s bei ng establi shed. If mean arteri al pressure at the
ci rcl e of Wi ll i s remai ns wi thin the range of cerebral bl ood flow autoregul ati on i n a patient who i s
not hypertensive, the postural hypotensi on may require l ittle treatment other than

to appropri atel y decrease the concentrati on of anestheti c drugs to preserve compensatory
refl exes. If the degree of hypotension encountered i s more severe, further head el evati on shoul d
be del ayed unti l the l evel of anestheti c is decreased; i n addi ti on, judicious use of fl ui ds and
vasopressors can reestabli sh effecti ve perfusi on.
Postural hypotension may al so appear i n the presence of inadequatel y repl aced blood loss when
the intravascul ar space has been functi onall y i ncreased ei ther by l oweri ng the l egs to hori zontal at
the termi nation of the l ithotomy posi tion or by returni ng a head-down til t to hori zontal. Vol ume
repl eti on i s the i ndi cated therapy, al though judi ci ousl y smal l doses of vasopressors may
sometimes be needed i ni ti all y.
Pressure Alopecia
Prolonged compression of hai r fol l icl es can produce hair l oss. Abel and Lewi s
17
descri bed pati ents
who had pai n, swell i ng, and exudation where the occi put had been supporting the wei ght of the
head for l ong peri ods i n the Trendel enburg positi on. Al opecia occurred between the 3rd and 28th
postoperative day; regrowth was compl ete withi n 3 months. Use of ti ght head straps to hol d
anesthetic face masks and prol onged hypotensi on and hypothermi a have also been associ ated with
compressi on al opeci a.
18
Frequentl y turning the pati ent' s head duri ng l ong operati ons
19
and use of
padded, soft head supports are recommended to reduce the risks of thi s compli cati on.
Pressure-Point Reactions
Wei ght-bearing bony promi nences can produce ischemic necrosi s of overl yi ng ti ssue unl ess
proper paddi ng i s appl i ed. Hypothermia and vasoconstri cti ve hypotensi on may enhance the
process. The heels, the el bows, and the sacrum are particul arl y vul nerabl e. The use of a vari ety of
pads (e.g., foam or gel ) may di sperse point pressure if used for protection. Whi le their use may
protect agai nst skin and soft ti ssue compressi on and ischemia, there are no studi es that have
proven thei r use to be benefi ci al i n reduci ng peri pheral neuropathies i n the peri operati ve peri od.
BRACHIAL PLEXUS AND UPPER EXTREMITY INJURIES
Br achi al P l exus Neur opat hy
P.649
Root Injuries
Shoul der braces pl aced tight agai nst the base of the neck can compress and injure the roots of the
brachial pl exus. Braces, i f needed at al l, are consi dered less harmful when placed more lateral l y
over the acromiocl avi cul ar joint.
The dorsal decubi tus posi tions do not usual ly threaten structures in the patient' s neck unl ess
consi derable l ateral di splacement of the head occurs. In that posi ti on, the roots of the brachi al
pl exus on the si de of the obtuse headshoulder angl e can be stretched and damaged. If the upper
extremi ty is fixed at the wri st, the stretch injury of the plexus can be accentuated as the head
moves laterall y away from the anchori ng poi nt of the wri st. Simil arl y, exaggerated rotati on of the
head away from an extended arm can be associ ated wi th a brachi al pl exus injury.
Sternal Retraction
Frequentl y, the patient undergoing a medi an sternotomy has both arms padded and secured
al ongsi de the torso. An al ternative is to have both arms abducted.
20
Vander Salm et al
21, 22

descri bed fi rst ri b fractures and brachi al pl exus i njuri es associated wi th medi an sternotomies.
They related the extent of the injury to the amount of retractor displ acement of the ri b, with the
most severe injury bei ng caused by di spl acement suffi cient to produce a first ri b fracture. Roy and
associates,
23
in a study of 200 consecutive adul ts schedul ed for cardi ac surgery via a medi an
sternotomy, posi ti oned the l eft arm ei ther abducted and padded on an arm board wi th the pal m
supi nated or secured by a draw sheet al ongside the trunk; the right arm was al ways pl aced
al ongsi de the trunk. They found a 10% i ncidence of upper extremi ty nerve i njury that was not
infl uenced by internal mammary artery harvest, internal jugul ar vei n catheteri zati on, or left arm
positi on. Surgi cal mani pul ati on was more contributory than extremi ty posi ti oni ng i n produci ng
trauma to the

brachial pl exus. Jel li sh et al
20
reported that there i s l ess slowi ng of somatosensory evoked
potential s (SSEPs) of the ul nar nerve during sternotomy when both arms are abducted i nstead of
tucked at the si des. However, they found no di fferences i n peri operati ve symptoms between
patients i n the arm-abducted versus arm-at-si de groups.
Long Thor aci c Ner ve Dysf unct i on
Several lawsui ts have centered on postoperative serratus anteri or muscl e dysfuncti on and wingi ng
of the scapul a (Fi g. 23-8) al l eged to be the resul t of posi ti on-rel ated i njuri es to the l ong thoraci c
nerve of Bel l, which arises from nerve roots C5, C6, and C7. Because C5 and C6 fi bers of the
nerve course through the middl e scal ene muscle and emerge from its lateral border to join the
fi bers from C7, i t has been proposed that neuropathi es of the l ong thoracic nerve are traumatic i n
origi n.
24
Johnson and Kendall
25
descri bed the wi del y vari abl e eti ol ogy of serratus anteri or muscl e
paral ysi s in a revi ew of 111 cases and found only 13% occurri ng after ei ther a surgical procedure
or an obstetri c deli very. Because the nerve is not routi nel y i nvol ved i n a stretch i njury of the
brachial pl exus and because the pl exus i s not routi nel y i nvol ved when long thoraci c nerve
dysfuncti on occurs, the rel ati onshi p between postoperati ve l ong thoracic nerve pal sy and pati ent
positi oning remains specul ati ve. Based on evidence of Foo and Swann
26
plus data from litigations,
Marti n
27
concl uded that i n the absence of demonstrable trauma, postoperati ve dysfuncti ons of the
long thoraci c nerve were qui te li kel y the result of coi nci dental neuropathi es, possi bl y of viral
origi n.
P.650
Axi l l ar y Tr auma f r om t he Humer al Head
Excessi ve abduction of the arm on an arm board may thrust the head of the humerus i nto the
axi l lary neurovascular bundle. The bundl e i s stretched at that poi nt and its neural structures may
be damaged. In the same manner, vessel s can be compressed or occluded and perfusi on of the
extremi ty can be jeopardi zed.
Radi al Ner ve Compr essi on
The radi al nerve, ari si ng from roots C6-8 and T1, passes dorsol ateral ly around the mi ddl e and
lower porti ons of the humerus i n i ts muscul ospi ral groove. At a point on the l ateral aspect of the
arm, approxi mately three fingerbreadths proxi mal to the l ateral epicondyl e of the humerus, the
nerve can be compressed against the underl yi ng bone and i njured. Pressure from the vertical bar
of an anesthesi a screen or a si mi lar device against the lateral aspect of the arm
28
and excessi ve
cycl i ng of an automatic bl ood pressure cuff
29
have been impl icated i n causi ng damage to the radi al
nerve. Postoperati ve radi al nerve dysfuncti on i s a rel ati vel y rare reason for malpractice
li tigati on.
30, 31

Cl i ni cal mani festati ons of a radial nerve lesi on include wrist drop, weakness of abduction of the
thumb, inabil i ty to extend the metacarpophalangeal joints, and loss of sensation in the web space
between the thumb and i ndex fi nger.
32
Radial nerve function can be rapi dl y assessed by noti ng the
patient' s abil i ty acti vely to extend the distal phal anx of the thumb.
FIGURE 23-8. Scapular wi ngi ng. The serratus anteri or muscl e (upper ri ght) i s suppl i ed
solel y by the l ong thoracic nerve that branches immediately from C5, C6, C7, and someti mes
C8 (l eft fi gure). Ari sing on the lateral ri bs and i nserting on the deep surface of the scapul a,
the muscl e keeps the shoul der gi rdle approxi mated to the dorsal ri b cage. Long thoraci c
nerve pal sy al lows dorsal protrusi on of the scapul a (lower ri ght). See text. (Reproduced wi th
permi ssi on from Marti n JT: Postoperati ve i sol ated dysfunction of the long thoraci c nerve: A
rare enti ty of uncertai n eti ology. Anesth Anal g 69:614, 1989.)
Medi an Ner ve Dysf unct i on
Isol ated peri operative i njuri es to the median nerve are uncommon and the mechanism is
obscure.
30, 31
A potenti al source of i njury i s iatrogeni c trauma to the nerve duri ng access to vessel s
in the antecubital fossa, as might occur duri ng veni puncture. Anecdotall y, thi s probl em appears to
occur pri mari l y i n men 20 to 40 years of age who cannot easi ly extend thei r

el bows compl etely. Forced el bow extensi on after admi ni strati on of muscl e rel axants and whil e
positi oning the arms, wi th resul tant stretch of the medi an nerve, has been suggested as one
potential mechani sm for thi s problem. A quick check of sensati on over the dorsal and pal mar
surfaces of the di stal phal anges of the fi rst and second fi ngers identi fi es an acute injury.
Ul nar Neur opat hy
Improper anesthetic care and patient malposi tioni ng have been impl icated as causati ve factors in
the development of ul nar neuropathi es si nce reports by Bdi nger
33
and Garriques
34
in the 1890s.
These factors li kel y play an eti ologic rol e for thi s problem i n some surgical pati ents. Other factors,
however, may contri bute to the development of postoperative ul nar neuropathi es. In a seri es of 12
inpati ents with newl y acqui red ul nar neuropathy, Wadsworth and Wil l iams
35
determi ned that
external compressi on of an ulnar nerve duri ng surgery was a factor in onl y two pati ents. Ul nar
neuropathi es develop i n medical as wel l as surgi cal pati ents.
36
The mechanisms of ul nar
neuropathy are uncl ear.
Typicall y, anesthesi a-rel ated ulnar nerve i njury i s thought to be associ ated wi th external
nerve compressi on or stretch caused by malpositi oning duri ng the intraoperati ve peri od.
Although thi s impli cati on may be true for some pati ents, three fi ndi ngs suggest that other factors
may contribute. Fi rst, pati ent characteri sti cs (e.g., mal e sex, high body mass i ndex [38], and
prol onged postoperati ve bed rest) are associated wi th these ul nar neuropathi es.
37
Vari ous reports
suggest that 70 to 90% of patients who have thi s probl em are men.
30, 31, 35, 36, 37
Second, many
patients with peri operati ve ul nar neuropathies have a hi gh frequency of contral ateral ul nar nerve
conducti on dysfuncti on.
38
This finding suggests that many of these pati ents li kel y have
asymptomati c but abnormal ul nar nerves before their anestheti cs, and these abnormal nerves may
become symptomati c duri ng the peri operati ve peri od. Fi nal l y, many pati ents do not noti ce or
compl ai n of ul nar nerve symptoms until more than 48 hours after thei r surgi cal procedures.
37, 38
A
prospecti ve study of ul nar neuropathy i n 1,502 surgi cal pati ents found that none of the pati ents
had symptoms of the neuropathy during the fi rst 2 postoperati ve days.
39
It i s not clear whether
onset of symptoms indicates the ti me that an i njury has occurred to the nerve. Pri eli pp et al
40

found that 8 of 15 awake vol unteers who had notabl e alterations i n their ulnar nerve SSEP si gnals
from direct ulnar nerve pressure did not perceive a paresthesi a, even when the SSEP waveforms
decreased as much as 72%.
El bow fl exion can cause ulnar nerve damage by several mechani sms. In some pati ents, the ul nar
nerve is compressed by the aponeurosi s of the flexor carpi ul nari s muscl e and cubi tal tunnel
retinacul um when the elbow i s fl exed by more than 110 degrees
41, 42
(Fi g. 23-9). In other pati ents,
this fi brotendi nous roof of the cubi tal tunnel i s poorly formed and can lead to anterior subl uxation
or di sl ocati on of the ul nar nerve over the medi al epi condyle of the humerus duri ng el bow fl exi on.
Thi s displ acement has been observed i n approximatel y 16% of cadavers in whom the flexor muscl e
aponeurosi s and supporti ng ti ssues have not been di ssected.
43, 44
Ashenhurst
44
has specul ated that
the ul nar nerve may be chroni cal l y damaged by recurrent mechani cal trauma as the nerve
subluxates over the medi al epi condyl e.
P.651
External compression in the absence of elbow flexi on al so may damage the ul nar nerve.
45, 46

Although compressi on withi n the medi al epi condyl ar groove may be possi bl e i f the groove i s
shal l ower than normal , the bony groove usual ly i s deep and the nerve i s wel l protected from
external compressi on.
47
External compression may occur distal to the medi al epi condyle, where
the nerve and i ts associated artery are rel ati vel y superfici al . In an anatomi c study, Contreras et
al
48
observed that the ul nar nerve and posteri or recurrent ul nar artery pass posteromedial ly to the
tubercle of the coronoi d process, where they are covered onl y by ski n, subcutaneous fat, and a
thin distal band of the aponeurosis of the flexor carpi ul nari s.
Why are men more l i kel y to have thi s compl i cation? There are several anatomi c di fferences
between men and women that may i ncrease the li kel i hood of peri operati ve ul nar neuropathy
developing i n men. Fi rst, two anatomi c differences may increase the chance of ul nar nerve
compressi on i n the regi on of the el bow. The tubercl e of the coronoi d process i s approxi matel y 1.5
times larger in men than women.
48
In additi on, there i s l ess adipose ti ssue over the medi al aspect
of the elbow of men compared with women of similar body fat composition.
48-50
Second, men may
be more l i kel y to have a wel l -developed cubi tal tunnel retinaculum than women, and the
retinacul um, i f present, i s thicker. A thi cker cubi tal tunnel retinacul um may i ncrease the risk of
FIGURE 23-9. Medi al -to-l ateral view of ri ght el bow. The cubi tal tunnel reti nacul um (CTR) is
lax i n extension (A) as i t stretches from the medi al epi condyl e (ME) to the ol ecranon (Ol ).
The reti nacul um ti ghtens i n fl exi on (B) and can compress the ul nar nerve (arrow). (Repri nted
with permission from O' Driscol l SW, Hori i E, Carmi chael SW et al : The cubi tal tunnel and
ul nar neuropathy. J Bone Joi nt Surg Am 73:613, 1991.)
ul nar nerve compressi on i n the cubi tal tunnel when the elbow i s fl exed.
Cli nical mani festati ons of ulnar nerve dysfunction vary wi th the locati on and extent of the lesion.
51

Nearl y al l pati ents

have numbness, ti ngl ing, or pai n in the sensory distributi on of the ul nar nerves once they become
symptomatic. However, there can be consi derable ul nar nerve dysfuncti on before symptoms
appear. Pri el i pp et al
40
found that onl y 8 of 15 mal e volunteers wi th si gni fi cant ul nar nerve
conducti on slowi ng noted any symptoms. More studies are needed to understand better the
mechani sm and natural hi story of ul nar neuropathy.
Ul nar nerve injury i s relati vel y common.
30, 31, 39
Al so, a significant proportion of pati ents have
symptoms of bi l ateral ulnar nerve dysfuncti ons both before and after surgery.
38
Therefore, some
have specul ated i t mi ght be hel pful duri ng the preanesthetic i nterview to i nquire about a hi story of
ul nar neuropathi es (crazy bone problems) or previ ous surgery at the el bow. If such a hi story i s
i ndi cated, the fi ndi ng must be recorded and a di scussi on wi th the pati ent or famil y should present
the possibi l ity of a postoperative recurrence despi te speci al precauti ons of paddi ng and
positi oning.
The time of recogni ti on of di gi tal anesthesi a associ ated wi th ulnar nerve dysfuncti on may be quite
important i n establ i shi ng the origi n of the postoperati ve syndrome. If ulnar hypesthesi a or
anesthesi a i s noted promptly after the end of anesthesi a, as i n the recovery faci l ity, the conditi on
is li kel y to be associ ated with events that occurred duri ng anesthesi a or surgery. If the
recogniti on i s del ayed for many hours, the l ikel i hood of cause shi fts from the i ntra-anesthetic
peri od to postoperati ve events. In a revi ew of cl osed cl aims, Krol l and associates
30
commented
that postoperati ve ul nar dysfuncti on can occur as a resul t of events i n the postanesthetic peri od
and that nerve injury may devel op i n certai n susceptibl e pati ents despi te conventi onall y accepted
methods of positi oni ng and paddi ng.
Opi oi ds may mask postoperati ve dysesthesi as and pai n, but even strong analgesics cannot mask a
loss of sensati on as a resul t of nerve dysfuncti on. It may be helpful to assess ul nar nerve function
and record these observati ons before di scharging the pati ent from the recovery room.
Arm Complications
An arm that is hyperabducted can force the head of the humerus i nto the axi ll ary neurovascul ar
bundl e and damage nerves and vessel s to the arm. Abduction of the arm to more than 90 degrees
from the trunk should be avoi ded. An arm board shoul d be securely attached to the operati ng
tabl e to prevent i ts acci dental rel ease. An arm that is not properly secured can sl ip over the edge
of the tabl e or arm board, resul ti ng i n injury to the capsule of the shoul der joi nt by excessi ve
dorsal extension of the humerus, fracture of the neck of an osteoporotic humerus, or injury to the
ul nar nerve at the el bow. Conversely, i n the unl ikel y event that the retai ning strap is excessi vel y
ti ght across the supi nated forearm (Fi g. 23-10), the potenti al exi sts for pressure to compress the
anterior interosseous nerve, a branch of the medi an nerve i n the upper forearm that courses wi th
its artery al ong the vol ar surface of the tough i nterosseous membrane. The resul t i s an i schemi c
injury to the distri buti on of the nerve and artery that resembles a compartment syndrome i n the
lower extremi ty and may requi re prompt surgi cal decompressi on.
52-54

P.652
Backache
Lumbar backache can be worsened by the li gamentous rel axati on that occurs with general ,
spi nal , or epi dural anesthesia. Loss of normal l umbar curvature in the supi ne positi on i s
apparentl y the i ssue. Paddi ng (see Fi g. 23-3) pl aced under the l umbar spi ne before the induction
of anesthesi a may hel p retai n l ordosi s and make a patient wi th known lumbar distress more
comfortabl e. Hyperl ordosis shoul d be avoi ded, however. Hyperextension of the lumbar spi ne,
especial ly to an angul ati on of more than 10 degrees at the L2-3 apex of the l umbar spine, may
resul t in i schemia of the spi nal nerves.
55

El evati on of the l egs can worsen the pai n of a herniated nucl eus pul posus. When the li thotomy
positi on i s contempl ated for a pati ent wi th a hi story of l ow back pai n or a herni ated l umbar di sk,
gentl e passi ve attempts to have the patient assume the posture before anesthesi a may be hel pful
i n determi ni ng whether the posi tion can be tol erated.
Perineal Crush Injury
The supi ne pati ent who i s pl aced on a fracture tabl e for repai r of a fractured femur usual l y has the
pel vi s retained i n pl ace by a verti cal pole at the peri neum (Fi g. 23-11), with the foot of the
i njured extremi ty fi xed to a mobi l e rest. A worm gear on the rest lengthens the di stance between
the foot and the pel vi s so that the bone fragments can be di stracted and reali gned. Unless the
pol e i s wel l padded, severe pressure can be exerted on the pel vi s, and damage can occur to the
geni tal i a and the pudendal nerves. Compl ete loss of peni le sensati on has been reported after use
of the fracture tabl e.
56, 57
The correct position for the pol e i s agai nst the pel vis between the
genitali a and the uni njured l i mb.
56

FIGURE 23-10. Arm restrai nt, i f excessi vely tight, can compress the anterior interosseous
nerve and vessel agai nst the i nterosseous membrane i n the volar forearm to produce an
ischemi c neuropathy. (Reproduced wi th permi ssi on from McLeskey CH [ed]: Geri atri c
Anesthesi ol ogy. Bal timore, Wi ll i ams & Wi l ki ns, 1997.)
Compartment Syndrome
If, for whatever reason, perfusi on to an extremi ty i s i nadequate, a compartment syndrome may
devel op. Characteri zed by i schemia, hypoxi c edema, elevated ti ssue pressure wi thi n fascial
compartments of the leg, and extensive rhabdomyol ysi s, the syndrome produces extensive and
potential ly l asti ng damage to the muscles and nerves i n the compartment. Because the pathol ogic
process is at ti ssue level , di stal pul ses and capi ll ary refi l l may remain i ntact whi le a compartment
syndrome is devel opi ng i n an extremi ty; thus, they are not useful indi cators of the ongoi ng
process. Ferrihemate, resul ti ng from myogl obi n destructi on, exerts a di rect toxi c effect on renal
tubul ar epi theli um, and renal fail ure i s li kel y.
58
Ci rcul ati ng debri s from i nfecti ons i n the involved
extremi ti es i s apt to be fi ltered by pul monary mi crovascul ature with injuri ous consequences for
the lung.
Causes of a compartment syndrome whi le a patient is i n any of the dorsal decubi tus posi ti ons
incl ude (1) systemic hypotensi on and l oss of dri vi ng pressure to the extremi ty (augmented by
el evati on of the extremi ty); (2) vascul ar obstruction of major l eg vessel s by intrapel vi c retractors,
by excessi ve fl exi on

of knees or hi ps, or by undue popl i teal pressure from a knee crutch; and (3) external compressi on
of the elevated extremi ty by straps or l eg wrappi ngs that are too ti ght, by the i nadvertent
FIGURE 23-11. Tracti on tabl e wi th peri neal post stabil i zi ng patient whi l e l eg is el ongated to
reposi ti on bone ends. El evated l eg ri sks hypoperfusi on; pel vi c post threatens geni tal ia.
(Reproduced wi th permi ssi on from Fi gure 6-6, (p. 54) of Marti n JT, Warner MA [eds]:
Positi oning i n Anesthesi a and Surgery, 3rd ed. Phil adelphia, WB Saunders, 1997.)
P.653
pressure of the arm of a surgi cal assi stant, or by the wei ght of the extremi ty agai nst a poorl y
supporti ve l eg hol der.
9, 59
A ti ght strap on an arm as wel l as ti ght drawsheets for mai ntaining
arms at the pati ent's si des may compress the anteri or i nterosseous neurovascular bundle and may
be associ ated wi th an anterior interosseous neuropathy or a forearm or a hand compartment
syndrome.
53, 54

Several cl i ni cal characteristics seem to be associ ated wi th peri operati ve compartment syndrome.
Prolonged l i thotomy posture in excess of 5 hours has been a common factor i n l i terature
anecdotes of postl ithotomy compartment syndromes. For lengthy procedures in the l i thotomy
posi ti on, wel l -padded hol ders that i mmobi l i ze the l i mb by supporti ng the foot wi thout compressi ng
the cal f or popl iteal fossa seem to be the l east threateni ng choi ce. There is considerabl e
vari abi l ity i n the perfusi on pressure of the l ower extremi ty i n elevated legs. Hal l iwil l et al
12
and
Pfeffer et al
13
found si gnifi cant blood pressure vari ati on at the ankl e i n vol unteers placed in
vari ous li thotomy posi ti ons. Several vol unteers had mean pressures of l ess than 20 mm Hg when
positi oned i n the hi gh l i thotomy positi on. Thi s pressure i s less than intracompartment pressures
commonly measured in many lithotomy positions.
Warner et al
60
have shown that peri operati ve compartment syndromes occur i n patients i n
positi ons other than li thotomy. In fact, the frequency of thi s problem occurs as often
(approxi matel y 1:9,000 pati ents) in anestheti zed patients who are posi tioned l ateral l y as in
si mi l ar pati ents who are posi ti oned i n l i thotomy. The di fference between compartment syndromes
in these two groups i s that pati ents i n a l ateral decubitus positi on tend to have compartment
syndromes of ei ther arm, whi l e those in a l ithotomy posi tion have compartment syndromes of the
lower extremi ties.
60

Finger Injury
In 1968, Courington and Li ttl e
61
descri bed the amputation of a young woman' s fi ngers that were
caught between the l eg and thi gh secti ons of the operati ng tabl e as the l eg secti on was returned
to the horizontal posi ti on at the termi nation of an operati on duri ng whi ch the pati ent was in the
li thotomy posi ti on. A towel used to create a boxing gloveli ke wrap on the hands of l ithotomized
patients or careful ly removing the pati ent's hands from the risk positi on before raisi ng the foot of
the tabl e may prevent such a tragic mi sadventure.
62

LATERAL DECUBITUS POSITIONS
P hysi ol ogy
Circulatory
In the l ateral decubi tus posi ti on, the patient is turned onto one si de of the trunk and stabi l ized to
prevent acci dental roll i ng toward ei ther the supi ne or the prone posture. It i s of practi cal and
legal importance to note that the si de of the body that rests on the tabl e i s the side that
determi nes the name of the posi ti on (l eft si de down = l eft l ateral decubi tus posi ti on).
If the l egs are maintai ned i n the l ong axis of the body, al most no pressure gradi ents exi st al ong
the great vessel s from head to foot. Small hydrostati c differences are detected between the values
when blood pressure is recorded simul taneousl y on the two arms.
If the l ower extremiti es are posi tioned bel ow the l evel of the heart, bl ood pool s i n the di stensi bl e
vessel s of the dangl i ng l egs because of gravi ty-i nduced i ncreases i n venous pressure and resul tant
venous stasi s. Wrappi ng the l egs and thi ghs i n compressi ve bandages has been commonl y used to
combat

venous pool i ng. Marked fl exi on of the l ower extremi ti es at knees and hi ps can parti al l y or
compl etel y obstruct venous return to the i nferi or vena cava ei ther by angulati on of vessel s at the
popl i teal space and i ngui nal l i gament or by thi gh compression agai nst an obese abdomen. A smal l
support pl aced just caudad of the down-si de axi ll a can be used to li ft the thorax enough to relieve
P.654
pressure on the axil l ary neurovascul ar bundl e and prevent di sturbed bl ood fl ow to the arm and
hand. However, thi s chest support (i nappropriately cal led an axi l lary rol l by some) has not been
proven to reduce the frequency of ischemi a, nerve damage, or compartment syndrome to the
down-si de upper extremity. It may, however, decrease shoul der di scomfort postoperati vel y. Any
paddi ng shoul d support onl y the chest wal l and i t shoul d be periodi cal l y observed to ensure that i t
doesn' t impi nge on the neurovascular structures of the axi l la.
In the l ow-pressure pulmonary ci rcuit, hydrostatic gradi ents occur between the two hemithoraces.
Al though the degree of gravi ty-induced l ateral displ acement of the heart i s di fferent in the two
lateral decubi tus posi tions, it i s general l y true that most of the down-si de l ung li es bel ow the l evel
of the atrium and that the up-si de l ung li es above it. Vascular congestion of the down-si de l ung
resembl es a zone 3 of West et al,
4
whereas the rel ati ve hypoperfusi on of the up-si de lung
resembl es a zone 2. Kaneko et al
63
found that the transi tion between zone 3 and zone 2 occurred
at approxi matel y 18 cm above the most dependent part of the l ung.
If the cervi cal spi ne of the patient who i s placed in a horizontal lateral decubitus positi on i s
careful ly mai ntai ned i n ali gnment wi th the thoracolumbar spi ne, al most no gradi ent occurs
between pressures i n the medi astinum and those in the head. However, if the head i s not
supported and suffi cient lateral angul ati on of the neck occurs in ei ther di rection, obstructi on of
jugular fl ow may occur.
Respiratory
In the presence of a suppl e chest, the l ateral decubi tus positi on can decrease the vol ume of the
down-si de hemithorax. The weight of the chest may force the down-si de rib cage i nto a l ess
expanded conformation. Gravi ty-induced shi fts of medi asti nal structures toward the down-si de
chest wal l tend further to reduce the vol ume of the dependent l ung. Abdominal viscera force the
down-si de diaphragm cephal ad i f the l ong axis of the trunk i s hori zontal or head down.
Spontaneous venti l ati on can partial ly compensate for the diaphragmati c stretchi ng in the
dependent hemithorax because the contracti le efficiency of the el ongated di aphragmati c muscl e
fi bers i s i ncreased. The compacted l ung base and zone 3 vascul ar congesti on decrease compl i ance
and interfere wi th the di stri buti on of gas duri ng positi ve-pressure ventil ati on. An elevated ki dney
rest pl aced against ei ther the down-si de rib margi n or fl ank, or that migrates i nto that posi tion as
the pati ent shi fts on it, further i nterferes with movement of the down-si de hemidi aphragm and
passi ve ventil ati on of the dependent l ung.
The up-si de hemithorax is much less compressed than the dependent si de, and because the l ung
li es above the l evel of the atri a, i t has l ess vascul ar congesti on than the down-si de l ung. As a
resul t, unless contral ateral fl exi on has stretched the up-si de fl ank muscles to the poi nt of ri gidi ty
and l i mi ted excursi ons of the costal margi n, positi ve-pressure ventilati on i s directed preferenti all y
to the more compl i ant up-si de l ung. The resul t can easi ly be excessi ve venti l ati on of the
underperfused up-si de l ung and hypoventi l ati on of the congested down-si de l ung. The potential for
a cl ini cal ly si gnifi cant venti lationperfusi on mismatch i s obvious, parti cularly i n the presence of
pul monary disease.
Var i at i ons of t he Lat er al Decubi t us P osi t i ons
Standard (Horizontal) Lateral Position
In the horizontal l ateral decubitus positi on (Fi g. 23-12), the pati ent i s roll ed onto one si de on a
flat tabl e surface and stabil i zed i n that posture by fl exing the down-si de thi gh. The down-si de
knee i s bent to retai n the leg on the tabl e and i mprove stabi li zati on of the trunk. The common
peroneal nerve of that si de is padded to mi ni mi ze compressi on damage caused by the wei ght of
the legs. The up-si de thi gh and leg are extended comfortabl y, and pi l l ows are placed between the
lower extremi ties. The head i s supported by pi l lows or a head rest so that the cervi cal and
thoraci c spi nes are properl y al igned. A smal l pad, thick enough to rai se the chest wal l and prevent
excessive compressi on of the shoul der or entrapment/compression of the neurovascl ar structures
of the axil l a, is pl aced just caudad to the down-si de axil l a. Thi s paddi ng may support adequate
perfusi on of the down-si de hand and mi ni mi ze ci rcumduction of the dependent shoulder, which
mi ght stretch its suprascapul ar nerve.
Arms may be extended ventrall y and retained on a singl e arm board wi th sui tabl e paddi ng between
them, or they may be i ndi vi dual l y retai ned on a padded two-l evel arm support that can al so help
to stabi li ze the thorax. An al ternate method of arm arrangement i s to flex each el bow and pl ace
the arms on sui tabl e padding on the tabl e i n front of the patient' s face.
The pati ent i s stabil i zed i n the lateral posi ti on by the use of one or more retai ning tapes or straps
stretched across the hi p and fi xed to the underside of the tabl e top. Care must be taken to see
that the hi p tapes or straps l i e safel y between the il i ac crest and the head of the femur rather
than over the head of the femur. An additional restrai ni ng tape or strap may be used across the
thorax or shoul ders i f needed.
Semisupine and Semiprone
The semi lateral postures are designed to al l ow the surgeon to reach anterol ateral (semi supine)
and posterol ateral (semi prone) structures of the trunk. In the semi supine posi tion, the up-si de
arm must be careful l y supported so that i t

i s not hyperextended and no tracti on or compressi on i s appl i ed to the brachial and axi l lary
neurovascul ar bundl es (Fi g. 23-13). The supporti ng bar shoul d be wel l wrapped to prevent
el ectrical grounding contact (see Fi g. 23-13A). Suffici ent noncompressi bl e paddi ng shoul d be
pl aced under the dorsal torso (see Fi g. 23-13, large fi gure) and hi p to prevent the pati ent from
rol l i ng supi ne and stretchi ng the anchored extremi ty. The pul se of the restrai ned wri st shoul d be
checked to ensure adequate circul ati on i n the el evated arm and hand (Fi g. 23-13B).
FIGURE 23-12. The standard l ateral decubi tus posi ti on. Proper head support, axi ll ary rol l,
and l eg pi l l ow arrangement are shown on lower fi gure. Down-si de leg is fl exed at hi p and
knee to stabil i ze torso. Retai ning straps and pad for down-si de peroneal nerve are not
shown. (Reproduced wi th permi ssi on from Fi gure 9-1, (p. 127) of Marti n JT, Warner MA
[eds]: Posi ti oni ng i n Anesthesi a and Surgery, 3rd ed. Phi l adel phi a, WB Saunders, 1997.)
P.655
Flexed Lateral Positions
Lateral Jackknife. The l ateral jackknife posi ti on pl aces the down-si de i li ac crest over the hi nge
between the back and thi gh secti ons of the tabl e (Fi g. 23-14). The tabl e top i s angul ated at that
poi nt to flex the thi ghs on the trunk l ateral l y. After the pati ent has been sui tabl y posi ti oned and
restrai ned, the chassi s of the tabl e i s ti pped so that the uppermost surface of the patient' s fl ank
and thorax becomes essenti al l y horizontal . As a resul t, the feet are bel ow the l evel of the atri a,
and si gni fi cant amounts of bl ood may pool in di stensi ble vessel s in each leg.
FIGURE 23-13. The semi supi ne posi ti on with dorsal pads supporti ng the torso, the extended
arm padded at the el bow, and the el evated arm restrai ned on a well cushi oned, adjustabl e
overhead bar (A). Axi ll ary contents (B) are not under tensi on and are not compressed by the
head of the humerus, and a pulse oxi meter ensures that the di gital ci rculation is not
compromised. The posi ti on i s safe onl y i f the arm does not become a hanging mechanism to
support the torso. (Reproduced wi th permission from Fi gure 7-2, (p. 176) of Col l ins VJ [ed]:
Pri nci pl es of Anesthesiol ogy, 3rd ed. Phi l adel phi a, Lea & Febi ger, 1993.)
The l ateral jackkni fe positi on i s usuall y intended to stretch the up-si de fl ank and wi den i ntercostal
spaces as an asset to a thoracotomy incisi on. However, i n terms of l umbar stress, restricti on by
the taut flank of up-si de costal margin motion, and pool i ng of bl ood i n depressed l ower
extremi ti es, the posi tion imposes a si gnificant physi ol ogic i nsult. Actuall y, its usefulness to the
surgeon i s bri ef, and i ts use should be li mi ted. Once the ri b-spreadi ng retractor i s pl aced i n the
inci sion, the posi ti on has reduced value for the rest of the operati on.
64

Kidney. The kidney posi tion (Fi g. 23-15) resembles the l ateral jackkni fe posi ti on, but i t adds the
use of an el evated rest (the ki dney rest) under the down-si de i li ac crest to increase the amount of
lateral flexion and improve access to the up-si de ki dney under the overhangi ng costal margi n.
Unl i ke the l ateral jackkni fe positi on, the kidney posi tion does not have a useful al ternative for a
flank approach to the kidney. Thus, the physiol ogi c i nsul ts associ ated wi th the posture need to be
l i mi ted by vi gi l ant anesthesi a and rapid surgery. Strict stabi li zi ng precauti ons shoul d be taken to
prevent the pati ent from subsequentl y shi fting caudad on the tabl e i n such a manner that the
el evated rest rel ocates i nto the down-si de fl ank and becomes a severe i mpedi ment to venti l ati on
of the dependent l ung.
FIGURE 23-14. The l ateral jackknife posi ti on, i ntended to open i ntercostal spaces. Note the
properl y pl aced restrai ni ng tapes (large fi gure) thrusting cephal ad to retai n the il i ac crest at
the fl exi on poi nt of the tabl e and prevent caudad sl i ppage, which compresses the down-si de
flank (insert). (Reproduced wi th permi ssi on from Fi gure 9-4, (p. 130) of Marti n JT, Warner
MA [eds]: Posi ti oni ng i n Anesthesi a and Surgery, 3rd ed. Phil adelphia, WB Saunders, 1997.)
Compl i cat i ons of t he Lat er al Decubi t us P osi t i ons
Eyes and Ears
Injuries to the dependent eye are unli kel y if the head i s properl y supported duri ng and after the
turn from the supi ne to the l ateral posi tion. If the pati ent' s face turns toward the mattress,
however, and the l i ds are not cl osed or the eyes otherwi se protected, abrasi ons of the ocul ar
surface can occur. Di rect pressure on the gl obe can di splace the crystall i ne l ens, i ncrease
intraocul ar pressure or, parti cul arl y i f systemi c hypotensi on i s present, cause ischemia.

In the l ateral posi tion, the wei ght of the head can press the down-si de ear agai nst a rough or
wri nkl ed supporti ng surface. Careful paddi ng wi th a pi l l ow or a foam sponge i s usual l y suffi ci ent
protecti on against contusi on of the ear. The external ear shoul d also be pal pated to ensure that it
has not been folded over i n the process of pl aci ng support beneath the head.
Neck
Lateral fl exi on of the neck is possi bl e when the head of a patient in the l ateral posi tion is
inadequately supported. If the cervical spi ne is arthriti c, postoperative neck pai n can be
troublesome. Pain from a symptomati c protrusi on of a cervi cal di sk can be i ntensi fi ed unless the
head is carefull y posi ti oned so that l ateral or ventral fl exi on, extension, or rotati on i s avoi ded.
Patients with unstabl e cervical spi nes can be i ntubated whil e awake and turned gentl y i nto the
operative posi ti on whi le repeated neurol ogi c checks, wi th whi ch the pati ent cooperates and
FIGURE 23-15. The flexed lateral (kidney) posi ti on. Upper panel s show i mproper l ocati ons of
the elevated transverse rest, the flexion poi nt of the table, in the fl ank (A) or at the l ower
costal margi n (B) to i mpede ventil ati on of the down-si de l ung. The il i ac crest at the proper
flexion point (C), al l owing the best possi bl e expansi on of the down-si de l ung. Restrai ni ng
tapes del eted for cl ari ty. (Reproduced wi th permission from Fi gure 9-6, (p. 132) of Marti n JT,
Warner MA [eds]: Posi ti oni ng i n Anesthesi a and Surgery, 3rd ed. Phi l adel phi a, WB Saunders,
1997.)
P.656
P.657
responds, are accompli shed to detect the devel opment of a posi ti oni ng i njury.
65

Suprascapular Nerve
Ventral ci rcumduction of the dependent shoulder can rotate the suprascapul ar notch away from
the root of the neck (Fi g. 23-16). Because the suprascapul ar nerve i s fi xed both paravertebral l y
and at the notch, ci rcumduction can stretch the nerve and produce troublesome, diffuse, dull
shoulder pain. The diagnosis i s establ i shed by bl ocki ng the nerve at the notch and produci ng pai n
rel ief. Treatment may requi re resecti ng the li gament over the notch to decompress the nerve. A
supporti ng pad pl aced under the thorax just caudad of the axi l la and thick enough to rai se the
chest off the shoul der shoul d prevent a circumducti on stretch i njury to the nerve.
Long Thoracic Nerve
Instances of postoperative wi ngi ng of the scapul a (see Fi g. 23-8) have foll owed use of the lateral
decubi tus posi ti on.
27
Al though coinci dental viral neuropathi es of the l ong thoracic nerve may pl ay
a major eti ologi c role i n postoperati ve appearances of scapular wi ngi ng i n pati ents for whom onl y
a dorsal decubitus positi on was used, the possi bi li ty of trauma to the nerve whi l e establi shi ng the
lateral positi on i s di fficult to refute. Lateral fl exi on of the neck may stretch the l ong thoraci c
nerve in the obtuse angl e of the neck.
VENTRAL DECUBITUS (PRONE) POSITIONS
P hysi ol ogy
Circulatory
In the prone posi tion, the circul atory dynamics vary accordi ng to the postural modi fi cation in use.
If the l egs remai n essenti al l y horizontal , pressure gradi ents in the bl ood vessels are mi ni mal . If
the pati ent i s kneel ing, or i f the tabl e chassi s is rotated head high, si gni fi cant pool i ng of venous
bl ood i n di stensi bl e dependent vessel s is l i kel y to occur.
Wi th the patient lying on the soft abdomi nal wal l, pressure of compressed viscera i s transmi tted to
FIGURE 23-16. Ci rcumduction of the arm displ aci ng the scapul a and stretchi ng the
suprascapul ar nerve between its anchori ng poi nts at the cervi cal spine and the suprascapul ar
notch. (Reproduced wi th permission from Fi gure 9-14, (p. 147) of Marti n JT, Warner MA
[eds]: Posi ti oni ng i n Anesthesi a and Surgery, 3rd ed. Phi ladel phi a, WB Saunders, 1997.)
the dorsal surface of the abdomi nal cavi ty. Mesenteric and paravertebral vessel s are compressed,
causi ng engorgement of vei ns wi thi n the spi nal canal . Obstruction of the inferior vena cava can
produce immedi ate, visi ble di stenti on of vertebral vei ns. Because bl eedi ng from inci sed vessel s
about the spi ne i s increased under these ci rcumstances, numerous modificati ons of the prone
positi on have been created to free the abdomen from pressure, reduce the congesti on of
intraspi nal vei ns, and faci li tate surgical hemostasis.
66

If the head of a prone pati ent i s bel ow the l evel of the heart, venous congesti on of the face and
neck becomes evident. Turni ng the patient' s head can alter arterial perfusion and venous drainage
in both extracrani al and intracrani al vessels. Conjuncti val edema is usual and refl ects the
infl uence of gravi ty on accumulation of extravascul ar fluid (see Compli cati ons of the Ventral
Decubitus Posi tions: Bl i ndness secti on).
If the head i s above the l evel of the heart, mean vascul ar pressures are decreased accordi ng to
the distance above the heart and conjunctival edema i s l ess evi dent or absent, but ai r entrainment
in open vei ns is possi bl e.
Kaneko et al
63
descri bed the perfusi on of the enti re l ung of prone subjects i n terms that
subsequently fi t the zone 3 of West et al .
4
Backofen and Schauble
67
found that even the carefully
establ i shed and supported prone posi ti on caused a si gni fi cant fall i n stroke volume and cardi ac
index, despite the devel opment of i ncreased vascular resi stance in both the systemic and
pul monary ci rcuits. No si gni fi cant changes were detected i n mean arterial pressure, ri ght atri al
pressure, or pul monary artery occl usi on pressure. On the basi s of these observations, they
recommend that, i n pati ents whose cardiovascul ar status is precari ous, i nvasive hemodynami c
moni tors be i ntroduced to detect otherwi se unrecognizabl e deterioration of cardiac functi on caused
by posi ti oni ng.
Respiratory
Usi ng computed tomography, Gattinoni 's group
68
found a dramati c redi stributi on of densi ti es from
the dorsal (paravertebral supi ne) to the ventral (substernal ) portions of the lungs when subjects
in respiratory failure were turned from the supi ne to the prone positi on. The origi nal areas of
compressi on atel ectasi s reopened when those parts of the l ung became nondependent, whereas
fresh areas of compression atel ectasi s formed rather promptl y i n newl y dependent areas of the
lung. In their study group, they found no change i n oxygenati on or shunti ng when pronation
occurred.
If the thorax i s suppl e or compliant, the body weight of an anestheti zed, prone pati ent compresses
the anteroposterior

di ameter of the rel axed chest to a degree that i s real but poorl y defi ned. If the parti cul ar prone
posture i n use all ows the pressure of the abdomi nal viscera to be suffi ci ent to force the di aphragm
cephal ad, the l ung i s shortened al ong i ts l ong axi s. Wi th both the dorsoventral and the
cephal ocaudad di mensi ons of the l ung decreased, and i n the presence of the rel ati ve vascul ar
congesti on of a zone 3 of West et al,
4
the compli ance of the compacted prone lung can be
anti cipated to decrease. The resul t of decreased pul monary compl i ance in a poorl y posi ti oned,
prone, anestheti zed pati ent is ei ther an i ncreased work of spontaneous venti l ation or the need for
hi gher i nfl ati on pressures during posi ti ve-pressure ventil ati on.
Proper posi tioni ng can retai n more nearl y normal pul monary compl i ance by minimi zi ng the
cephal ad shift of the di aphragm caused by compressed abdomi nal vi scera. If the pati ent is
arranged so that the abdomen hangs free, the l oss of functi onal resi dual capaci ty i s less i n the
prone posi ti on than in ei ther the supine or the lateral positi on.
69
Rehder et al
70
noted that the
weight of the freed abdomi nal contents had an inspi ratory effect on the di aphragm when the
pronated patient was properl y supported by pads under the shoul der gi rdl e and pel vi s.
Var i at i ons of t he Vent r al Decubi t us P osi t i on
P.658
Full (Horizontal) Prone
In the so-call ed ful l or hori zontal prone posi ti on (Fi g. 23-17), the requirement to elevate the trunk
off the supporti ng surface so that the ventral abdomi nal wall i s freed of compressi on al most
al ways resul ts in the head and l ower extremiti es bei ng below the level of the spi ne. If the tabl e
top i s angul ated at the trunkthigh hi nge to remove the l umbar l ordosi s and separate the l umbar
spi nous processes, and i f the chassi s is then rotated head-up suffi ci entl y to level the patient' s
back, a si gni fi cant perfusi on gradi ent may devel op between the l egs and the heart. Wrappi ng the
legs i n compressi ve bandages, or the use of ful l -length elasti c hosiery, mini mi zes pool i ng of bl ood
in di stensi ble vessels and supports venous return.
Various ventral supports, incl udi ng paral l el rol l s of ti ghtl y packed sheets, padded and adjustabl e
metal frames, and four-pi l l ar frames, have been devi sed to free the abdomen from
compressi on.
66, 71
Each has meri t, and no speci fi c uni t has been shown to be better than the others
for hemodynami c or respi ratory mai ntenance or pati ent safety. The choice i s based on the
physi que of the patient, the requirements of the surgi cal procedure, and the avail able equipment.
Pronated patients wi th l i mi ted mobil i ty of the neck, a hi story of postural neck pai n, or a hi story
suggesting a symptomati c cervi cal di sk shoul d have thei r heads retai ned i n the sagi ttal pl ane,
ei ther wi th a skul l -pi n head cl amp
72
or wi th a face rest. If the neck i s pai n free and i ts mobi li ty i s
sati sfactory, the head can be turned l ateral l y and supported to prevent pressure on the down-si de
eye and ear.
73
However, forced rotati on of the pronated head shoul d be careful l y avoi ded l est i t
induce postoperati ve neck pai n or cervi cal nerve root or vascular compressi on.
When a pati ent i s schedul ed to be pronated after inducti on of anesthesi a, it i s worthwhi le during
the preanestheti c i ntervi ew to obtain and record i nformati on about any l i mi tations that may exist
FIGURE 23-17. The cl assic prone posi ti on. A. Fl at tabl e wi th rel axed arms extended
al ongsi de pati ent' s head. Paral lel chest roll s extended from just caudad of cl avicl e to just
beyond i ngui nal area, wi th pi l low over pel vi c end. El bows and knees are padded, and l egs are
bent at the knees. Head i s turned onto a C-shaped foam sponge that frees the down-si de eye
and ear from compressi on. B. Same posture wi th arms snugl y retai ned al ongsi de torso. C.
Tabl e fl exed to reduce l umbar l ordosi s; subgl uteal area straps pl aced after the l egs are
l owered to provi de cephal ad thrust and prevent caudad sl i ppage. (Reproduced wi th
permi ssi on from Fi gure 10-1, (p. 156) of Marti n JT, Warner MA [eds]: Posi ti oni ng i n
Anesthesi a and Surgery, 3rd ed. Phi ladel phi a, WB Saunders, 1997.)
in hi s or her abi li ty to rai se the arms overhead during work or sl eep.
66
If the pati ent i s
symptomatic, i t may be prudent to pl ace the arms alongsi de the torso after pronati on (see the
di scussi on of the Thoraci c Outlet Syndrome, later). If the arms are pl aced al ongsi de the head
(i .e., extended ventral ly at the shoul der, flexed at the el bow, and abducted onto arm boards; the
surrender positi on), the musculature about the shoul ders should be under no tensi on, nei ther
humeral head shoul d stretch or compress its axi ll ary neurovascul ar bundle (i .e., shoul ders shoul d
be abducted l ess than 90 degrees), ul nar nerves at the el bow shoul d be padded, and the pul ses at
the wrists should remai n ful l. Anteri or (forward) fl exion of the shoul ders may reduce tensi on on
the neurovascul ar structures of the axi ll a.
Prone Jackknife
The prone jackkni fe posture i s used to provi de access to the sacral , peri anal, and peri neal areas
as wel l as to the l ower al imentary canal (Fi g. 23-18). The thi ghs are flexed on the trunk more
than is usual in the full prone position, with the tabl e surface hi nges determi ni ng the degree of
flexion achi evable.
66

Prone Kneeling
Kneel i ng posi ti ons have been used to i mprove operati ve conditi ons in the l umbar and
cervi cooccipi tal areas (Fi g. 23-19).

Numerous frames have been constructed to support the wei ght of a kneeli ng pati ent, and thei r
FIGURE 23-18. The prone jackkni fe posi ti ons. A. Low jackkni fe positi on wi th the trunkthigh
hi nge of the table used as the fl exi on posi ti on and augmented by a pi l l ow under the pel vi s. B.
Full jackknife posi ti on with the thi ghleg hinge of the table used as the flexi on poi nt to
achi eve more acute angul ati on of the hips on the torso. (Reproduced wi th permi ssi on from
Fi gure 10-14 & 10-15, (p. 163 & 164) of Marti n JT, Warner MA [eds]: Posi tioni ng in
P.659
useful ness agai n depends on local use and the physi que of the pati ent. If the vertebral col umn i s
unstabl e, kneel i ng frames are not as useful as parall el l ongi tudi nal supports because kneel i ng
ri sks appl i cati on of shearing forces at the fracture si te, wi th the potenti al for damage of the
contents of the spinal canal. In massi vel y obese pati ents who must be operated on i n the prone
positi on, kneeli ng frames tend to prevent pressure on the abdomen more successful l y than
longi tudi nal frames.
Compl i cat i ons of t he Vent r al Decubi t us P osi t i ons
Eyes and Ears
The eyes and ears may sustai n i njury i n the prone positi on. The eyeli ds shoul d be cl osed, and
each eye shoul d be protected i n some manner so that the l i ds cannot be accidentall y separated
and the cornea scratched. Insti l lati on of lubri cation in the eyes shoul d be consi dered, although the
val ue of thi s treatment i s debated. The eyes shoul d also be protected agai nst the head turni ng
medial ly after posi tioni ng as wel l as agai nst pressure bei ng exerted on the gl obe. Moni toring wi res
and i ntravenous tubi ng shoul d be checked after pronati on to see that none has mi grated beneath
the head. If the head is retai ned in the sagittal pl ane, the eyes shoul d be checked after
positi oning to ensure that they are safe from compressi on by any head rest.
Conjuncti val edema usual ly occurs in the eyes of the pronated pati ent i f the head i s at or bel ow
the level of the heart. It is usuall y transient, inconsequenti al, and requi res onl y reestabl i shment
of the normal ti ssue perfusion gradi ents of the supi ne posi tion, or of a sli ght amount of head-up
ti l t, to be redi stri buted.
Blindness. Permanent l oss of vi si on can occur after nonocul ar surgical procedures, especi al l y
those performed i n a ventral decubi tus posi ti on.
74-89
The occurrence of thi s devastating
compl i cati on i s particularl y associ ated wi th extensi ve surgical procedures done i n the prone
positi on, such as reconstructi ve spine surgery, where there is associ ated blood loss, anemi a, and
hypotensi on. Visual l oss after neurovascul ar and cardi opul monary bypass procedures i s well
recogni zed and may be rel ated to emboli c events produced by the surgical interventi on i tsel f,
hypoperfusion, or other nonposi ti oni ng causes.
90-93
Vi sual l oss after noncardi ac, nonneurovascul ar
procedures may initi al l y be noti ced by a l oss of acui ty, a l oss of visual fi el d, or both.
Speculated causes of significant permanent postoperati ve visual loss usuall y involve compromi se
of oxygen del i very to el ements of the visual pathway and i ncl ude i schemi c optic neuropathy
FIGURE 23-19. The Andrews kneel ing frame wi th Wi ltse' s thoraci c jack i n use. (Reproduced
with permission from Fi gure 10-9, (p. 161) of Marti n JT, Warner MA [eds]: Posi ti oni ng i n
(anteri or or posteri or), retinal artery occl usi on (central or branch), and corti cal bl i ndness.
94
No
case series exi st to provi de i nformati on regardi ng the frequency of these events after nonocular,
noncardiac surgery in a general surgi cal popul ation. Roth et al
76
surveyed approxi matel y 61,000
patients undergoi ng nonocular surgery (i ncludi ng cardiac surgery) over a 4-year peri od and
identi fi ed 34 ocular injuri es (mostl y corneal abrasi ons), i ncl udi ng one case of permanent
postoperative vi sual l oss from ischemic opti c neuropathy after l umbar spi nal fusi on. In a revi ew of
3,450 spi nal surgeri es, Stevens et al
82
identi fi ed three patients who had permanent postoperati ve
visual l oss. Brown et al
95
identi fi ed three pati ents in whom postoperati ve ischemic opti c
neuropathy devel oped after noncardiac surgery over a 10-year peri od in one i nstituti on. Warner et
al
96
noted none of nearl y 11,000 prone-positi oned pati ents developed perioperati ve visi on loss.
However, these authors subsequently have experienced several patients who have devel oped
compl ete bl i ndness after spi nal surgery performed wi th pati ents posi ti oned prone. Refl ecting
concern about the apparent increased i nci dence of peri operati ve bl i ndness, the Ameri can Soci ety
of Anesthesi ologists, Commi ttee on Professi onal Liabi li ty, has created a formal regi stry to moni tor
and document the i ncidence of this compl icati on (see http://www.asahq.org).
Posi ti oni ng appears to be a ri sk factor for some of these events. Studi es noti ng a relative hi gh
frequency of postoperati ve visual l oss i n spi nal surgery patients have impl i cated posi ti oni ng as
one causati ve factor.
77, 78, 79, 80, 83, 92
Use of the kneechest posi tion,
77
the prone posi ti on,
78, 83, 97
and
the horseshoe head rest
79
have been ci ted as potenti al causes of visual l oss, perhaps

by di rect pressure on the gl obe i ncreasi ng the i ntraocular pressure beyond the perfusi on pressure
of the reti na. Other reports, i ncludi ng those of spi nal surgery pati ents, descri be vi sual loss after
prol onged procedures, i ntraoperati ve hypotensi on, and massi ve bl ood l oss,
74, 75, 76, 81, 82
which may
prevent adequate oxygen del i very to the vi sual apparatus. For exampl e, al l pati ents wi th i schemi c
optic neuropathy i n the seri es of Brown et al
95
experi enced peri ods of si gnificant anemi a
(hemogl obin concentrati on <8 g/dL) and i ntraoperati ve hypotensi on. It i s possi bl e that venous
congesti on and edema in the head associated wi th the prone posi ti on may be a contributi ng factor.
Neck Problems
Anesthesi a impai rs refl ex muscle spasm that protects the skeleton agai nst moti on that woul d be
pai nful i f the patient were al ert. Lateral rotation of the head and neck of an anesthetized,
pronated patient, parti cularl y one with an arthri ti c cervi cal spine, can stretch rel axed skeletal
muscles and li gaments and i njure arti cul ati ons of cervi cal vertebrae. Postoperative neck pai n and
li mi tati on of motion can resul t. The arthri ti c neck i s usual l y best managed by keeping the head in
the sagi ttal pl ane when the pati ent i s prone.
Extremes of head and neck rotation can al so i nterfere with fl ow in either the i psil ateral or
contral ateral vessel s to and from the head. Excessive head rotati on can reduce flow in both the
carotid
98
and vertebral systems.
99
Impai red cerebral perfusion is the obvi ous consequence.

Brachial Plexus Injuries
Stretch injuri es to the roots of the brachi al pl exus (Fi g. 23-20A) on the side contral ateral to the
turned face are possibl e i f the contral ateral shoul der i s hel d firml y caudad by a wri st restraint. If
an arm is pl aced on an arm board al ongside the head, care must be taken to ensure that the head
of the humerus i s not stretchi ng and compressi ng the axi ll ary neurovascul ar bundl e (see Fi g. 23-
20B,C).
P.660
When an arm is pl aced on an arm board al ongside the head, the forearm natural ly pronates. As a
resul t, the ul nar nerve, l yi ng in the cubi tal tunnel (the groove between the olecranon process and
the medi al epi condyle of the humerus), i s vul nerabl e to bei ng compressed by the wei ght of the
el bow (see Fi g. 23-20D). Consequently, the medial aspect of the el bow must be wel l padded and
its wei ght borne pri nci pal l y on the medi al epicondyl e.
Asking pati ents about thei r abi l ity to work or sl eep wi th arms elevated overhead may i dentify
patients with thoraci c outl et obstructi on.
66
A useful preoperati ve test i f the history i s i n questi on
is to have the patient cl asp hands behi nd the occiput during the i nterview (Fi g. 23-21). If the
patient describes dysesthesi as, i t may be prudent to keep the arms al ongsi de the trunk in the
prone posi ti on. Agoni zi ng, debi l itati ng, and unremitting postoperati ve pai n has been known to
fol l ow overhead arm pl acement in pronated pati ents who have had pri or di scomfort i n thei r arms
in that positi on.
66

FIGURE 23-20. Sources of potenti al injury to the brachi al pl exus and i ts peri pheral
components when the pati ent i s in the prone posi ti on. A. Neck rotation, stretchi ng roots of
the plexus. B. Compression of the pl exus and vessels between the clavi cle and fi rst ri b. C.
Injury to the axi ll ary neurovascul ar bundl e from the head of the humerus. D. Compression of
the ul nar nerve before, beyond, and withi n the cubi tal tunnel. E. Area of vul nerabi li ty of the
radial nerve to lateral compressi on proxi mal to the el bow. (Reproduced wi th permi ssi on from
Fi gure 10-29, (p. 185) of Marti n JT, Warner MA [eds]: Posi ti oni ng i n Anesthesi a and Surgery,
3rd ed. Phil adelphia, WB Saunders, 1997.)
Breast Injuries
The breasts of a pronated woman, if forced l ateral l y by ventral chest supports, can be stretched
and i njured al ong thei r sternal borders. Medi al and cephalad di splacement seems better

tolerated. Di rect pressure on breasts (parti cul arly i f breast prostheses are present) can cause
ischemi a to breast ti ssue and shoul d be avoi ded.
Abdominal Compression
Compressi on of the abdomen by the weight of the prone pati ent's trunk can cause vi scera to force
the diaphragm cephal ad enough to i mpair venti lation. If i ntra-abdomi nal pressure approaches or
exceeds venous pressure, return of bl ood from the pel vi s and l ower extremi ties i s reduced or
obstructed. Because the vertebral venous plexuses communi cate di rectly wi th the abdomi nal
veins, i ncreased i ntra-abdomi nal pressure i s transmi tted to the perivertebral and i ntraspi nal
surgical field in the form of venous di stenti on and i ncreased diffi culty wi th hemostasi s. All of the
vari ous supporti ve pads and frames, when properl y used, are desi gned to remove pressure from
the abdomen and avoid these probl ems.
66

Viscerocutaneous Stomata
Stomata that drai n visceral contents i nto contai ners affi xed to the abdomi nal wal l are at ri sk in
FIGURE 23-21. Assessment of a potenti al thoracic outl et syndrome. A. The pati ent has a
hi story of distress when tryi ng to work or sleep with arms over head. B. Intervi ew was
carri ed out wi th pati ent's hands cl asped on occi put and radi al pul ses checked for dampi ng.
(Reproduced wi th permi ssi on from Fi gure 10-30, (p. 186) of McLeskey CH [ed]: Geri atric
Anesthesi ol ogy. Bal timore, Wi ll i ams & Wi l ki ns, 1997.)
P.661
the prone positi on i f they li e agai nst a part of the ventral supporti ng frame or pad (Fi g. 23-22).
Compressi ve ischemi a of the stomal ori fi ce can cause i t to sl ough.
Knee Injuries
Obese pati ents, or those who have pathologi c condi tions of the knees, can have their knee joints
i njured i n the kneel i ng posi ti on if the supportive ledges are not heavi l y padded (see Fi g. 23-19).
Often there i s no sui tabl e alternati ve posi tion for these pati ents, and the possibi l ity of
postoperative knee problems caused by the kneel i ng prone posi ti on shoul d be careful l y di scussed
in the preanesthetic intervi ew.
HEAD-ELEVATED POSITIONS
P hysi ol ogy
Circulatory
Coonan and Hope
100
have revi ewed ci rculatory changes that occur i n al ert humans with the change
from the supi ne to the erect positi on. As the head i s rai sed above the l evel of the heart, pressure
gradi ents devel op and i ncrease wi th the degree of elevation. Bl ood shi fts from the upper body
toward the feet. Atrial fi l li ng pressures decrease, sympatheti c tone increases, parasympatheti c
tone decreases, the renin-angiotensi n-al dosterone system i s activated, and fl ui d and el ectrolytes
are retai ned by the kidneys.
101, 102
Al bi n et al
103, 104
and Dal rympl e
105
noted si mi l ar alterations i n
cardi ovascul ar parameters when the head-el evated posi ti on was establ ished after pati ents were
FIGURE 23-22. Postural supports compromi si ng vi sceral stoma. Both the verti cal abdominal
support of a devi ce desi gned to mai ntai n a patient i n the l ateral posi ti on (A) and the
longi tudi nal chest rol l s supporti ng a pronated pati ent (B) can cause i schemi c compressi on of
a viscerocutaneous anastomosis and subsequent necrosis. Surgical repair of the stoma may
be needed. (Modi fi ed wi th permi ssi on from Fi gure 22-18, (p. 340) of McLeskey CH [ed]:
Geriatri c Anesthesiology. Balti more, Wi l li ams & Wil ki ns, 1997.)
anesthetized. Al though si gni fi cant changes were not encountered wi th l ess than 60 degrees of
head-up ti lt, the magni tude of changes i n anesthetized pati ents was often greater than i n the
awake patients.
The presence of an intracrani al pathol ogi c process can be expected to exacerbate potential ly
harmful reducti ons i n cerebral bl ood flow associated wi th head el evati on.
106
In the anesthetized,
seated patient, mean arteri al pressure should be measured at the l evel of the ci rcl e of Wi ll i s
because that si te is more rel i abl e as an i ndi cator of cerebral perfusi on pressure i n the head-
el evated posture than i s measurement at the l evel of the arm or wri st.
100
Addi ti onal i nformati on
regardi ng the neurosurgi cal i mpl i cati ons of the head-el evated (si tti ng) posi ti on appear in Chapter
27.
Respiratory
As the pati ent becomes more upright in the head-el evated dorsal decubitus positi on, the
inspi ratory stroke of the diaphragm becomes l ess i mpeded by the bul k of abdomi nal vi scera.
Spontaneous chest wall motion requires less effort, and less pressure is needed to i nfl ate the
lungs duri ng passi ve inspirati on. Functi onal resi dual capacity i ncreases in the head-el evated
positi ons.
107

Var i at i ons of t he Head- El evat ed P osi t i ons
Sitting
The classi c si tti ng posi tion for surgery places the pati ent i n a semi recl ining posture on an
operating tabl e, wi th the legs elevated to approximatel y the l evel of the heart and the head flexed
ventral ly on the neck (Fi g. 23-23). Head flexion should not be suffi cient to force the chin i nto the
suprasternal notch (see Mi dcervi cal Tetrapl egia section). Elasti c stockings or compressi ve wraps
around the l egs reduce pool i ng of bl ood i n the lower extremi ties. The head often i s hel d i n pl ace
by some type of a face rest or by a three-pi n skul l fi xati on frame.
SupineTilted Head Up
A dorsal recumbent positi on wi th the head of the pati ent elevated is used for many operati ons
invol vi ng the ventral and lateral aspects of the head (Fi g. 23-24) and neck, and occasi onal l y wi th
the neck fl exed, for transcrani al access to the top of the brai n. Its purpose i s to improve access to
the surgi cal target

for the operating team as wel l as to drai n blood and i rri gation sol utions away from the wound. The
back secti on of the surgi cal table can be el evated as needed to produce a l ow sitti ng posi ti on (see
Fi g. 23-24A), or the enti re table can be rotated head-hi gh wi th the patient' s extended l egs
supported by a foot rest (see Fi g. 23-24B). Al though the degree of til t typi cal ly is not great, smal l
pressure gradi ents are created al ong the vascul ar axi s that can pool blood i n the l ower extremi ties
or entrai n ai r i n patulous vessels that are incised above the l evel of the heart.
FIGURE 23-23. A. Conventi onal neurosurgi cal si tti ng posi tion. The l egs are at approxi matel y
the level of the heart and gently fl exed on the thighs; the feet are supported at right angles
to the l egs; subgl uteal paddi ng protects the sci ati c nerve. The frame of the head holder is
properl y cl amped to the si de rai l s of the back secti on i n the event of hemodynami cal ly
si gni fi cant ai r embol i sm. B. Improper attachment of the head frame to the tabl e si de rai l s at
the thigh secti on. In this posi tion, the pati ent' s head coul d not be qui ckl y l owered because i t
woul d requi re di sengagi ng the skul l cl amp. (Reproduced wi th permi ssi on from Fi gure 7-1, (p.
72) of Marti n JT, Warner MA [eds]: Posi ti oning i n Anesthesi a and Surgery, 3rd ed.
Phi ladelphi a, WB Saunders, 1997.)
P.662
FIGURE 23-24. Head-el evated posi ti ons often used for operati ons about the ventral and
ventrol ateral aspects of the head, face, neck, and cervical spi ne. A. The l egs are at
approxi mately heart l evel and the gradi ent i nto the head i s appreci abl e but sl i ght. B. The fl at
For operations around the shoulder joint, the pati ent may be pl aced in a head-el evated semisupi ne
positi on, wi th the upper torso rotated toward the nonsurgi cal shoul der and supported by a fi rm rol l
or pad (Fi g. 23-25). The upper trunk is moved laterall y unti l the rai sed surgi cal shoul der extends
beyond the edge of the operating tabl e. The torso i s supported so that the hi ps are on the tabl e,
the surgical shoulder is off and above the tabl e edge, and the head rests on ei ther a pil l ow (see
Fi g. 23-25A) or a horseshoe head rest (see Fi g. 23-25B). Access is thereby provided to both the
dorsal and ventral aspects of the shoul der gi rdl e. The surgical arm remains on the ventral torso
and i s prepared and draped to be mobi le i n the surgical fiel d.
LateralTilted Head Up
The l ateral decubi tus posi ti on wi th the head somewhat el evated, a means of access to
occi pi tocervi cal l esions, has al so been referred to as the park bench posi tion.
108
Al l the stabil i zi ng
requi rements needed for the usual l ateral decubi tus posi ti on appl y. The head may be hel d fi rml y i n
a three-pi n skul l fi xati on hol der, which can be readjusted as needed during surgery, or supported
by pi l l ows or paddi ng. Al though the degree of head elevation used typi cal ly is l ess than 15
degrees, the posi ti on does not compl etel y remove the threat of ai r emboli zation. The
anesthesiol ogi st has good access to the pati ent' s face and ventral thorax for purposes of
moni toring, manipulation,

and resuscitati on. Consi derabl e attention shoul d be di rected to avoi di ng compressi on of neck
tabl e and foot rest are useful when a thyroidectomy is planned under regi onal anesthesi a.
(Reproduced wi th permi ssi on from Fi gure 7-7, (p. 89) of Marti n JT, Warner MA [eds]:
Positi oning i n Anesthesi a and Surgery, 3rd ed. Phi l adel phi a, WB Saunders, 1997.)
FIGURE 23-25. A. The barber chai r posi ti on for surgery around the shoulder joint. B. The
upper torso i s rotated toward the nonsurgical shoul der and supported wi th a fi rm rol l or pad.
P.663
veins, which can lead to an increase i n intracrani al pressure and to edema of the tongue.
ProneTilted Head Up
The ventral decubi tus posture wi th the table rotated head hi gh (Fi g. 23-26) can be used to access
dorsal structures of the head and neck. Usual l y the percei ved advantage of this positi on compared
to a si tti ng posi ti on i s the avoi dance of air embol ization. Al though the pressure gradi ents for air
entrainment i nto patulous vei ns are less than i n the full si tti ng posi ti on, the hazard i s not
el i mi nated. As a resul t of the posi ti ve-pressure i nflation cycl e of passi ve ventil ati on, a bothersome
recurrent fl ux of cerebrospi nal fl uid i nto and out of the exposed wound may be encountered. The
posture al so restricts resusci tati ve access to the ventral thorax.
Compl i cat i ons of t he Head- El evat ed P osi t i ons
Postural Hypotension
In the anestheti zed patient, establ i shi ng any of the head-el evated posi ti ons i s frequently
accompani ed by some degree of reducti on i n systemi c bl ood pressure. The normal protecti ve
refl exes are i nhi bi ted by drugs used during anesthesi a. Measuri ng mean arteri al pressures at the
level of the ci rcl e of Wil l is i s recommended to assess cerebral perfusion pressures more
accurately.
Air Embolus
Air embol izati on is potential ly lethal . In the bloodstream, ai r mi grates to the heart, where i t
creates a compressi ble foam that destroys the propul sive effi ciency of ventricul ar contracti on and
irri tates the conducti on system. Air can al so move into the pulmonary vascul ature, where bubbl es
obstruct smal l vessels and compromise gas exchange, or it can cross through a patent foramen
oval e to the l eft si de of the heart and the systemi c circul ati on.
FIGURE 23-26. The skull -pi n head rest used to stabi l ize a pati ent i n the head-el evated
prone posi tion. Note the chest roll s used to free the abdomen from compression and the
gl uteal strap to mi ni mize caudad sl i ppage after head-up ti l t. (Reproduced wi th permi ssi on
from Fi gure 7-6, (p. 88) of Marti n JT, Warner MA [eds]: Posi ti oni ng i n Anesthesia and
Surgery, 3rd ed. Phi l adel phi a, WB Saunders, 1997.)
The potenti al for venous ai r emboli zati on i ncreases wi th the degree of elevati on of the operati ve
si te above the heart. Al though the occurrence of ai r emboli i s a rel ati vel y frequent phenomenon i n
head-el evated posi ti ons, most of the embol i are small i n vol ume, cl inicall y si l ent, and recogni zabl e
onl y by sophi sti cated Doppl er detecti on techni ques. Neverthel ess, the potential for conti nuing,
dangerous accumul ati ons of entrai ned air requi res i mmedi ate detecti on of the emboli zati on, a
careful search for i ts portal of entry, and prompt treatment of i ts cl ini cal effects.
Pneumocephalus
In the usual crani otomy, most of the brai n l i es subjacent to the incisi on. After the dura is i nci sed,
cerebrospi nal fl ui d i s removed to i mprove worki ng condi tions, and the surgical field is open to the
ai r. During cl osure of the crani otomy, most of the intracranial air escapes from the wound and any
residual pneumocephalus is of l i ttl e consequence. However, when an i nci sion i s made through the
dura i n the posteri or fossa or cervi cal spine of a seated pati ent, the bulk of the brai n li es above
the incisi on. Cerebrospi nal fl ui d drai ns downward out of the wound, and ti ssue retracti on can all ow
ai r to bubbl e up over the surfaces of the brain to become trapped i n the upper reaches of the
cranium.
109
When brain mass is decreased by ventricul ar drai nage, steroi ds, and di uresi s, the
space avai labl e to a pneumocephal us i s enl arged. Di ffusi on of ni trous oxide into the accumulated
ai r, or the warmi ng of trapped gas, can produce a tensi on pneumocephal us wi th si gns of i ncreased
i ntracrani al pressure and del ayed awakening from anesthesi a.
Toung et al
110
found postoperative pneumocephal us i n al l of a group of seated patients and in
most of those who had been i n the prone or the park bench posi ti on. Intraventricul ar ai r was
present in most of the seated patients and was rare in those in the other positi ons. None of their
group of 100 pati ents had neurol ogi c changes attri butabl e to the trapped intracranial air.
Standefer et al
111
reported a 3% i ncidence of symptomatic (tension) pneumocephalus in seated,
anesthetized pati ents whose duras were opened.

P.664
TABLE 23-1 Summary of Task Force Consensus
Preoperative assessment: When judged appropri ate, i t is helpful to ascertai n that
patients can comfortabl y tol erate the anti ci pated operati ve positi on.
Upper Extremity Positioning:
Arm abducti on shoul d be l i mi ted to 90 degrees or less in supine pati ents. Pati ents
who are posi ti oned prone may comfortabl y tol erate arm abducti on of 90 degrees or
more.
Arms should be posi ti oned to decrease pressure on the postcondylar groove of the
humerus (ulnar groove). When arms are tucked at the si de, a neutral forearm
positi on i s recommended. When arms are abducted on arm boards, either
supinati on or a neutral forearm positi on i s acceptabl e.
Prol onged pressure on the radi al nerve i n the spiral groove of the humerus shoul d
be avoi ded.
Extension of the el bow beyond a comfortabl e range may stretch the medi an nerve.
Lower Extremity Positioning:
Lithotomy posi tions that stretch the hamstri ng muscle group beyond a comfortabl e
range may stretch the sci ati c nerve.
Ocular Compression
Pressure from a padded head rest on the eyes of a patient who has been pl aced i n a head-el evated
positi on can di sl ocate a crystal li ne lens or render the gl obe i schemic. Uni lateral bli ndness has
been reported as a resul t (see Bl indness secti on).
112
Modern skull -pi n head clamps that gri p firml y
when properl y appl i ed have made ocul ar compressi on i n the sitting posi tion a rari ty. In the head-
el evated lateral decubi tus or prone posi tion, the threats to the eyes are those descri bed i n the
precedi ng discussions of those nonel evated postures.
Edema of the Face, Tongue, and Neck
Severe postoperati ve macrogl ossi a, apparentl y because of venous and lymphati c obstruction, can
be caused by prol onged, marked neck fl exi on.
113
Try to avoi d pl aci ng the pati ent' s chi n firml y
against the chest and use of an oral ai rway to protect the endotracheal tube. El l is et al
114
reported
a patient who needed a tracheostomy because of massi ve swell i ng of the tongue, l i ps, pharynx,
and epigl ottis occurri ng shortl y after extubati on at the end of a l engthy anestheti c in the si tti ng
positi on that involved deli berate hypotension. Extremes of neck fl exi on, wi th or wi thout head
rotati on, have been widel y used to gai n access to structures i n the posteri or fossa and cervical
spi ne, but their potenti al for damage shoul d be understood and excessi ve fl exi onrotati on avoi ded
if possibl e. Moore and associ ates
115
have descri bed fi ve cases of macrogl ossi a in pati ents wi th
posterior fossa di sease and have suggested that the pri mary mechanism is neurol ogical l y
determi ned rather than being the result of ei ther vascul ar obstruction or l ocal trauma. Thi s
Prol onged pressure on the peroneal nerve at the fi bul ar head shoul d be avoi ded.
Nei ther extensi on nor fl exi on of the hi p i ncreases the ri sk of femoral neuropathy.
Protective Padding:
Padded armboards may decrease the ri sk of upper extremity neuropathy.
The use of chest rol ls i n laterall y posi ti oned pati ents may decrease the ri sk of
upper extremi ty neuropathies.
Paddi ng at the el bow and at the fi bul ar head may decrease the ri sk of upper and
lower extremi ty neuropathies, respecti vel y.
Equipment:
Properl y functioni ng automated blood pressure cuffs on the upper arms do not
affect the ri sk of upper extremity neuropathi es.
Shoul der braces i n steep head-down posi tions may increase the ri sk of brachial
pl exus neuropathi es.
Postoperative Assessment: A simpl e postoperati ve assessment of extremi ty nerve
functi on may l ead to earl y recogni ti on of peri pheral neuropathies.
Documentation: Charti ng speci fi c positi oning actions duri ng the care of pati ents may
resul t in i mprovements of care by (1) hel ping practi tioners focus attention on rel evant
aspects of pati ent posi ti oni ng and (2) providi ng i nformati on that conti nuous
improvement processes can use to l ead to refinements i n pati ent care.
probl em al so has been descri bed with the use of transesophogeal echocardi ography probes.
Midcervical Tetraplegia
Thi s devastati ng i njury occurs after hyperfl exi on of the neck, wi th or wi thout rotati on of the head,
and is attri buted to stretching of the spi nal cord wi th resulti ng compromi se of i ts vascul ature i n
the mi dcervi cal area. An element of spondyl osis or a spondyloti c bar may be i nvol ved.
116, 117
The
resul t is paral ysis bel ow the general l evel of the fifth cervi cal vertebra. Al though most reports i n
the li terature have descri bed the condi ti on as occurri ng after the use of the si tti ng positi on,
mi dcervi cal tetrapl egia has al so occurred after prol onged, nonforced head fl exi on for intracrani al
surgery in the supi ne posi ti on.
Sciatic Nerve
Stretch injuri es of the sci ati c nerve can occur i n some seated pati ents if the hi ps are markedl y
flexed wi thout bendi ng the knees. Prol onged compressi on of the sci atic nerve as i t emerges from
the pel vi s i s possi bl e i n a thi n, seated pati ent i f the buttocks are not sui tabl y padded. Foot drop
may be the result of i njuri es to ei ther the sci ati c nerve or the common peroneal nerve and can be
bi l ateral .
PERIOPERATIVE PERIPHERAL NEUROPATHIES
P r event i on
The Ameri can Soci ety of Anesthesi ol ogi sts approved an advi sory on peri pheral neuropathi es i n
1999.
118
Thi s advisory incl udes perti nent li terature and a summary of the opi ni ons of anesthesi a
provi ders on a vari ety of posi ti oni ng and

peri pheral neuropathy i ssues. The paucity of li terature rel ated to these i ssues li mi ted the advi sory
to recommendati ons based on opini ons and current practi ces of a broadly representati ve group of
anesthesia providers from around the United States. Addi ti onal i nput and opi ni ons were obtained
from consul tants from around the world. A summary of the fi ndi ngs of the advi sory i s shown i n
Tabl e 23-1.
P r act i cal Consi der at i ons
Efforts to prevent peri operative neuropathi es are frequentl y debated, and there often i s confusion
over how to manage a neuropathy once i t has occurred. In general , there are no data to support
recommendations on any of these issues. Therefore, the fol l owi ng opi nions have been formul ated
by personal experi ence, gui ded by advi ce from neurol ogists who primaril y care for patients wi th
peri pheral neuropathies, and seasoned or supported by specul ati on deri ved from anecdotal case
reports.
P addi ng- Exposed P er i pher al Ner ves
Many types of paddi ng materi al s are advocated to protect exposed peri pheral nerves. They often
consi st of cl oth (e.g., bl ankets and towels), foam sponges (e.g., eggcrate foam), and gel pads.
There are no data to suggest that any of these materi als i s more effecti ve than any other, or that
any i s better than no paddi ng at al l . A good rul e of thumb woul d be to posi ti on and pad exposed
peri pheral nerves to (1) prevent their stretch beyond normal ly tol erated li mits whil e awake; (2)
avoi d thei r di rect compressi on, i f possi bl e; and (3) di stri bute over as l arge an area as possi ble any
compressi ve forces that must be pl aced on them.
P r ol onged Dur at i on i n One P osi t i on
Prolonged duration in one posi tion appears to increase the ri sk of neuropathy and other
i ntegumentary damage. For exampl e, prol onged duration in li thotomy posi ti ons greatly i ncreases
the ri sk of l ower extremi ty neuropathy.
119, 120
When possi bl e, i t woul d appear prudent to l i mi t as
P.665
much as practical the ti me any patient spends i n one posi ti on. However, intermi ttent movement of
the li mbs or head duri ng the intraoperati ve peri od may i ncrease the opportunity for a number of
di fferent probl ems, i ncl udi ng but not li mited to di sl odgi ng an endotracheal tube, abradi ng a
cornea, or movi ng an extremi ty i nto a subopti mal posi ti on. Practiti oners must judge the benefi ts
versus risks of any i ntraoperati ve changes i n a patient' s posi tion.
Cour se of Act i on f or t he P at i ent wi t h a Neur opat hy
Although each situation is uni que and requi res careful assessment, the foll owi ng gui del i nes may
suggest a basi c course of acti on that wil l l ead to appropri ate care:
121

Is the neuropathy sensory or motor? Sensory lesi ons are more frequently transient than
motor l esions. If the symptoms are numbness or ti ngl ing onl y, i t may be appropri ate to
inform the pati ent that many of these neuropathi es can be expected to resol ve duri ng the
first 5 days.
39
The patient should be instructed to avoi d postures that might compress or
stretch the i nvol ved nerve. Arrangements should be made for frequent contact with the
patient. A cal l to al ert a neurologi st i s appropri ate, and i f the symptoms sti ll persi st on
postoperative day 5, the neurologi st shoul d be consulted.
If the neuropathy has a motor component, a neurologist shoul d be consulted i mmedi atel y.
El ectromyographic studi es may be needed to assess the locati on of any acute l esi on. This
knowl edge may di rect an appropriate treatment plan. The studi es may also demonstrate
chroni c abnormal iti es of the nerve or, if appl i cabl e, the contralateral nerve.
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anal ysi s of 488 cases. Neurosurgery 14:649, 1984
112. Hol l enhorst RW, Svei n HJ, Benoi t CF: Unil ateral bl i ndness occurri ng duri ng anesthesi a for
P.667
neurosurgi cal operati ons. Arch Ophthal mol 52:819, 1954
113. McAl l ister RG: Macrogl ossia: A posi tional compl i cation. Anesthesi ology 40:199, 1974
114. El li s SC, Bryan-Brown CW, Hyderal ly H: Massi ve swell i ng of the head and neck.
115. Moore JK, Chaudhri S, Moore AP, Easton J: Macrogl ossi a and posteri or fossa di sease.
116. Hitselberger WE, House WF: A warning regarding the si tti ng posi ti on for acousti c tumor
surgery. Archi ves of Otolaryngology 106:69, 1980
117. Wi l der BL: Hypothesi s: The etiol ogy of midcervi cal quadri pl egi a after operati on with the
patient in the si tti ng posi tion. Neurosurgery 11:530, 1982
118. American Society of Anesthesiologists Task Force on Prevention of Perioperative
Peripheral Neuropathies: Practice advisory for the prevention of perioperative
peripheral neuropathies. Anesthesiology 92:1168, 2000
119. Warner MA, Martin JT, Schroeder DR et al : Lower extremi ty motor neuropathy associ ated
wi th surgery performed on pati ents in a l ithotomy posi tion. Anesthesi ology 81:6, 1994
120. Warner MA, Warner DO, Harper CM et al : Lower extremi ty neuropathi es associ ated wi th
the li thotomy posi ti on. Anesthesi ology 93:938, 2000
121. Warner MA: Perioperative neuropathies. Mayo Clin Proc 73:567, 1998
> Tabl e of Contents > Secti on IV - Prepari ng for Anesthesi a > Chapter 24 - Moni tori ng the Anestheti zed Pati ent
Chapter 24
Monitoring the Anesthetized Patient
Glenn S. Murphy
Jeffery S. Vender
KEY POINTS
Moni tori ng represents the process by whi ch anesthesiol ogi sts recogni ze and eval uate potenti al
physi ol ogi c probl ems i n a ti mel y manner. The term i s derived from monere, which in Lati n means
to warn, remi nd, or admoni sh. In perioperati ve care, moni toring i mpl ies the foll owing four
essential features: observati on and vi gi l ance, i nstrumentation, interpretati on of data, and
initi ati on of correcti ve therapy when indi cated.
Moni tori ng i s an essenti al aspect of anesthesia care. Pati ent safety is enhanced when
appropriate moni toring i s operati onal and cl i ni cal judgments are proper. Effecti ve monitori ng
reduces the potenti al for poor outcomes that may foll ow anesthesi a by identi fyi ng derangements
Effective monitoring reduces the potential for adverse outcomes i n the
peri operative setting by identi fyi ng derangements before they result i n seri ous
injury.
Alterations i n venti lati on, cardi ac output, distri buti on of pul monary bl ood flow,
and metabol i c acti vi ty can all infl uence the capnograph di spl ay duri ng carbon
di oxi de gas anal ysi s.
During di rect invasi ve arterial pressure moni toring, systemi c fi deli ty i s
optimized when the catheter and tubi ng are stiff, the mass of the fluid is small,
and the l ength of the connecting tubing i s not excessi ve.
On the basi s of avai l abl e evi dence, i t i s difficult to draw meani ngful concl usi ons
regardi ng the effecti veness of pul monary artery catheter monitori ng in reduci ng
morbi dity and mortali ty i n criti cal ly i ll pati ents. Expert opinion suggests that
peri operative compli cati ons may be reduced i f pul monary artery catheters
(PACs) are used in the appropri ate pati ents and setti ngs, and i f cl inici ans
i nterpret and appl y the data provided by the PAC correctl y.
Transesophageal echocardiography provi des a more accurate esti mation of
ventri cul ar prel oad than pulmonary artery catheteri zati on. Transesophageal
echocardi ography al so all ows the cl i ni cian to rapi dl y assess patients for
evidence of myocardial ischemia, cardi ac val vular dysfuncti on, and causes of
peri operative hemodynami c instabil i ty.
before they resul t i n seri ous or i rreversi bl e i njury. El ectronic monitors i mprove a physi cian' s
abi li ty to respond because they are abl e to make repetiti ve measurements at hi gher frequenci es
than humans and do not fatigue or become distracted. Moni toring devi ces i ncrease the specifi ci ty
and preci si on of cl i ni cal judgments. At no ti me i n the hi story of anesthesi a have practiti oners had
the capabil i ty routi nel y to moni tor so many di verse physi ol ogi c vari ables i n real ti me, often
noni nvasively, as they do today. Our understanding of the physi ol ogi c effects of anesthesi a and i ts
inherent ri sks i s enhanced by using appropri ate i ntraoperati ve physiol ogi c moni toring.
Thi s chapter discusses the methods by whi ch anesthesiol ogi sts moni tor organ function during
anesthesia care. The descripti ons of the technol ogic and sci enti fi c pri nci pl es used i n monitori ng
devices have been si mplified for clarity.
Cost contai nment has been rai sed as a reason to di scourage the use of expensi ve, technol ogi cal ly
advanced monitori ng systems. The value of a given moni tor depends on the cl ini cal experti se of
the anesthesi ol ogi st, the cli ni cal setting, the anestheti c techni que, and the performance of the
specific equipment in question. Monitori ng devices shoul d not be deni ed sol el y on the basi s of
expense.
1
Al though i t i s appropriate for society to demand cost contai nment, anesthesi ologists
have a responsibi l ity to assess how moni toring shoul d be used. Professi onal soci eti es, regul atory
agenci es, and the l egal professi on have pl ayed i mportant rol es i n establi shi ng current moni toring
practi ces.
Standards for basi c anestheti c moni tori ng have been establi shed by the Ameri can Soci ety of
Anesthesi ol ogi sts (ASA).

Since 1986, these standards have emphasi zed the evoluti on of technol ogy and practice. Today's
standards (last affirmed on October 15, 2003) emphasi ze the i mportance of regul ar and frequent
measurements, integrati on of cl inical judgment and experi ence, and the potenti al for extenuating
ci rcumstances that can i nfluence the appl icabi l i ty or accuracy of moni toring systems.
2

Standard I requi res qual i fi ed personnel to be present i n the operati ng room, to monitor the patient
conti nuousl y and modify anesthesi a care based on cl ini cal observati ons and the responses of the
patient to dynami c changes resul ting from surgery or drug therapy. Standard II focuses attenti on
on conti nual l y eval uati ng the pati ent' s oxygenati on, ventil ati on, ci rcul ati on, and temperature.
Standard II speci fi cal l y mandates the foll owi ng:
1. Usi ng an oxygen analyzer wi th a low concentration li mi t alarm during general anesthesia.
2. Quanti tatively assessi ng bl ood oxygenati on duri ng any anesthesi a care.
3. Conti nuously ensuri ng the adequacy of ventil ati on by physi cal diagnosti c techni ques duri ng
al l anesthesi a care. Quanti tati ve moni tori ng of ti dal vol ume and capnography are encouraged
in pati ents undergoing general anesthesi a.
4. Ensuri ng the adequacy of ci rcul ati on by the conti nuous di spl ay of the el ectrocardiogram
(ECG), and determi ni ng the arterial bl ood pressure at least at 5-mi nute i nterval s. Duri ng
general anesthesi a, ci rculatory function is to be conti nual l y eval uated by assessi ng the
quali ty of the pul se, ei ther electroni cal l y or by pal pati on or auscultati on.
5. Endotracheal i ntubation or l aryngeal mask ai rway i nserti on requires quali tati ve i dentificati on
of carbon dioxi de i n the expired gas. Duri ng general anesthesi a, capnography and end-ti dal
carbon dioxi de analysi s are encouraged.
6. During all anestheti cs, the means for conti nuousl y measuri ng the pati ent's temperature must
be avai l abl e. When changes i n body temperature are intended or anti ci pated, temperature
should be conti nuousl y measured and recorded on the anesthesia record.
The ASA standards emphasi ze the melding of physical signs with i nstrumentati on. El ectroni c
moni tori ng, no matter how sophi sti cated or comprehensi ve, does not necessari ly reduce the need
for cli nical ski l l s such as inspection, pal pati on, and auscul tati on. Al though the authors bel ieve that
P.669
el ectronic moni tors augment cli ni cal judgments when properl y used, there i s li ttl e evi dence that
el ectronic moni tors, by themselves, reduce mortal ity or morbi di ty. Moreover, there i s consi derable
controversy regardi ng the need to appl y specific monitors i n uni que cl i ni cal situations, parti cul arl y
those that may add si gni fi cant cost. Moni tori ng can be classi fi ed as invasi ve, mi ni mall y invasi ve,
or noni nvasi ve. Invasi ve moni tors place pati ents at risk for compl i cations related to thei r
appl icati on and use. Anesthesiol ogi sts must bal ance the potenti al ri sk of i nsti tuti ng i nvasi ve
moni tori ng wi th the presumed benefits deri ved from i ts appl i cati on.
The variety of devices available for patient moni toring i s expansive and changi ng as advances i n
bi omedi cal engi neering fi nd their way into the marketpl ace. The Association for the Advancement
of Medi cal Instrumentati on has been effective i n promoti ng desi gn gui del i nes to ensure patient
and operator safety and reduce stress and di stracti ons often associ ated with medi cal moni toring.
3

The prol iferati on of al arm tones duri ng anesthesia care can be di sturbi ng and may paradoxi cal l y
impai r cl i ni cal vi gi lance. Moni toring systems may be i nsuffi cientl y sensi ti ve to reject errors.
During routi ne anesthesia care, a mi ni mum of fi ve alarms (i nspi red oxygen, ai rway pressure,
oxi metry, bl ood pressure, and heart rate) shoul d be operati onal. Unfortunatel y, spuri ous warnings
occur wi th hi gh frequency duri ng routi ne anesthesi a moni tori ng. The integrati on of al arm si gnals i s
an i mportant area i n need of continui ng evaluati on. Loeb
4
reported that anesthesi a provi ders have
di fficul ty i n accuratel y recogni zi ng the source of an alarm tone. Al arm annunci ators usi ng unique
sound and vi sual prompts are i ncorporated into anesthesi a equi pment. Warning si gnal s for
ventil ati on, oxygenati on, drug admini stration, temperature, and cardiovascular parameters need
to be desi gned so that probl em i dentificati on i s fast, si mpl e, and rel evant.
INSPIRATORY AND EXPIRED GAS MONITORING: OXYGEN
The concentrati on of oxygen i n the anesthetic ci rcui t must be measured. Measuring i nspired
oxygen does not guarantee the adequacy of arteri al oxygenati on.
5
Gas machi ne manufacturers
place oxygen sensors on the inspired limb of the anesthesi a circui t to ensure that hypoxi c gas
mi xtures are never del i vered to patients. Oxygen monitors require a fast response time (2 to 10
seconds), accuracy ( pm2%), and stabi li ty when exposed to humi di ty and i nhal ati on agents.
P ar amagnet i c Oxygen Anal ysi s
Oxygen i s a hi ghl y paramagneti c gas. Paramagneti c gases are attracted to magnetic energy
because of unpai red electrons i n thei r outer shel l orbi ts. Di fferenti al paramagneti c oxi metry has
been i ncorporated i nto a vari ety of operati ng room moni tors. These instruments detect the change
in sample l i ne pressure resul ti ng from the attracti on of oxygen by switched magnetic fields. Signal
changes duri ng electromagnetic swi tching correl ate with the oxygen concentrati on in the sampl e
li ne.
Gal vani c Cel l Anal yzer s
Gal vani c cel l anal yzers meet the performance criteri a necessary for operati ve monitori ng. These
anal yzers measure the current produced when oxygen diffuses across a membrane and i s reduced
to mol ecular oxygen at the anode of an electri cal circui t. The el ectron fl ow (current) i s
proporti onal to the parti al pressure of oxygen i n the fuel cel l. Gal vani c cell analyzers requi re
regul ar repl acement of the galvanic sensor capsule. In the sensor, the el ectric potenti al for the
reduction of oxygen resul ts from a chemical reaction. Over ti me, the reactants require
repl eni shment.
6

P ol ar ogr aphi c Oxygen Anal yzer s
Pol arographi c oxygen anal yzers are commonl y used in anesthesi a moni toring. In this
el ectrochemical system, oxygen di ffuses through an oxygen-permeable polymeri c membrane and
parti cipates i n the foll owi ng reaction: O
2
+ 2H
2
O + 4e 4 OH
-
. The current change is proportional
to the number of oxygen mol ecules surrounding the el ectrode. Pol arographi c oxygen sensors are
versati l e and are i mportant components of gas machi ne oxygen anal yzers, bl ood gas analyzers,
and transcutaneous oxygen anal yzers.

MONITORING OF EXPIRED GASES
Car bon Di oxi de
Expiratory CO
2
monitoring (PECO
2
) has evol ved as an i mportant physi ol ogic and safety
moni tor. CO
2
is usuall y sampl ed near the endotracheal gas del ivery interface. Al terations i n
ventil ati on, cardi ac output (CO), di stri buti on of pul monary bl ood fl ow, and metabol i c activi ty
infl uence PECO
2
and the capnograph di spl ay obtai ned duri ng quanti tati ve expi red gas anal ysi s.
Capnometry is the measurement and numeric representati on of the CO
2
concentrati on during
inspi ration and expi rati on. A capnogram is a continuous concentrati onti me di splay of the CO
2

concentration sampl ed at a pati ent's ai rway during venti l ati on. Capnography is the conti nuous
moni tori ng of a pati ent's capnogram. The capnogram i s di vi ded i nto four di sti nct phases (Fi g. 24-
1). The fi rst phase (AB) represents the i ni tial stage of expi ration. Gas sampl ed duri ng thi s phase
occupi es the anatomi c dead space and is normall y devoi d of CO
2
. At poi nt B, CO
2
-contai ni ng gas
presents i tsel f at the sampl ing site, and a sharp upstroke (BC) is seen in the capnogram. The
sl ope of this upstroke is determi ned by the evenness of venti lati on and al veolar emptyi ng. Phase
CD represents the al veol ar or expi ratory pl ateau. At thi s phase of the capnogram, al veolar gas i s
bei ng sampl ed. Normal l y, thi s part of the waveform i s almost hori zontal. Poi nt D is the hi ghest
CO
2
value and i s cal l ed the end-ti dal CO
2
(ETCO
2
). ETCO
2
is the best reflection of the al veol ar CO
2

(PACO
2
). As the pati ent begins to i nspi re, fresh gas i s entrained and there i s a steep downstroke
(DE) back to basel i ne. Unl ess rebreathi ng of CO
2
occurs, the basel ine approaches zero.
The uti l i ty of capnography depends on an understandi ng of the rel ati onshi p between arteri al CO
2

(PaCO
2
), al veolar CO
2
(PACO
2
), and ETCO
2
. Thi s concept assumes that ventil ati on and perfusi on
are appropri ately matched, that CO
2
is easi ly di ffusi bl e across the capi l laryal veolar membrane,
and that no sampl i ng errors occur duri ng measurement. If these condi ti ons are met, changes in
ETCO
2
reflect changes in PaCO
2
even if it i s assumed that al l alveol i do not empty at the same
ti me. If one assumes an ideal ized mathemati cal model of venti l ati onperfusi on, ETCO
2

PACO
2

PaCO
2
. If the PaCO
2
PACO
2
gradi ent is constant and small , capnography provi des a noni nvasi ve,
conti nuous, real -ti me refl ecti on of ventil ati on. Duri ng general anesthesi a, the ETCO
2
PaCO
2

gradient typi cal l y i s 5 to 10 mm Hg. A maldi stri bution of venti lation and perfusion (

P.670
FIGURE 24-1. The normal capnogram. Poi nt D del i neates the end-ti dal CO
2
. ETCO
2
is the
best reflecti on of the al veolar CO
2
tensi on.
/

) or probl ems i n gas sampl i ng may result i n a widening of the ETCO
2
PaCO
2
gradi ent.

/

maldi stributi on i s a common cause of an i ncreased PaCO
2
PACO
2
gradi ent. Other pati ent factors
that may influence the accuracy of ETCO
2
moni toring by widening the PaCO
2
ETCO
2
gradi ent
incl ude shal l ow ti dal breaths, prol ongation of the expi ratory phase of venti l ati on, or uneven
al veol ar emptyi ng.
Dead space (wasted) venti l ati on i s the extreme example of

/

mi smatch, where a compl ete absence of perfusi on in the presence of adequate al veol ar ventil ati on
occurs. Because onl y perfused al veol i can partici pate i n gas exchange, the nonperfused alveol i
have a PaCO
2
of zero. The venti l ati on-weighted average of the perfused and nonperfused al veoli
determi nes the ETCO
2
. Therefore, conditi ons resul ting i n an increase of dead space ventil ati on
lower the ETCO
2
measurement and increase the PaCO
2
ETCO
2
gradi ent. The common cl i ni cal
causes associ ated wi th a wi dened PaCO
2
ETCO
2
gradi ent include emboli c phenomena (thrombus,
fat, air, amniotic flui d), hypoperfusi on states wi th reduced pul monary bl ood flow, and chroni c
obstructive pul monary disease. In contrast, conditi ons that i ncrease pul monary shunt (perfusi on i n
the absence of venti l ati on) resul t i n minimal changes i n the PaCO
2
ETCO
2
gradi ent.
Capnography i s an essential element i n determini ng the appropri ate pl acement of endotracheal
tubes. The presence of a stabl e ETCO
2
for three successi ve breaths i ndi cates that the tube is not
in the esophagus. A conti nuous, stable CO
2
waveform ensures the presence of alveol ar venti lation
but does not necessari l y i ndi cate that the endotracheal tube i s properl y positi oned i n the trachea.
For example, the tip of the tube coul d be l ocated i n a mai n-stem bronchus. Capnography i s al so a
moni tor of potenti al changes in perfusi on or dead space, i s a very sensiti ve i ndi cator of anestheti c
ci rcuit di sconnects and gas ci rcuit l eaks, and i s a method to detect the qual i ty of CO
2
absorption.
Increases in ETCO
2
can be expected when CO
2
production exceeds venti l ati on, such as i n
hyperthermia or when an exogenous source of CO
2
is present. Tabl e 24-1 summari zes the common
el ements that may be reflected by changes i n ETCO
2
during anesthesi a care.
TABLE 24-1 Factors That May Change End-Tidal Co
2
(ETCO
2
) During Anesthesia

Increases in ETCO
2
Decreases in ETCO
2
ELEMENTS THAT CHANGE CO
2
PRODUCTION
Increases in metabolic rate Decreases in metabolic rate
Hyperthermi a Hypothermia
Sepsi s Hypothyroi di sm
Mal i gnant hyperthermi a
Shi veri ng
A sudden drop i n ETCO
2
to near zero fol l owed by the absence of a CO
2
waveform i s a potenti al l y
li fe-threatening probl em that coul d i ndi cate mal positi on of an endotracheal tube i nto the pharynx
or esophagus, sudden severe hypotensi on, pul monary emboli sm, a cardi ac arrest, or an arti fact
resul ti ng from disruption of sampl i ng l i nes. When a sudden drop of the ETCO
2
occurs, it i s
essential to quickl y veri fy that there i s pul monary venti l ati on and to identi fy physi ol ogic and
mechani cal factors that mi ght account for a zero-li ne capnogram. During l ife-savi ng
cardi opul monary resuscitati on, the generati on of adequate perfusion can be assessed by the
restoration of the CO
2
waveform.
Whereas abrupt decreases i n the ETCO
2
are often associ ated wi th an al tered cardi opulmonary
status (e.g., embol i sm or hypoperfusi on), gradual reductions i n ETCO
2
more often

refl ect decreases i n PaCO
2
that occur after i ncreases i n mi nute venti lati on where venti lation
overmatches CO
2
production.
The size and shape of the capnogram waveform can be informati ve.
7
A slow rate of ri se of the
second phase (BC, see Fi g. 24-1) i s suggesti ve of ei ther chroni c obstructi ve pul monary di sease or
acute airway obstructi on as from bronchoconstricti on (asthma). A normal l y shaped capnogram
with an increase in ETCO
2
suggests alveol ar hypoventil ati on or an i ncrease in CO
2
production.
Transient increases i n ETCO
2
are often observed during tourniquet rel ease, aortic unclampi ng, or
the admini stration of bicarbonate.
Several methods for the quantifi cati on of CO
2
have been appl i ed to patient moni tori ng systems.
One of the most commonly used methods i s based on i nfrared absorption spectrophotometry
(IRAS).
Infrared Absorption Spectrophotometry
Asymmetri c, polyatomi c mol ecul es li ke CO
2
absorb infrared l ight at speci fi c wavel engths.
Operati ng room IRAS devi ces can detect CO
2
, N
2
O, and the potent i nhaled anesthetic agents.
Operating room i nstruments are desi gned to measure the unique energy absorbed by the gases
and vapors of i nterest when a sampl e of the i nspi red and expi red gas i s pl aced i nto the opti cal
path of an i nfrared beam.
8
The mixtures compli cate the anal ysis because of interacti ons between
the gases and vapors and the cl oseness of absorpti on spectra for the gases of i nterest. All
anesthetic vapors absorb i nfrared l ight at 3.6 m. Therefore, manufacturers usi ng this si gnature
cannot di spl ay with certai nty the concentration of a speci fic anesthetic agent of i nterest. Opti cal
fil ters and uni que detecti on systems enhance the sensi tivity of IRAS monitori ng and permi t
estimati on of CO
2
, N
2
O, and the speci fi c potent inhal ati onal agent present i n the measurement
chamber. IRAS devi ces have fi ve components: an i nfrared l i ght source, a gas sampl er, an opti cal
path, a detecti on system, and a si gnal processor. The li ght source produces the infrared energy.
The l i ght i s focused and fil tered so that the quali ty of the photons wi th respect to the energy and
Hyperthyroi dism
ELEMENTS THAT CHANGE CO
2
ELIMINATION
Hypoventi lati on Hyperventi l ati on
Rebreathi ng Hypoperfusi on
Pul monary emboli sm
P.671
frequency i s stable over time. Narrow wavelengths are then presented to the gas stream. Once the
sampl e has entered the measurement chamber, a detecti on system cal i brated to determi ne the
concentration of a specific gas or agent over ti me i s acti vated. Changes i n temperature, pressure,
and acousti c characteristics i n the detecti on chamber can be used to determi ne the concentrati on
of the gas or agents of i nterest. Si gnal detectors create el ectri cal currents anal yzed by the signal
processor, which transforms the current change to a measurement. The capnogram or agent
waveform is an oscil l oscopi c representati on of the electri cal current changes over ti me. The
si gnal -processi ng section of an IRAS i nstrument has a memory secti on that correl ates the
absorbed energy with a concentration as predi cted by the Lambert-Beer l aw.
Mul t i pl e Expi r ed Gas Anal ysi s
Most operating room gas analyzers i ncorporate methods so that they can moni tor concentrati ons
of at l east O
2
, CO
2
, and the inhal ed anestheti c agents. Mass spectrometry systems bombard the
gas mi xture wi th el ectrons, creati ng ion fragments of a predi ctabl e mass and charge. These
fragments are accel erated in a vacuum. A sampl e of thi s mi xture enters a measurement chamber,
where the fragment stream i s subjected to a hi gh magneti c fi el d. The magneti c fi el d separates the
fragments by their mass and charge. The fragments are defl ected onto a detector plate, and each
gas has a speci fic l andi ng si te on the detector pl ate. The i on impacts are proporti onal to the
concentration of the parent gas or vapor. The processor secti on of the mass spectrometer system
calculates the concentration of the gases of interest.
Another uni que approach to moni tor respiratory gases i s based on Raman scatteri ng. Raman
scatteri ng resul ts when photons generated by a hi gh-i ntensi ty argon l aser col l i de wi th gas
mol ecul es. After i mpact, the gases are momentari ly excited to unstabl e vi brati onal and rotatory
states. When the gases return to thei r normal state, photons of a characteri sti c frequency are
emitted. The scattered photons are measured as peaks i n a spectrum that determi ne the
concentration and compositi on of respi ratory gases and i nhal ed vapors. Advances i n l aser
technol ogy have made Raman spectroscopic moni tors avail able for cli nical use. The i nstrument i s
fast and easy to cal i brate. O
2
, N
2
, N
2
O, CO
2
, and H
2
O vapor are all measurabl e usi ng Raman
scatteri ng technol ogy.
The cli nical i ndicati ons for routine CO
2
and O
2
gas moni tori ng are wel l documented. Moni tors
equipped to measure anestheti c gases are also preval ent and desirable. Ni trogen monitori ng
provi des quanti fi cati on of washout duri ng preoxygenati on. A sudden ri se i n N
2
in the exhaled gas
indicates ei ther i ntroducti on of air from l eaks in the anesthesi a del i very system or venous ai r
embol i sm. Cri ti cal events that can be detected by the anal ysi s of respi ratory gases and anestheti c
vapors are li sted in Tabl e 24-2.
TABLE 24-2 Detection of Critical Events by Implementing Gas Analysis
EVENT MONITORING MODALITY
Error i n gas del i very
O
2
, N
2
, CO
2
, agent anal ysi s
Anesthesi a machi ne mal functi on
O
2
, N
2
, CO
2
, agent
Disconnecti on
CO
2
, O
2
, agent anal ysi s
Vapori zer mal functi on or contaminati on Agent anal ysi s
OXYGENATION MONITORING
The assessment of oxygenation is an integral part of anesthesia practi ce. Earl y detecti on and
prompt i nterventi on may l imit seri ous sequelae of hypoxemia. The cli ni cal si gns associ ated wi th
hypoxemi a (e.g., tachycardi a, al tered mental status, cyanosi s) are often masked or di fficult to
appreci ate during anesthesi a. The mechani sms responsi bl e for hypoxemi a are mul tifactori al.
Oxygen anal yzers assess oxygen delivery to the pati ent. Other noninvasive technol ogies detect the
presence of arteri al hypoxemi a. Arteri al oxygen moni tors do not ensure adequacy of oxygen
del i very to, or uti li zation by, the ti ssues and shoul d not be consi dered a replacement for arteri al
bl ood gas measurements when more definiti ve i nformati on regardi ng oxygenati on i s desi red.

P ul se Oxi metr y
Pul se oxi metry i s the standard of care for monitori ng oxygenati on during anesthesi a. Pul se
oxi meters measure pul se rate and oxygen saturati on of hemogl obi n (Hb) (SpO
2
) on a noni nvasive,
conti nuous basis. Fi gure 24-2 displ ays the oxyhemogl obin di ssoci ati on curve that defi nes the
rel ati onship of hemogl obi n saturation and oxygen tensi on. On the steep part of the curve, a
predi ctabl e correl ati on exists between SaO
2
and PO
2
. In thi s range, the SaO
2
i s a good refl ecti on
of the extent of hypoxemia and the changi ng status of arterial oxygenati on. Shi fts in the
oxyhemogl obi n dissoci ation curve to the ri ght or to the l eft defi ne changes in the affini ty of Hb for
oxygen. At a PO
2
of >75 mm Hg, the SaO
2
plateaus and l oses its abi l ity to reflect changes in PaO
2
.
Anesthesi a ci rcuit l eaks
N
2
, CO
2
anal ysi s
Endotracheal cuff l eaks
N
2
, CO
2
Poor mask or LMA fit
N
2
, CO
2
Hypoventi lati on
CO
2
anal ysi s
Mal i gnant hyperthermi a
CO
2
Airway obstructi on
CO
2
Ai r embol i sm
CO
2
, N
2
Circui t hypoxi a
O
2
anal ysi s
Vapori zer overdose Agent anal ysi s
LMA, l aryngeal mask airway.
Modi fi ed wi th permi ssion from Knopes KD, Hecker BR: Monitori ng anesthetic gases. In
Lake CL (ed): Cl i ni cal Monitori ng, p 24. Phi l adel phi a, WB Saunders, 1990.
P.672
Pul se oxi metry i s based on several premi ses:
1. The col or of bl ood i s a functi on of oxygen saturati on.
2. The change i n col or results from the opti cal properti es of Hb and its i nteracti on wi th oxygen.
3. The rati o of O
2
Hb and reduced Hb can be determi ned by absorption spectrophotometry.
Pul se oxi metry combines the technol ogy of pl ethysmography and spectrophotometry.
Pl ethysmography produces a pul se trace that i s hel pful i n tracking circul ati on. Oxygen saturation
is determi ned by spectrophotometry, whi ch is based on the Beer-Lambert l aw. At a constant li ght
intensi ty and Hb concentrati on, the i ntensi ty of l ight transmi tted through a tissue i s a logari thmi c
functi on of the oxygen saturati on of Hb. Two wavelengths of l ight are requi red to distingui sh O
2
Hb
from reduced Hb. Li ght-emitting diodes in the pul se sensor emit red (660 nm) and near i nfrared
(940 nm) l ight. The percentage of O
2
Hb and reduced Hb i s determi ned by measuri ng the rati o of
i nfrared and red l i ght sensed by a photodetector. Pul se oximeters perform a pl ethysmographi c
anal ysi s to di fferenti ate the pul satil e arterial Hb saturati on from the nonpul satil e signal resul ti ng
from venous absorpti on and other tissues such as ski n, muscle, and bone. The absence of a
pul satil e waveform duri ng extreme hypothermi a or hypoperfusi on l i mi ts the abi li ty of a pul se
oxi meter to cal cul ate the SpO
2
.
The SpO
2
measured by pul se oximetry i s not the same as the arteri al saturation (SaO
2
) measured
by a l aboratory co-oxi meter. Pul se oximetry measures the functi onal saturation, whi ch i s defi ned
by the foll owing equation:
Functi onal SaO
2
= O
2
Hb/(O
2
Hb + reduced Hb) 100
Laboratory co-oxi meters use mul tipl e wavel engths to distingui sh other types of Hb by thei r
characteri sti c absorption. Co-oxi meters measure the fracti onal saturation, whi ch i s defi ned by
the foll owing equation:
Fractional SaO
2
= O
2
Hb/(O
2
Hb + reduced Hb + COHb + MetHb) 100
In cli ni cal ci rcumstances where other Hb moieti es are present, the SpO
2
measurement i s hi gher
FIGURE 24-2. The oxyhemoglobi n dissoci ati on curve. The rel ati onship between arteri al
saturation of hemogl obi n and oxygen tensi on i s represented by the si gmoid-shaped
oxyhemogl obi n dissoci ation curve. When the curve i s left-shifted, the hemogl obi n molecul e
bi nds oxygen more tightl y. (Reproduced wi th permi ssi on from Brown M, Vender JS: Non-
invasi ve oxygen moni tori ng. Cri t Care Cli n 4:493, 1988.)
than the SaO
2
reported by the bl ood gas l aboratory. In most patients, MetHb and COHb are
present in l ow concentrati ons so that the functi onal saturation approximates the fractional value.
Pul se oxi metry has been used in all patient age groups to detect and prevent hypoxemi a. The
cl i ni cal benefi ts of pul se oxi metry are enhanced by its simpli ci ty. Modern pul se oxi meters are
noni nvasive, conti nuous, and autocal i brati ng. They have quick response ti mes and thei r battery
backup provi des moni tori ng during transport. The cl i ni cal accuracy i s typi cal l y reported to be pm
2 to 3% at 70 to 100% saturati on and 3% at 50 to 70% saturati on. Publ i shed data from
numerous i nvestigations support accuracy and preci si on reported by i nstrument manufacturers.
The appropri ate use of pul se oxi metry necessi tates an appreciation of both physi ol ogi c and
technical l i mi tati ons. Despi te the numerous cl i ni cal benefi ts of pul se oxi metry, other factors affect
its accuracy and rel i abi l ity. Factors that may be present duri ng anesthesia care and that affect the
accuracy and rel i abi l i ty of pul se oximetry i ncl ude dyshemoglobins, vi tal dyes, nai l pol i sh, ambi ent
li ght, l i ght-emitting di ode vari abi l ity, moti on arti fact, and background noise. Electrocautery can
interfere with pul se oximetry i f the radi ofrequency emi ssi ons are sensed by the photodetector.
Reports of burns or pressure necrosi s exi st but are i nfrequent. These compl i cations can be
reduced by i nspecti ng the di gi ts duri ng monitori ng.
Recent devel opments in pul se oxi metry technol ogy permi t more accurate measurements of SpO
2

duri ng pati ent movement or low-perfusi on condi ti ons. These i nstruments use complex si gnal
processi ng of the two wavelengths of li ght to improve the si gnal -to-noise ratio and reject artifact.
Studi es i n vol unteers suggest that the performance of pulse oxi meters incorporati ng thi s
technol ogy i s superi or to conventional oximetry duri ng moti on of the hand.
9

There i s overwhel mi ng evidence supporti ng the capabil i ty of pul se oximetry for detecting
desaturation before i t i s cli nical l y apparent. Pul se oximetry has wide appl icabil i ty i n many hospi tal
and nonhospi tal settings. However, there are no defi ni ti ve data demonstrati ng a reducti on i n
morbi dity or mortali ty associ ated with the advent of pul se oxi metry. An ol der l arge, randomi zed
trial did not detect a si gni fi cant difference i n postoperative compl i cations when routine pulse
oxi metry was used.
10
However, there was a sense that use of SpO
2
provi ded earl y warni ng of
hypoxemi a, and anesthesiol ogi sts usi ng SpO
2
fel t a greater level of comfort than those who did
not use SpO
2
. A reducti on of anesthesia mortal ity, as wel l as fewer malpracti ce cl ai ms for
respiratory events, coi nci dent wi th the i ntroducti on of pul se oximeters suggests that the routine
use of these devices may have been a contributi ng factor. Pulse oxi metry i s an inexpensi ve,
essential tool for anesthesi a care.
BLOOD PRESSURE MONITORING
Peri operative measurement of arterial bl ood pressure i s an important indicator of the adequacy of
ci rculati on. Systemi c bl ood pressure moni toring i s commonly performed i ndi rectl y

using extremity-encircling cuffs or di rectl y by i nserti ng a catheter i nto an artery and transduci ng
the arteri al pressure trace. Today, anesthesi ologi sts have a variety of techniques avai labl e for
measuri ng changes i n systoli c, di astol i c, and mean arterial pressure (MAP).
I ndi r ect Measur ement of Ar t er i al Bl ood P r essur e
The si mpl est method of bl ood pressure determi nati on esti mates systoli c bl ood pressure by
pal pati ng the return of the arteri al pulse whil e an occluding cuff i s defl ated. Modi ficati ons of this
technique i nclude the observance of the return of Doppl er sounds, the transduced arteri al pressure
trace, or a photoplethysmographic pulse wave as produced by a pul se oximeter.
Auscultati on of the Korotkoff sounds permi t estimati on of both systoli c (SP) and di astol i c (DP)
bl ood pressures. MAP can be cal culated using an esti mati ng equati on (MAP = DP + 1/3 [SP-DP]).
Korotkoff sounds resul t from turbulent fl ow wi thin an artery created by the mechani cal
deformati on from the blood pressure cuff. Systol ic bl ood pressure i s si gnal ed by the appearance of
the fi rst Korotkoff sound. Disappearance of the sound or a muffl ed tone signal s the di astol i c bl ood
P.673
pressure.
The detecti on of sound changes i s subjecti ve and prone to errors based on defici encies i n sound
transmission or hearing. Cuff deflation rate al so infl uences accuracy. Qui ck defl ati ons
underesti mate bl ood pressure. Pal pati on and auscul tatory techni ques requi re pul sati l e bl ood fl ow
and are unrel i abl e during conditi ons of low fl ow. These techni ques are reasonabl y accurate when
aneroid gauges are wi thin cal i brati on, the encircling cuff is appropriately si zed and posi ti oned, the
infl ati on is above the true systoli c pressure, and the Korotkoff sounds or pul se i s properly
identi fi ed.
The Ameri can Heart Associ ati on recommends that the bl adder wi dth for i ndi rect bl ood pressure
moni tori ng shoul d approximate 40% of the ci rcumference of the extremi ty. Bl adder l ength should
be suffi cient to enci rcl e at l east 60% of the extremi ty. Fal sel y hi gh estimates resul t when cuffs
are too smal l , when cuffs are appl ied too l oosel y, or when the extremity is bel ow heart level .
Fal sel y l ow esti mates resul t when cuffs are too large, when the extremi ty is above heart l evel , or
after qui ck defl ati ons.
Since 1976, mi croprocessor-control led osci l lotonometers have repl aced auscul tatory and pal patory
techniques for routi ne peri operati ve bl ood pressure moni tori ng. Standard osci ll ometry measures
mean bl ood pressure by sensi ng the poi nt of maximal fluctuations in cuff pressure produced whi l e
deflating a blood pressure cuff. Most current i nstruments use osci ll ometri c techni ques to measure
systol i c, di astol i c, and mean bl ood pressures by determi ni ng parameter i dentificati on points duri ng
cuff deflation.
In a generi c noninvasi ve osci l lometri c moni tor (noni nvasive bl ood pressure, or NIBP), cuff
pressure i s sensed by a pressure transducer whose output i s di gi ti zed for processi ng. After the
cuff is inflated by an air pump, cuff pressure i s hel d constant whi le oscil l ati ons are sampled. If no
osci l lations are sensed by the pressure transducer, the mi croprocessor swi tches open a defl ati on
val ve, and the next lower pressure l evel is sampl ed for the presence of oscil l ati ons. The
mi croprocessor control l ing the operati on of the NIBP compares the ampl i tude of oscil l ati on pairs
and numeri cal l y di spl ays the bl ood pressure esti mate. Fi gure 24-3 depi cts how a typi cal NIBP is
obtai ned. In thi s exampl e, the effect of respi ratory variation, a premature ventri cul ar compl ex,
and cuff movement are demonstrated.
FIGURE 24-3. Di agram i ll ustrating moti on arti fact, a premature ventri cul ar contracti on, and
respiratory artifact as sensed by a Dinamap noni nvasive blood pressure moni tor. (Reproduced
with permission from Ramsey M: Bl ood pressure moni toring: Automated osci l lometri c devi ces.
J Cli n Monit 7:56, 1991.)
Automated osci ll ometry has been demonstrated to correl ate wel l wi th direct i ntra-arterial
measurement of MAP and di astol i c bl ood pressure. Automated oscil l ometry may underesti mate
systol i c bl ood pressure, with mean errors reported from -6.9 to -8.6 mm Hg compared with direct
radial artery pressure measurements.
Osci l lometry requi res the careful eval uation of several cardi ac cycl es at each i ncrement of
deflation to smooth out pronounced respi ratory variations or motion artifacts. Cuff movement or
erratic pulse transmission infl uences accuracy. In the anesthetized pati ent, automated
osci l lometry i s usual ly accurate and versati le. A vari ety of cuff si zes makes i t possi bl e to use
osci l lometry i n al l age groups.
Problems With Noninvasive Blood Pressure Monitoring
Cuff-based pressure moni toring conti nues to be the standard method used i n the peri operati ve
peri od. When cl ini cal ci rcumstances requi re frequent bl ood pressure readi ngs for a prol onged
peri od, i t i s advisable periodi cal ly to move the cuff to al ternati ve si tes. Fai l ure to defl ate the cuff
increases venous pressure. Hematomas have been descri bed both beneath and di stal to the cuff.
Tremors or shi veri ng can del ay cuff defl ati on and prol ong the defl ati on cycl e. A compartment
syndrome attri buted to a prol onged i nfl ati on cycl e has been described. Ulnar neuropathy has been
reported after the use of automated cycl ed blood pressure cuffs. Compressi on of the ul nar nerve
can be avoi ded by appl yi ng the enci rcl i ng cuff proxi mal to the ul nar groove. Automated sequenci ng
may alter the timing of i ntravenous drug admi ni stration when the access si te i s l ocated in the
same extremi ty. Hydrostatic errors resul t when bl ood pressure cuffs are pl aced on extremiti es that
are above or below the level of the ri ght atri um. The hydrostati c offset can be

mathemati cal l y corrected by addi ng or subtracti ng 0.7 mm Hg for each centi meter that the cuff i s
off the horizontal plane of the heart.
Indirect Continuous Noninvasive Techniques
Several methods for monitori ng bl ood pressure continuousl y and noni nvasi vely have been
desi gned and eval uated for i ntraoperati ve bl ood pressure surveil l ance. These techniques provi de
cl i ni ci ans wi th a continuous bl ood pressure esti mate and an accurate di splay of the arteri al bl ood
pressure trace. Indirect continuous noninvasi ve techni ques (ICNTs) conti nue to be eval uated
because i t i s desirabl e to enhance beat-to-beat bl ood pressure moni tori ng whil e reducing the
inherent ri sks and costs of direct intra-arterial moni toring. Cli ni cal studi es suggest that accuracy
and preci si on of ICNTs are satisfactory, even under condi ti ons of rapi dl y changi ng
hemodynamics.
11, 12, 13
At present, however, ICNTs are not consi dered substi tutes for di rect arterial
pressure monitori ng in cri tical l y i l l pati ents in the operati ng room.
I nvasi ve Measur ement of Vascul ar ( Ar t er i al Bl ood) P r essur e
Indwell i ng arterial cannulati on permi ts the opportuni ty to moni tor arteri al bl ood pressure
conti nuousl y and to have vascul ar access for arterial blood sampl i ng. Intra-arterial bl ood pressure
moni tori ng uses sal ine-fil l ed tubi ng to transmi t the force of the pressure pulse wave to a pressure
transducer that converts the di spl acement of a si li con crystal i nto voltage changes. These
el ectrical si gnal s are ampl ified, fi ltered, and displ ayed as the arterial pressure trace. Intra-arterial
pressure transduci ng systems are subject to many potenti al errors based on the physi cal
properti es of fl uid moti on and the performance of the catheter-transducer-ampl i fi cation system
used to sense, process, and di splay the pressure pul se wave.
The behavi or of transducers, fl ui d coupli ngs, signal ampl ificati on, and displ ay systems can be
descri bed by a compl ex second-order di fferenti al equation. Sol vi ng the equati on predicts the
output and characteri zes the fidel i ty of the system's abi li ty fai thfull y to di spl ay and esti mate the
arteri al pressure over ti me. The fi del i ty of fluid-coupl ed transducing systems is constrai ned by two
properties: damping () and natural frequency (Fo). Zeta () descri bes the tendency for sal i ne i n
the measuri ng system to extingui sh motion. Fo descri bes the tendency for the measuring system
to resonate. The fi deli ty of the transduced pressure depends on opti mi zi ng and Fo so that the
P.674
system can respond appropri ately to the range of frequenci es contained i n the pressure pul se
wave. Anal ysis of hi gh-fidel i ty recordi ngs of arteri al bl ood pressure i ndi cates that the pressure
trace contai ns frequenci es from 1 to 30 Hz.
The performance of a transduci ng system i s often descri bed by i ts bandwidth. The bandwi dth
contai ns the frequenci es i n whi ch the transducing system fai thful l y reproduces the frequenci es
contai ned in the pul se pressure wave. Conventional di sposabl e, sal i ne-coupl ed transducers wi th 60
in of pressure tubing have an acceptabl e bandwi dth and commonly have frequency responses
approachi ng 30 Hz. If the system begi ns to resonate (ri ngi ng) or becomes damp (inerti a), the
fidel i ty of the system i s impai red and esti mates of bl ood pressure become less accurate.
Measuring the bandwi dth of transducer systems requires compl i cated equi pment. Esti mates of
and Fo can be obtai ned at the bedsi de.
Studies have demonstrated that system fidel i ty i s optimized when catheters and tubi ng are sti ff,
the mass of the fl ui d i s smal l , the number of stopcocks is l i mi ted, and the connecting tubi ng i s not
excessive. Dampi ng l owers the effective bandwi dth of the transducer system, which promotes the
potential for resonance. Fi gure 24-4 demonstrates the effect of damping on the character of the
arterial pressure trace. In cli ni cal practice, underdamped cathetertransducer systems tend to
overesti mate systol i c pressure by 15 to 30 mm Hg and ampli fy artifact (catheter whip). Li kewise,
excessive increases i n reduce fi del i ty and underesti mate systoli c pressure. The presence of ai r
bubbl es i n the coupli ng fl ui d reduces the natural frequency of the transducing system. For cl inical
use, i t i s suffi ci ent to pl ace the transducer at the l evel of the right atrium, open the stopcock to
atmosphere, and bal ance the el ectroni c ampl ifyi ng system to di spl ay zero. Peri odi c checks of the
zero reference point ensures that transducer dri ft i s el i mi nated.
Gardner
14
suggested usi ng the fast fl ush test to determi ne the natural frequency and dampi ng
characteri sti cs of the transduci ng system. This test examines the characteri sti cs of the resonant
waves recorded after the release of a flush. Dampi ng i s esti mated by the ampl itude rati o of the
FIGURE 24-4. The relationshi p between the frequency of fl ui d-fil l ed transduci ng systems and
dampi ng. The shaded area represents the appropriate range of dampi ng for a given natural
frequency (Fn). The si ze of the wedge al so depends on the steepness of the arterial pressure
trace and heart rate. (Reproduced wi th permi ssion from Gardner RM: Di rect bl ood pressure
measurement: Dynami c response requi rements. Anesthesiol ogy 54:231, 1981.)
first pai r of resonant waves and the natural frequency i s esti mated by di vi di ng the paper speed by
the interval cycl e. Kl einman et al
15
have confi rmed the uti l ity of the fast flush test. Because many
therapeutic decisi ons are based on changes in arteri al bl ood pressure, i t is i mperati ve that
anesthesiol ogi sts understand the physi cal l imi tation i mposed by flui d-fi l l ed pressure transducer
systems. Si gni fi cant exaggeration of pressure measurements occur when the transducer system
has a resonant frequency i n the range of the pressure wave frequenci es. Systol ic pressure i s
underesti mated when measured with overdampi ng systems and overesti mated by underdampi ng or
resonati ng systems. Mean pressure esti mates are typicall y less affected even when dampi ng and
resonance are not opti mal.
Arterial Cannulation
Mul ti pl e arteri es can be used for di rect measurement of bl ood pressure, including the radi al,
brachial , axi ll ary, femoral , and dorsal is pedi s arteri es. The radi al artery remains the most popul ar
si te for cannul ation because of i ts accessibi l ity and the presence of a coll ateral bl ood suppl y. In
the past, assessment of the patency of the ulnar ci rcul ati on by performance of an Al l en' s test has
been recommended before cannul ati on. Al l en' s test i s performed by compressi ng both radi al and
ul nar arteri es whi l e the pati ent tightens hi s or her fi st. Releasi ng pressure on each respecti ve
artery determines the dominant vessel suppl yi ng bl ood to the hand. The prognostic val ue of the
All en' s test i n assessing the adequacy of the col lateral ci rculation has not been confirmed.
16, 17

Radi al artery cannulati on and blood pressure moni tori ng have been associ ated wi th several
problems. The radi al artery pulse pressure wave i s subject to i naccuraci es inherent to i ts distal
location. After separati on from cardiopul monary bypass, l arge pressure gradients between aortic
and radi al arteri es have been descri bed.
Complications of Invasive Arterial Monitoring
Traumatic cannul ati on has been associ ated with hematoma formation, thrombosis, and damage to
adjacent nerves. Abnormal radial artery blood fl ow after catheter removal occurs frequently.
Studi es suggest that bl ood fl ow normal i zes i n 3 to 70 days. Radial artery thrombosi s can be
mi ni mi zed by usi ng smal l catheters, avoi di ng pol ypropylene-tapered catheters, and reduci ng the
duration of arteri al cannul ation. Flexi bl e gui dewi res may reduce the potential trauma associ ated
with catheters negotiati ng tortuous vessel s. During cannula removal , the potenti al for
thromboembolism may be diminished by compressi ng the proxi mal and di stal arteri al segment
whi l e aspi rati ng the cannula duri ng wi thdrawal .
Many cannulation si tes have been used for di rect arteri al bl ood pressure moni tori ng (Tabl e 24-3).
Three techniques for cannul ati on are common: direct arteri al puncture,

gui dewire-assi sted cannul ati on (Seldi nger' s techni que), and the transfi xi onwithdrawal method. A
necessary condi ti on for percutaneous placement i s i dentifi cati on of the arterial pul se, whi ch may
requi re a Doppl er fl ow detecti on devi ce i n patients wi th poor peri pheral pul ses.
P.675
TABLE 24-3 Arterial Cannulation and Direct Blood Pressure Monitoring
ARTERIAL CANNULATION
SITE
CLINICAL POINTS OF INTEREST
Radi al artery Preferred si te for moni tori ng
Nontapered catheters preferred
Arteri al cannul ati on i s regarded as an i nvasive procedure wi th a documented morbi di ty. Ischemi a
after radial artery cannul ati on resul ti ng from thrombosis, proximal embol i , or prol onged shock has
been descri bed.
18
Contri buti ng factors incl ude severe atherosclerosi s, diabetes, low cardi ac
output, and i ntense peri pheral vasoconstri cti on. Ischemi a, hemorrhage, thrombosi s, embol ism,
cerebral ai r emboli sm (retrograde flow associated wi th fl ushi ng), aneurysm formati on,
arteriovenous fistul a formation, skin necrosi s, and i nfection have occurred as the di rect resul t of
arterial cannulati on, arterial bl ood sampli ng, or hi gh-pressure flushi ng.
Conti nuous-flush devi ces are i ncorporated i nto disposabl e transducer kits and i nfuse at 3 to 6
mL/h. In neonates, the i nfusi on volume may contribute to fl ui d overload. Continuous-flush devi ces
have l ittle effect on the blood pressure measurement. However, pressurized fl ush systems may
serve as a source of an air embol i sm. Removi ng ai r from the pressuri zed infusi on bag, stopcocks,
and tubi ng mi ni mi zes the potenti al for air embol ism.
Direct arteri al pressure moni tori ng requires constant vi gil ance. The data di splayed must correl ate
with cl i ni cal condi ti ons before therapeuti c interventi ons are i ni tiated. Sudden increases i n the
transduced bl ood pressure may represent a hydrostati c error because the posi ti on of the
transducer was not adjusted after change i n the operating room table' s hei ght. Sudden decreases
often resul t from ki nki ng of the catheter or

tubing. Before ini ti ati ng therapy, the transducer system shoul d be rezeroed and the patency of
Ul nar artery Compli cati on simil ar to radi al
Pri mary source of hand blood fl ow
Brachi al artery Inserti on si te medi al to bi ceps tendon
Medi an nerve damage i s potenti al hazard
Can accommodate 18-gauge cannul a
Axi ll ary artery Inserti on si te at juncti on of pectoral i s and deltoid
muscle
Speci al i zed kits avai l abl e
Femoral artery Easy access i n low flow states
Potential for l ocal and retroperi toneal hemorrhage
Longer catheters preferred
Dorsal i s pedi s artery Col l ateral circul ati on = posterior ti bi al artery
Higher systol i c pressure esti mates
P.676
the arteri al cannula veri fi ed. This ensures the accuracy of the measurement and avoi ds a
potential ly dangerous medi cati on error.
Cent r al Venous and P ul monar y Ar t er y Moni t or i ng
Central venous cannul as are important portals for i ntraoperati ve vascul ar access and for the
assessment of changes i n vascul ar vol ume. Central venous cannul as permi t the rapi d
administrati on of flui ds, inserti on of PACs, insertion of transvenous el ectrodes, moni toring of
central venous pressure (CVP), and a site for observation and treatment of venous ai r emboli sm.
The right internal jugular vei n i s the preferred site for cannul ati on because it i s accessi ble from
the head of the operati ng tabl e, has a predi ctabl e anatomy, and has a hi gh success rate i n both
adults and chi ldren.
19
The l eft-si ded i nternal jugul ar vei n i s also avai l abl e but i s l ess desirable
because of the potenti al for damagi ng the thoraci c duct or di fficul ty i n maneuveri ng catheters
through the jugularsubcl avi an juncti on. Accidental caroti d artery puncture i s a potenti al probl em
with either l ocati on.
Three techniques (posteri or, central , and anterior) have been descri bed for i nternal jugul ar
cannul ati on. Each i nserti on poi nt i s referenced to the triangl e formed by the sternal and clavi cul ar
heads of the sternocl eidomastoi d muscl e and the cl avicl e. Veni puncture usi ng a 22-gauge seeker
needle mi ni mi zes trauma to adjacent structures. When the locati on of the i nternal jugul ar vei n i s
di fficul t to ascertai n, ul trasonography can assi st in i dentifyi ng the proxi mi ty of i nternal jugul ar
vein and the carotid artery. Al ternati ves to the internal jugul ar vei n incl ude the external jugul ar,
subcl avi an, antecubital, and femoral vei ns.
Central Venous Pressure Monitoring
The benefi t of CVP moni tori ng has been the subject of consi derabl e debate. Proponents of CVP
moni tori ng beli eve that CVP pressures are essenti all y equi valent to right atri al pressures and
serve as a refl ecti on of right ventricul ar prel oad.
20
Conditions that affect ri ght atri al pressure al so
infl uence the CVP pressure trace. The normal CVP waveform consi sts of three peaks (a, c, and v
waves) and two descents (x, y), each resul ti ng from the ebb and fl ow of blood in the ri ght atrium
(Fi g. 24-5). Correspondi ng events occur in the l eft atrium and si mil ar pressure contours are
observed during moni toring of pulmonary artery pressure when the PAC is pl aced i n the occl uded
positi on.
FIGURE 24-5. The normal central venous pressure trace. (Redrawn with permi ssi on from
Mark JB: Central venous pressure monitori ng: Cl i ni cal i nsi ghts beyond the numbers. J
Cardi othorac Vasc Anesth 5:163, 1991.)
The character of the CVP trace depends on many factors, i ncl udi ng heart rate, conduction
di sturbances, tri cuspi d val ve functi on, normal or abnormal i ntrathoraci c pressure changes, and
changes i n ri ght ventri cul ar compl i ance. In pati ents wi th atri al fi bril l ati on, a waves are absent.
When resi stance to the emptying of the right atrium i s present, l arge a waves are often observed.
Exampl es i ncl ude tri cuspi d stenosi s, ri ght ventri cul ar hypertrophy as a result of pulmonic stenosi s,
or acute or chroni c l ung di sease associ ated wi th pulmonary hypertensi on. Large a waves may also
be observed when ri ght ventri cul ar compli ance i s i mpai red.
Tri cuspi d regurgi tati on typi cal l y produces gi ant v waves that begi n i mmedi atel y after the QRS
compl ex. Large v waves are often observed when ri ght ventricul ar i schemi a or fai lure is present or
when ventricul ar compl i ance i s impai red by constri cti ve peri cardi ti s or cardi ac tamponade. A
promi nent v wave duri ng CVP monitoring may suggest right ventri cul ar papil l ary muscle ischemi a
and tri cuspi d regurgi tati on. When right ventricul ar compl iance decreases, the CVP often i ncreases
with promi nent a and v waves fusing to form an m or w configuration.
Central venous pressure monitori ng i s often unrel i abl e for esti mati ng left ventri cul ar fi l li ng
pressures, especi all y when cardiopul monary disease processes al ter the normal cardi ovascul ar
pressurevol ume rel ati onshi ps. CVP monitori ng is l ess i nvasi ve and l ess costl y than pul monary
artery monitori ng and offers uni que understandi ng of ri ght-si ded hemodynami c events and the
status of vascular vol ume.
Pulmonary Artery Monitoring
The devel opment of the flow-di rected, bal l oon fl otati on PAC was a major advance i n hemodynamic
moni tori ng, and i t has become an important tool i n the quanti tative assessment of
cardi opul monary functi on. Numerous arti cl es have revi ewed the vari ous appl i cations and benefi ts
of pul monary artery moni toring.
21
Use shoul d be gui ded by the informati on needed for enhanced
di agnosi s and therapy.
22
Today, PAC monitoring is commonly used i n surgical pati ents to hel p
eval uate and treat hemodynamic al terati ons, whi ch contri bute si gnifi cantly to the morbi dity and
mortal i ty i nherent to the surgi cal care of hi gh-ri sk pati ents.
In 1993, the ASA publ i shed practice gui del i nes that exami ned the evi dence supporti ng the
cl i ni cal effecti veness of PAC moni toring. These gui delines were updated i n 2003.
23
Issues
such as the ti ming of PAC moni tori ng, i ts effect on treatment decisi ons, pati ent sel ecti on and case
mi x, and evi dence regardi ng PAC moni tori ng contri buti on to posi ti ve or negati ve outcomes were
eval uated usi ng stri ngent evidence-based methodol ogy. This effort identified many flaws in the
body of evi dence, whi ch made i t di fficul t to draw meaningful conclusi ons regarding the
effecti veness of PAC monitori ng to reduce morbi di ty or mortal ity. The consensus opi ni on i mpl i es
that PAC moni tori ng may reduce perioperati ve compl i cati ons i f criti cal hemodynami c data obtai ned
duri ng appropri ate PAC moni tori ng are accuratel y interpreted and appropriate treatment is tai l ored
to the condi ti ons as they change over ti me.
23
Monitori ng the hemodynamic status of hi gh-ri sk
patients may reduce cardi ac compl i cations (e.g., myocardi al ischemia, congesti ve heart fai l ure,
dysrhythmi as), renal insuffi ciency, brai n injury, and pul monary compl icati ons.
Pul monary artery catheters permit the measurement of intracardi ac pressures, thermodi luti on CO
(TCO), mi xed venous oxygen saturati on, intracavi tary el ectrograms, and l ung water. This
information can hel p defi ne cl i ni cal probl ems, monitor the progressi on of hemodynamic
dysfuncti ons, and gui de the response of corrective therapy.

The measurement of i ntracardi ac pressures can indirectl y assess left ventri cul ar preload, diagnose
the exi stence of pulmonary hypertensi on, or differenti ate cardi ac and noncardi ac causes of
pul monary edema. PACs all ow for the rapi d and reproduci bl e measurements of TCO, calculati on of
oxygen del ivery (CO arterial O
2
content), and assessment of cardi ac work. Hemodynamic
measurements are often predi cated on the manipulation of prel oad, afterload, and contracti li ty.
Several deri ved i ndi ces of hemodynamic function necessi tate measurements commonly obtained
from PAC monitori ng (Tabl e 24-4).
P.677
Access to mi xed venous bl ood from the pulmonary artery port provi des an i ndi rect assessment of
the bal ance between O
2
del i very and O
2
uti li zati on. Mi xed venous oxygen saturati on (S

O
2
) measurements are needed to calcul ate mixed venous oxygen content (C

O
2
). C

O
2
is an important vari abl e used for cal cul ating i ntrapul monary (Eq. 24-1) or intracardi ac shunts
(Eq. 24-2).

Where CCO
2
= capil l ary O
2
content, CaO
2
= arteri al O
2
content, C

O
2
= mixed venous O
2
content,

s/

t = shunt fraction, SaO
2
= arteri al O
2
saturati on, SRAO
2
= ri ght atrial O
2
saturati on, S

O
2
= mixed venous O
2
saturati on, and

TABLE 24-4 Derived Hemodynamic Variables
NAME ABBREVIATION CALCULATION UNITS
Cardi ac i ndex CI CO/BSA 1 mi n/m
2
Systemi c vascular
resistance
SVR (MAP-CVP/CO) 80 dyne-cm/s
Pulmonary vascular
resistance
PVR (MPAP-PCWP/CO)
80
dyne-cm/s
Stroke i ndex SI CI/heart rate mL/beat/m
2
Left ventri cul ar stroke
work index
LVSWI SI (MAP-PCWP)
0.0136
gm/beat/m
2
Ri ght ventri cul ar stroke
work index
RVSWI SI (MPAP-CVP)
0.0136
gm/beat/m
2
BSA, body surface area; MAP, mean arteri al pressure; CVP, central venous pressure;
MPAP, mean
pul monary arteri al pressure; PCWP, pul monary capi l lary wedge pressure.
p/

s = pul monary-to-systemi c shunt.
The val i di ty of PAC moni tori ng depends on a properl y functi oni ng pressure moni tori ng system,
correctl y i denti fyi ng the true pul monary capi l l ary wedge pressure (PCWP), and i ntegrati on of the
vari ous factors that affect the relationshi p of PCWP, and the other cardiac pressures and vol umes
that are determinants of ventri cul ar function. Figure 24-6 depicts the transduced pressure waves
observed as a PAC i s fl oated to the wedged posi tion. Catheter pl acement is most commonly
performed by observi ng the pressure waves as the catheter i s fl oated from the CVP posi ti on
through the right heart chambers i nto the pulmonary artery.
Pul monary artery catheter moni tori ng necessitates an appreci ation of the various physiologi c
determi nants of CO and oxygen deli very. The PAC i s used to continuousl y monitor the pul monary
artery pressure and i ntermi ttentl y moni tor pul monary wedge pressure. PCWP i s used to assess l eft
ventri cul ar prel oad i ndi rectly by refl ecti ng changes i n l eft ventri cul ar end-di astoli c pressure
(LVEDP). Fi gure 24-7 depi cts the rel ati onshi p between the various pressures i n the
cardi opul monary system.
FIGURE 24-6. Pressure traci ng observed during the flotation of a pul monary artery catheter.
(Reproduced wi th permi ssi on from Di zon CT, Barash PG: The value of moni toring pul monary
artery pressure i n cl i ni cal practi ce. Conn Med 41:622, 1979.)
It has been well demonstrated that ri ght-si ded pressures i n the heart often are poor i ndi cators of
left ventri cular fi l li ng, either as absol ute numbers or in terms of the di recti on of change in
response to therapy. The correl ati on of these pressures as esti mates of LVEDP (or l eft ventricul ar
end-di astoli c vol ume [LVEDV]) i s di rectl y rel ated to thei r proxi mi ty to the l eft ventricl e and the
status of ventri cul ar compl iance. Assumi ng an open condui t from the catheter ti p to the left
ventri cle, when the PAC is occl uded (wedged), the ri ght-si ded heart chambers and val ves are
bypassed. Duri ng end-di astol e, there i s cessati on of forward bl ood fl ow, and a stati c flui d col umn
is presumed to exist from the l eft ventri cl e to the PAC ti p. Ideal ly, changes i n LVEDP are refl ected
by al l proxi mal pressures (l eft atri al , pulmonary venous, pul monary artery end-di astoli c pressure
[PAEDP], and PCWP). Al terati ons of i nternal or external forces appl i ed to the open condui t duri ng
PCWP measurements may i nval i date the PCWP-LVEDP-LVEDV rel ati onshi p.
Factors Affecting the Accuracy of Pulmonary Artery Catheter Data
Pulmonary Vascular Resistance. Any disease process or conditi on that increases pul monary
vascul ar resi stance has the

potenti al to reduce pul monary bl ood flow and al ter the rel ati onshi p between PCWP and PAEDP.
Pathologi c condi tions such as acute or chroni c l ung disease, pul monary emboli , al veol ar hypoxi a,
acidosis, and hypoxemia, and many vasoactive drugs increase pulmonary vascul ar resi stance and
have the potenti al to modi fy the PCWPPAEDP relationshi p. Tachycardi a shortens ventricul ar
di astole and al so increases pul monary vascul ar resi stance.
AlveolarPulmonary Artery Pressure Relationships. West et al
25
descri bed a gravi ty-
dependent di fference between venti lation and perfusion in the l ung. The vari abi l i ty in pulmonary
blood flow is a result of differences in pulmonary artery (PA), alveol ar (Palv), and venous
pressures (PV) and i s categori zed into three di sti nct zones. Onl y Zone III (PA > PV > Pal v) meets
the cri teria for uni nterrupted bl ood fl ow and a continuous communi cati on wi th di stal intracardi ac
pressures. Increases i n al veol ar pressure, decreases i n perfusi on, or changes i n positi oning can
FIGURE 24-7. The anatomic posi tion of a pul monary artery catheter i n the pul monary artery.
The dashed l i ne posi ti ons the i nflated bal l oon i n the wedged posi ti on. (RA, ri ght atri um;
RV, ri ght ventri cl e; PA, pul monary artery; Al v, al veolus; Pcap, pul monary capi l lary; PV,
pul monary vei n; LA, left atri um; LV, l eft ventricl e.) I, II, and III characteri ze the rel ati onshi p
of P
aveol ar
, P
ar t er i al
, and P
venous
as described by West. The bottom of the figure shows a
progressi ve correlation of vascul ar pressures. (Reproduced wi th permissi on from Vender JS:
Invasi ve cardi ac monitori ng. Cri t Care Cl in 4:455, 1988.)
P.678
convert areas of Zone III i nto either Zone II or I. Fl ow-di rected PACs usual l y advance to gravi ty-
dependent areas of hi ghest blood fl ow.
The location of a PAC can be confirmed by a l ateral chest fil m to ascertai n that the catheter tip is
bel ow the l evel of the l eft atri um. The foll owing characteristics suggest that the PAC tip is not i n
Zone III: PCWP > PAEDP, nonphasic PCWP traci ng, and i nabil i ty to aspi rate bl ood from the distal
port when the catheter is wedged.
Respiratory Pattern and Airway Pressure. Changes i n intrathoraci c and i ntrapl eural pressure
affect transmural cardiac pressures. Transmural pressure i s defi ned as the net di stending pressure
of the left ventri cle. Changes i n i ntrathoracic pressure affect the PCWPLVEDP rel ati onshi p.
Positi ve endexpiratory pressure (PEEP) therapy can i nduce changes i n both i ntravascular and
intrapl eural pressures. PEEP i ncreases al veol ar pressure, potenti al l y converti ng Zone III areas to
Zone II. If PEEP is transmi tted across the al veol i , i ntrapl eural pressure i ncreases. Pul monary
compl i ance determines the extent of thi s effect. PEEP al ters ventricul ar distensibi l ity and
decreases venous return. Thi s causes a di sproporti onate increase i n PCWP (and LVEDP) compared
with changes in LVEDV.
The effect of PEEP therapy is minimal if the levels of PEEP are low (10 cm) and the PAC i s
located in Zone III. Hi gher l evels of PEEP i nfluence the PCWPLVEDP relationshi p. During hi gh
PEEP therapy, esophageal pressure measurements can be made to determine i ntrapleural
pressure. Alternati vely, subtracti ng 1 to 2 mm Hg from the di spl ayed wedge pressure for each 5
cm H
2
O of PEEP therapy gi ves an esti mate when PEEP i s above 10 cm H
2
O.
Intracardiac Factors. Pathol ogi c obstructi on at the mi tral val ve secondary to mi tral stenosis,
atri al myxoma, or cl ot can interfere wi th the abil i ty of l eft atri al pressure to reflect LVEDP.
Simil arl y, mi tral regurgitati on, a noncompl i ant left atri um, or l eft-to-ri ght intracardi ac shunti ng
often is associ ated with large v waves.
Decreases in l eft ventricul ar compl iance, aortic regurgitati on, or premature closure of the mi tral
val ve may reverse the l eft atrial pressureLVEDP pressure gradient. When this occurs, PCWP is not
a val i d reflecti on of LVEDV.
Fi gure 24-8 graphi cal l y depi cts the rel ati onshi p between LVEDP and LVEDV. The LVEDPLVEDV
rel ati onship is not li near. A famil y of LVEDPLVEDV compl iance curves characterizes the effect of
changing the stiffness of the l eft ventri cl e. Ventri cul ar compl iance i s a dynamic factor infl uenced
by many physi ologi c and pathol ogi c vari ables. The LVEDPLVEDV compl iance curves suggest that
at l ow prel oads, l arger increases i n LVEDV produce small er changes in LVEDP. Conversely, at
hi gher prel oads, a si mi l ar change i n LVEDV produces a greater pressure change. For a gi ven
LVEDV, any decrease in ventri cular compl i ance resul ts in an i ncrease i n LVEDP. This expl ai ns the
devel opment of hydrostati c pul monary edema at normal LVEDV. Factors that are associ ated wi th
changes i n ventricul ar compl i ance are li sted in Tabl e 24-5.
Complications of Pulmonary Catheter Monitoring
Adverse effects from PAC monitori ng can resul t duri ng central venous access, the catheteri zation
procedure, or any ti me after

PAC pl acement. Central venous access represents an i nvasi ve process with i nherent risks, some of
whi ch are potenti al l y l ife threateni ng.
Uni ntenti onal puncture of nearby arteri es, bl eedi ng, neuropathy, and pneumothorax may resul t
from needle inserti on i nto adjacent structures. Air emboli sm may occur i f a cannula i s open to the
atmosphere and ai r is entrained duri ng or after CVP pl acement. Dysrhythmias are common duri ng
the catheteri zati on procedure, wi th a reported inci dence of 4.7 to 68.9%. Ventri cul ar tachycardia
or fi bri l l ati on may be i nduced during catheter advancement. Catheter advancement has been
associated wi th right bundl e-branch bl ock and, i n pati ents wi th preexi sti ng l eft bundl e-branch
bl ock, may preci pitate compl ete heart block. Tabl e 24-6 summari zes the adverse effects as
reported by the ASA task force on pul monary artery catheteri zati on.
23

TABLE 24-5 Decreased Left Ventricular Compliance: Common Etiologies
Myocardi al i schemi a Cardiac tamponade
Restri cti ve myopathi es Myocardi al fi brosi s
Ri ght-to-left i ntraventri cular shunts Inotropi c drugs
Aorti c stenosi s Hypertension
FIGURE 24-8. Typi cal ventricular compl i ance curve. (Reproduced with permission from
Vender JS: Invasi ve cardiac moni toring. Cri t Care Cl i n 4:455, 1988.)
P.679
TABLE 24-6 Adverse Effects Associated with Pulmonary Artery Monitoring
COMPLICATION REPORTED INCIDENCE(%)
Central venous access
Arterial puncture 1.113
Postoperati ve neuropathy 5.3
Pneumothorax 0.31.1
Ai r embol i sm 0.34.5
Fl otati on of pul monary artery catheter
Mi nor dysrhythmi as 468.9
Ventricular tachycardi a or fi bri l l ati on 0.362.7
Ri ght bundl e-branch bl ock 0.14.3
Compl ete heart bl ock (pri or l eft bundle-branch bl ock) 08.5
Compli cati ons associ ated wi th catheter resi dence
Pulmonary artery rupture 0.11.5
Posi ti ve cul tures from catheter ti p 1.434.8
Sepsi s secondary to catheter resi stance 0.711.4
Thrombophl ebi ti s 6.5
Venous thrombosi s 0.566.7
Pulmonary infarction 0.15.6
Mural thrombus 2861
The rate of i atrogeni c deaths associated wi th PAC moni tori ng i s uncertai n. The most dreaded
compl i cati on associated wi th PAC moni tori ng is pul monary artery rupture. Pul monary hypertension,
coagulopathy, and hepari ni zation are often present i n pati ents who have died of pulmonary artery
rupture. Perforati ons and subsequent hemorrhage can be avoided by restri cti ng overwedgi ng,
mi ni mi zi ng the number of bal l oon infl ati ons, and usi ng proper techni que duri ng bal loon i nflations.
Infecti on i s a potential compli cation of the conti nued use of CVP and PAC catheters. Gui deli nes for
the preventi on of i ntravascul ar catheter-rel ated i nfections have recently been publ i shed by the
Centers for Di sease Control and Preventi on (CDC).
24
Methods recommended to reduce the
inci dence of l ocal and bl oodstream infecti ons i nclude (1) educati on and trai ning of cli nici ans who
insert and mai ntai n central catheters;

(2) use of maximal steri le barri er precautions (mask, cap, steri l e gl oves and gown, and l arge
steri l e drape); (3) use of 2% chl orhexidi ne for ski n preparati on; and (4) avoi dance of routi ne
repl acement of CVP and PAC catheters sol el y for the purpose of reducing the risk of infection.
Since the advent of PACs, several modi fi cati ons have been i ntegrated i nto the design that enhance
thei r moni toring capabi li ties. The fi rst si gnifi cant desi gn modi fi cati on i ncorporated a thermi stor at
the ti p, permi tti ng the measurement of CO. Other features have been introduced for cl i ni cal use or
eval uation. These include mi xed venous oximetry, measurement of ri ght ventricul ar ejection
fracti on, pacing opti ons, and conti nuous CO moni tori ng (CCOM).
Mixed Venous Oximetry
Conti nuous esti mates of S

O
2
provi de a refl ecti on of total ti ssue oxygen bal ance. Oxygen del i very (

O
2
) equal s the arteri al oxygen content multi pli ed by the CO (

O
2
= [Hb 13.8] CO), where 13.8 represents the vol ume of oxygen carried by Hb converted to
grams per li ter. Oxygen consumption (

O
2
) i s determi ned by the di fference between arteri al and venous oxygen del i very. The rel ati onshi p
between S

O
2
,

O
2
, and

O
2
is demonstrated i n the fol l owing equati on deri ved from the Fi ck relationshi p:
Val vul ar or endocardi al vegetati ons 2.2100
Deaths attri buted to pul monary artery catheter 0.021.5
ASA Task Force on Pul monary Artery Catheri zati on. Practi ce Gui del i nes for Pul monary
Artery Catheri zati on: an updated report by The Ameri can Soci ety of Anesthesi ologi sts
Task Force on Pulmonary Catheri zati on. Anesthesi ology 99:9881014, 2003.
P.680

Thi s equati on i ndi cates that changes i n S

O
2
vary directly with changes in CO, Hb, and SaO
2
and inversely with

O
2
. The normal S

O
2
is 75%, whi ch denotes ti ssue oxygen extracti on = 25%.
The oxi metri c PAC uses refl ectance spectrophotometry and technology si mil ar to pul se oximetry.
Several wavelengths are transmi tted through opti cal fi bers embedded i n the pul monary artery. The
refl ected i ntensi ty of l ight identi fi es the saturati on of bl ood surroundi ng the ti p of the PAC. Three-
wavelength i n vivo systems correl ate wel l wi th si mul taneous sampl es measured by co-
oxi metry.
26, 27
An example of the uti li ty of mixed venous oxi metry is depi cted i n Fi gure 24-9.

Indicator Dilution Applications
Indi cator di l uti on determi nati on of CO i s based on a concept proposed by Stewart and tested by
Hami l ton and col l eagues. TCO determi nation is the most widel y used adaptati on of the i ndi cator
di l uti on pri nci pl e, which was fi rst described by Fegl er i n 1954.
28
Today, 5% dextrose or 0.9%
sali ne is used as the i ndi cator. A thermistor l ocated at the PAC ti p records the decrease in
temperature as the bolus of cool ed i njectate passes through the pul monary artery. Computers
contend with the complexi ty of the TCO equation, whi ch i ncl udes the fol l owi ng factors: speci fic
heat of the bl ood and the i ndi cator fluid, the vol ume of injectate, catheter si ze, speci fi c gravi ty of
the bl ood and i ndi cator, the vol ume of the i njectate, and the area of the bl ood temperature curve.
Compari son studi es suggest that usi ng ei ther room-temperature or iced i njectates provi des
accurate esti mates of CO. Iced injectate is preferred because i t produces a more exacting curve
wi th a better si gnal -to-noise ratio.
29

FIGURE 24-9. Thi s S

O
2
recordi ng i n a postcoronary artery bypass pati ent demonstrates the effects of shi veri ng
and its treatment, and the relationshi p between S

O
2
, cardiac output (CO), and metaboli c rate (

O
2
). (Reproduced wi th permi ssi on from Vender JS: Invasi ve cardi ac monitoring. Crit Care Clin
4:455, 1988.)
When properl y performed, TCO measurements correlate well with di rect Fi ck or dye di l uti on
estimates of CO. In cl i ni cal practi ce, tri pli cate determi nati ons are averaged to i ncrease precisi on.
Differences i n val ues of 12 to 15% are not of cl i ni cal significance. TCO esti mates vary with the
respiratory cycl e. This variabi li ty can be reduced by performi ng measurements at peak inspirati on
or end expi rati on. Preci si on i s enhanced by ensuri ng that the rate of i njecti on and the volume are
constant. Most CO computers delay the repeat measurement 30 to 90 seconds to stabi li ze the
thermal environment of the pul monary thermi stor.
Adaptations for Continuous Cardiac Output Monitoring
Conti nuous CO moni tori ng offers the potenti al to i denti fy acute changes in ventri cular performance
as they occur. A properly posi ti oned PAC provi des access to the right atri um, ri ght ventri cle, and
pul monary artery outflow tract. These l ocati ons provi de many opti ons for assessment of CCOM.
Several thermal techni ques are currently used. Pulsed thermodil uti on uses a coi led ri ght
ventri cul ar fi l ament that is randoml y heated. A thermi stor at the ti p of the PAC detects changes in
bl ood temperature and sends the temperature informati on to a microcomputer that uses stochasti c
anal ysi s to create a thermodi l ution curve. CO is computed continuousl y from a conservati on of
heat equati on.
30

Another techni que appl i es heat to a thermi stor l ocated at the ti p of a PAC. The ri ght ventri cul ar
outfl ow subsequentl y cool s the tip. The temperature changes regi stered are proporti onal to the
decreased temperature produced by ri ght ventri cul ar bl ood fl ow. Both of these systems requi re
cal i brati on usi ng standard thermodil uti on before i ni tiating the CCOM mode. CCOM compares
favorably with bolus CO measurements, even under condi tions of varyi ng pati ent temperature and
CO.
31

Right Ventricular Ejection Fraction
Cal cul ati on of right ventri cul ar ejection fracti on and end-di astoli c vol ume may be performed wi th a
special PAC that uses a rapi d response thermistor and a sophisticated computer system. Thi s
system anal yzes the exponenti al decay of the pul monary artery temperature over several cardi ac
cycl es and cal cul ates the ejecti on fracti on by subtracti ng the mean resi dual fracti on from the CO.
Studies have demonstrated good correlation wi th i n vitro techni ques and cli nical util i ty for
detecti ng i ntraoperati ve ri ght ventri cul ar ischemia.
32, 33, 34
Right ventri cul ar ejection fracti on
moni tori ng has been recommended when i mpai rment of ri ght ventricular functi on i s suspect.
Accuracy requires proper placement. Atrial fi bri l l ati on and tri cuspi d regurgitati on can affect the
accuracy of the thermal decay methodol ogy.
Clinical Benefits of Pulmonary Artery Monitoring
The debate regarding the cl ini cal benefi t of PAC moni tori ng has persi sted since the mi d 1980s.
Peri operative outcomes have been reported to be improved, worsened, or unchanged by PAC use.
At the present time, assessment of the benefi ts of PAC monitori ng is hampered by the l ack of wel l -
desi gned outcome tri al s. Interpretati on of most cli ni cal trial s i s signi ficantl y l imi ted by important
flaws i n study desi gn, which include inadequate sampl e si ze to detect meani ngful outcomes, l ack
of randomi zati on, and lack of standardi zati on of treatments based on PAC data.
24
A study by
Sandham et al . was desi gned to address many of the methodol ogi c l imi tati ons present i n previ ous
PAC outcome trial s.
35
Thi s large-scal e, randomi zed, controll ed, si ngl e-bl i nd study exami ned the
impact of PAC monitoring in hi gh-ri sk pati ents undergoing major surgi cal procedures. Pati ents
were randomi zed to a protocol group (PACs used to achi eve speci fi c targeted hemodynami c
treatment goals) or a standard care group (no PAC use). No di fferences i n major morbidi ty or
mortal i ty were observed between the two groups. Addi tional wel l -desi gned studi es are needed to
determi ne the benefits and risks of i nvasi ve right-heart catheteri zati on.
Inadequate understanding and appli cati on by physi ci an users have been i mpl i cated as condi ti ons
that l imi t the benefi t of PAC monitori ng. To opti mi ze cl inical outcome and reduce compli cati ons,
the care provi der must be abl e to interpret and use the data provi ded by the PAC. A questi onnai re
that measured physi ci an knowledge of the techni cal and theoretical aspects of PAC moni toring was
administered to cri ti cal care speci ali sts i n the United States and Europe. These surveys revealed
knowl edge of pul monary artery catheteri zati on is not uni formly good among intensi ve care uni t
physi ci ans, wi th onl y half of respondents abl e to read the PCWP correctl y from a clearl y marked
tracki ng.
36, 37
Changes i n trai ning and credenti ali ng have been proposed to improve these
defici encies i n knowl edge.
38, 39
In experi enced and knowl edgeabl e hands, the PAC can add val uabl e
information wi th l imited risk.
NONINVASIVE TECHNIQUES FOR CARDIAC OUTPUT
The quest for technicall y si mpl e, noninvasi ve methods for accuratel y esti mating CO conti nues.
Three methods are avai labl e for cl i ni cal use.
I mpedance P l et hysmogr aphy
Impedance pl ethysmography i s based on determi ni ng the pulsati l e changes in resi stance occurring
duri ng ventricul ar ejection. Four el ectrodes are appl i ed to the neck and thorax and a small el ectri c
current i s appl i ed. Impedance measurements (dZ/dT) are made usi ng two thoraci c el ectrode pai rs.
Changes i n i mpedance correl ate wi th stroke volume. CO i s esti mated by determi ni ng stroke
vol ume and ventri cul ar ejecti on ti me.
40
El ectrode pl acement is an important source of error. Other
factors infl uenci ng bioi mpedance measurements i ncl ude i ntrathoraci c fl ui d shi fts and changes i n
hematocri t. More than 150 val i dati on studies have been publ i shed, and both poor and good
correlations between i mpedance pl ethysmography and a reference method have been reported.
41

Al though i mpedance pl ethysmography has not gained wide acceptance, the technique offers
cl i ni ci ans a simple, qui ck method to determi ne CO with mi ni mal di rect pati ent ri sk.

Doppl er Ul t r asonogr aphy
Doppl er ul trasonography can measure the vel ocity of blood in the ascendi ng or descendi ng aorta
or outflow tract of the pulmonary artery. CO i s cal cul ated by mul tipl yi ng the ti me-weighted
average velocity of blood fl ow by an esti mate of aorti c or pul monary artery cross-secti onal area
that can be di rectl y measured or predi cted from a nomogram. Accuracy and precisi on depend on
the esti mate of the vessel diameter and the al ignment of the Doppl er probe. Vel oci ty
measurements are most accurate when the Doppl er probe and the blood fl ow are parall el. If the
al ignment exceeds 25 degrees, vel oci ty measurements l ose preci si on. Suprasternal, transtracheal ,
and transesophageal probes have been desi gned for cl i ni cal use.
42, 43
The devel opment of
esophageal Doppler probes al l ows for conti nuous, mi nimal l y i nvasi ve esti mation of CO, and may
al low for opti mi zati on of i ntravascul ar vol ume status without the use of a CVP or PAC.
44

Ar t er i al P ul se Cont our Anal ysi s
Pul se contour anal ysi s of the arteri al pressure waveform al lows cl i ni cians to determi ne beat-to-
beat measurements of left ventri cul ar output. Computer al gori thms are used to calcul ate the area
under the systol ic porti on of the arteri al pul se waveform (from the end of di astol e to the end of
the ejecti on phase). Stroke vol ume i s determi ned by di vi di ng the resul ti ng area by the aorti c
impedance. A li mitati on of arteri al pul se contour anal ysi s is that the techni que requi res cal i brati on
with another method of measuri ng cardi ac output. Reference cardiac output determi nati ons for
cali brati on can be obtained usi ng moderatel y invasi ve (thermodil uti on CO usi ng a PAC or
transpul monary themodil uti on usi ng a central venous and arterial li ne) or mi ni mal ly i nvasive
(l i thium di l uti on usi ng a peri pheral venous and arteri al catheter) technol ogy. A number of cl i ni cal
studi es have demonstrated that the precisi on and accuracy of arteri al pul se contour analysi s i s
acceptable when compared wi th thermodi l ution CO measurements obtained by PACs.
45, 46

TRANSESOPHAGEAL ECHOCARDIOGRAPHY
The use of transesophageal echocardi ography (TEE) i n the peri operati ve period has i ncreased
si gni fi cantl y si nce i ts first appl icati on i n humans was reported by Frazen i n 1976. (See al so
Chapter 3) Rapi d technol ogical advances have occurred since then, i ncl udi ng a reducti on i n
P.681
transducer si ze, the devel opment of mul ti pl ane probes, and the use of pul sed-wave, conti nuous-
wave, and col or flow Doppl er. Improvements i n computer design and i mage acqui si tion have
al lowed for a more comprehensi ve exami nati on of the heart and surroundi ng structures. TEE
appears to offer distinct advantages over other monitors of cardi ovascul ar functi on and can
provi de the anesthesi ol ogist wi th uni que di agnosti c information in the operati ng room.
Modern TEE machi nes offer a number of i magi ng techni ques. In M-mode, or moti on mode, all of
the structures along a narrow ul trasound beam are pl otted on the x-axi s versus ti me on the y-
axi s. M-mode al l ows onl y a few mil l imeters of the heart to be vi suali zed at any one ti me. Two-
di mensional (2-D) mode uses multi ple scanni ng li nes to create a two-di mensional i mage of a cross
secti on of the heart. Thi s i mage i s updated 30 to 60 ti mes per second, whi ch produces a real -ti me
di spl ay of cardiac moti on.
Doppl er technol ogy provi des informati on about bl ood flow i n the heart and major vessel s. The
Doppl er effect is based on the principl e that movi ng objects (red bl ood cel ls) change the frequency
of the emi tted ultrasound beam. If an object is movi ng toward the transducer, the ul trasound
beam is compressed, which increases the frequency of the transmitted si gnal . An object movi ng
away from the transducer l owers the frequency of the transmi tted ultrasound beam. Thi s
information al l ows the cal culation of blood fl ow vel oci ty wi thi n the cardi ovascul ar system. Current
TEE machines use three Doppl er systems: pul sed-wave, conti nuous-wave, and col or flow Doppl er.
Pul sed-wave Doppler uses a si ngl e crystal to emi t and receive short bursts of ultrasound at a
known frequency (pulse repeti ti on frequency). By measuring the ti me requi red for the transmi tted
ul trasound bursts to return to the transducer, the velocity of blood fl ow at preci se l ocati ons in the
heart can be measured. A major li mi tati on of pul sed-wave Doppl er i s that hi gh-velocity flows
cannot be accuratel y quantified. The maxi mal vel oci ty that can be measured is l i mi ted to one hal f
of the pul se repetiti on frequency; thi s is known as the Nyqui st l i mi t. Conti nuous-wave Doppler
uses two crystals (one to transmit, one to recei ve) to measure bl ood fl ow vel oci ty conti nuousl y.
Thi s al l ows for accurate measurement of hi gh-vel oci ty fl ows, but does not permi t precise
local izati on. Col or flow Doppl er uses pul sed-wave technol ogy to measure bl ood fl ow vel oci ty at
mul tipl e si tes. Bl ood flow toward the transducer i s coded red and fl ow away from the transducer is
coded bl ue. Rapi dl y accel erati ng or turbul ent flow i s coded green. By superi mposi ng thi s col or map
on a 2-D i mage of the heart, the directi on and velocity of bl ood flow in the heart can be easil y
imaged.
Moni t or i ng Appl i cat i ons
There are a number of important moni tori ng appl i cations for TEE in the peri operati ve period. In
1996, the ASA and the Soci ety of Cardi ovascul ar Anesthesi ol ogi sts publ i shed practi ce gui del i nes to
defi ne the proper i ndi cati ons for performing TEE i n the operative setting.
47
Indi cati ons were
di vi ded i nto three categori es.
Category I i ndi cati ons are supported by the strongest evi dence or expert opini on; TEE frequently
is useful in i mproving cli nical outcomes and i s often i ndi cated, dependi ng on pati ent ri sk and
practi ce setti ng. Category II indi cati ons are supported by weaker evidence and expert consensus;
TEE may be useful i n improvi ng cl i ni cal outcomes, dependi ng on i ndi vi dual circumstances.
Category III indi cati ons have li ttl e current sci enti fi c or expert support, and TEE is i nfrequently
useful i n improvi ng cl ini cal outcomes. These i ndi cati ons are summari zed i n Tabl e 24-7.
TABLE 24-7 Indications for Perioperative Transesophageal Echocardiography
Category I indications: Supported by the strongest evi dence or expert opi ni on; TEE i s
frequently useful i n improvi ng cl i ni cal outcomes i n these setti ngs and i s often indi cated,
dependi ng on i ndi vi dual circumstances (e.g., patient ri sk and practi ce setting).
Intraoperative evaluation of acute, persi stent, and l i fe-threateni ng hemodynami c
di sturbances i n whi ch ventri cular functi on and its determi nants are uncertai n and have
not responded to treatment
Intraoperati ve use in val ve repair
Intraoperati ve use in congeni tal heart surgery for most lesions requi ri ng
cardi opul monary bypass
Intraoperative use in repai r of hypertrophi c obstructi ve cardiomyopathy
Intraoperati ve use for endocardi ti s when preoperati ve testi ng was i nadequate or
extensi on of i nfecti on to peri val vul ar ti ssue is suspected
Preoperati ve use i n unstabl e pati ents wi th suspected thoracic aortic aneurysms,
di ssection, or di srupti on who need to be eval uated qui ckl y
Intraoperati ve assessment of aorti c valve functi on i n repai r of aorti c di ssecti ons wi th
possi bl e aorti c valve involvement
Intraoperati ve eval uation of peri cardial wi ndow procedures
Use i n intensive care unit for unstable patients with unexplai ned hemodynami c
di sturbances, suspected val ve di sease, or thromboembol i c problems (i f other tests or
moni tori ng techniques have not confi rmed the diagnosis or pati ents are too unstable to
undergo other tests)
Category II indications: Supported by weaker evi dence and expert consensus; TEE
may be useful i n i mproving cl i ni cal outcomes i n these setti ngs, dependi ng on i ndi vi dual
ci rcumstances, but appropri ate i ndicati ons are l ess certai n.
Perioperative use i n patients wi th increased ri sk of myocardi al i schemi a or infarction
Perioperative use i n patients wi th increased ri sk of hemodynami c di sturbances
Intraoperati ve assessment of val ve repl acement
Intraoperati ve assessment of repai r of cardiac aneurysms
Intraoperati ve eval uati on of removal of cardi ac tumors
Intraoperative detecti on of forei gn bodi es
Intraoperati ve detecti on of ai r embol i duri ng cardi otomy, heart transpl antation
operations, and upright neurosurgi cal procedures
Intraoperative use during intracardi ac thrombectomy
Intraoperati ve use duri ng pul monary embol ectomy
Intraoperati ve use for suspected cardi ac trauma
Preoperati ve assessment of pati ents with suspected acute thoraci c aortic dissecti ons,
aneurysms, or disruption
Intraoperati ve use during repai r of thoraci c aorti c dissecti ons wi thout suspected aorti c
valve involvement
Intraoperati ve detecti on of aortic atheromatous di sease or other sources of aortic
embol i
Intraoperati ve eval uation of peri cardectomy or peri cardial effusi ons, or eval uation of
peri cardi al surgery
Intraoperati ve eval uation of anastomoti c si tes duri ng heart or l ung transplantati on
Moni tori ng pl acement and functi on of assi st devices
Category III indications: Little current sci enti fi c or expert support; TEE i s infrequentl y
useful i n improvi ng cl ini cal outcomes i n these setti ngs, and appropri ate i ndi cations are
uncertain.
Intraoperati ve eval uation of myocardi al perfusi on, coronary artery anatomy, or graft
patency
Intraoperati ve use during repai r of cardiomyopathies other than hypertrophi c
obstructive cardiomyopathy
Intraoperati ve use for uncompl i cated endocardi tis duri ng noncardi ac surgery
Intraoperati ve moni tori ng for embol i during orthopaedi c procedures
Intraoperati ve assessment of repair of thoracic aortic injuri es
Intraoperati ve use for uncompl icated peri carditi s
Intraoperati ve eval uati on of pl europul monary di seases
Transesophageal echocardiography i s used extensivel y as a monitor of ventri cul ar functi on.
TEE appears to provi de more accurate esti mates of left ventri cul ar prel oad than pul monary
artery catheteri zati on. In echocardi ography, prel oad i s determi ned by measuri ng end-di astoli c
area. Studies i n patients undergoi ng cardi ac or vascular surgery reveal ed that end-di astoli c area
calculated by TEE correl ated well wi th l eft ventri cul ar prel oad, whereas pul monary artery diastoli c
pressure correlated poorl y wi th l eft ventri cul ar preload.
48, 49
Left atri al and l eft ventricul ar
pressures may al so be cal culated using Doppler measurements of fl ow across the mi tral valve, or
from the pul monary vei ns i nto the l eft atri um. TEE estimates of intracardi ac fi ll i ng pressures
correlate wel l wi th data obtai ned from PACs.
50
Left ventricul ar contracti l ity can be estimated usi ng
a vari ety of techniques. Ejecti on fracti on can be determi ned by measuri ng l eft ventri cul ar end-
di astoli c area (EDA) and end-systol i c area (ESA):

Stroke volume can be calcul ated by measuring the Doppl er vel oci ty of fl ow across an area of the
heart (aorti c val ve, pul monary artery, left ventricul ar outfl ow tract) and mul tipl yi ng this val ue
ti mes the area through whi ch the fl ow occurs. The stroke vol ume ti mes heart rate yiel ds CO. The
use of bi pl ane or mul ti pl ane probes appears to i ncrease the accuracy of CO measurements.
51

Transesophageal echocardiography may provi de a more meaningful reference standard for
myocardial i schemia than ECG. Wi thi n seconds of the onset of myocardi al i schemi a, abnormal
inward moti on and thi ckeni ng of the affected myocardi al segment occurs. Wall moti on
abnormali ties precede changes i n the ECG or PAC. Cl ini cal studies suggest that many epi sodes of
ischemi a detected by TEE are mi ssed by standard i ntraoperati ve ECG moni toring.
52, 53
However, not
al l wall moti on abnormal iti es are because of i schemi a. Ventri cul ar paci ng, conducti on
abnormali ties, transl ati onal moti on of the heart, stunned myocardi um, and changes i n l oadi ng
condi ti ons can all mimi c myocardial i schemia on TEE.
Transesophageal echocardiography i s the onl y i ntraoperati ve monitor that provides i nformati on on
the structure and functi on of the mi tral , aortic, tri cuspi d, and pul moni c valves. The severi ty of
stenoti c or regurgitant val vul ar disease can be determi ned usi ng Doppl er studi es. One of the most
important indi cati ons for TEE in the operating room i s i n the assessment of patients requiri ng
val vul ar surgery. The use of TEE before cardi opul monary bypass provi des new i nformation or
prompts changes in val ve surgery in 9 to 13% of cases.
47
In pati ents undergoi ng mitral val ve
repai r, postcardi opul monary bypass TEE reveal ed persistent val vul ar dysfunction in 6 to 11% of
patients, l eading to second pump runs i n 3 to 10% of cases.
47

Transesophageal echocardiography may be used to determine the eti ology of acute hypotension in
the peri operati ve period. Left ventricular fail ure or dysfuncti on can be

Moni toring pl acement of i ntra-aorti c bal loon pumps, automati c implantable cardi ac
defibri ll ators, or pul monary artery catheters
Intraoperati ve moni tori ng of cardioplegi a admi ni strati on
TEE, transesophageal echocardi ography.
Reproduced wi th permission from American Society of Anesthesi ologi sts and Soci ety of
Cardi ovascul ar Anesthesiol ogi sts Task Force on Transesophageal Echocardi ography:
Practi ce gui del i nes for perioperative transesophageal echocardiography. Anesthesiol ogy
84:96, 1996.
P.682
P.683
di fferenti ated from other common causes of severe hypotensi on, such as hypovol emi a or
decreased systemi c vascular resi stance. Unusual causes of acute hypotensi on, i ncl udi ng peri cardial
tamponade, pul monary embol ism, and aorti c di ssecti on, can be rapi dl y di agnosed wi th TEE. The
early detecti on of the cause of hemodynami c i nstabi li ty al lows for the appropri ate therapy to be
insti tuted (vol ume expansion, inotropes, vasopressors).
Transesophageal echocardiography i s moderatel y i nvasi ve and is associ ated wi th major and minor
compl i cati ons. Major compl icati ons (esophageal trauma, dysrhythmi as, hemodynami c i nstabi l ity)
occur in 0.2 to 0.5% of exami nati ons.
47
Minor compl icati ons (l i p injuri es, dental i njuri es,
hoarseness, dysphagi a) occur in 0.1 to 13% of cases and may be rel ated to endotracheal
intubati on rather than TEE.
47
Compl icati on rates may be reduced when exami nati ons are
performed by experi enced practi ti oners. Most compl i cation rates have been reported from studies
in awake pati ents; some compli cati ons may be less frequent i n anestheti zed surgical patients.
MONITORING NEUROLOGIC FUNCTION
The best assessment of neurol ogi c function is a thorough neurologi c exami nati on that evaluates
the integrati on of brai n and spinal cord function. However, anesthesi a, sedati on, and muscl e
rel axants, as wel l as exi sti ng neuropathol ogy or trauma, may si gni fi cantl y i mpai r the sensi tivity or
even the abi l ity to perform a standard neurol ogi c exami nati on i n the operati ng room. Therefore,
moni tori ng neurologi c functi on has become an i mportant component of anesthesi a care.
Intraoperative neurologi c moni tori ng often gui des anesthesi a and surgical deci sion making. Many
intraoperative factors have the potential to infl uence spontaneous or evoked neural acti vi ty.
General anesthesi a can infl uence synapti c transmi ssi on and neural acti vi ty di rectl y or by al tering
physi ol ogi c factors such as blood flow or blood pressure.
I nt r acr ani al P r essur e Moni t or i ng
Intracranial pressure (ICP) monitori ng was i ni tial ly used i n trauma, where the rel ati onshi p
between uncontrol led ICP elevation and fatality has been fi rml y establ i shed.
54
ICP can be
moni tored by i nserti on of a subarachnoid bol t, a ventricul ar catheter, or an epidural transducer, or
by i nserti on of a fi beropti c sensor i n the crani al cavi ty. Each of these techniques requi res a burr
hole for i ntracrani al access.
The cerebrospi nal fl ui d (CSF) pressure wave is pulsati l e and oscil l ates wi th the cardi ac and
respiratory cycl e. Normal ICP i s l ess than 15 mm Hg. Conti nuous recordi ngs of the ICP i n
neurotrauma vi cti ms demonstrate three distinct pathologi c waveforms. A waves (pl ateau waves)
are found in pati ents wi th el evated basel i ne ICP and consi st of a further elevation of ICP for
peri ods from 5 to 20 mi nutes; A waves result from abrupt increases i n regi onal cerebral bl ood
vol ume where cerebral bl ood fl ow i s decreased because of brain swel li ng, venous obstruction, or
obstruction of CSF fl ow. B and C waves are of lesser magnitude and are related to respi ratory
pattern and bl ood pressure. Unl i ke A waves, they are not thought to be useful i n gui di ng therapy
or predi cti ng outcome.
Intracranial pressure moni toring assumes that cerebral perfusi on pressure (CPP = MAP - ICP) i s
uni forml y di stri buted and that i ntracrani al hypertensi on results i n i schemi a, displ acement,
compressi on, or herniation of the brai n. ICP moni tori ng does not measure neural function or
neural recovery.
El ect r oencephal ogr am
The el ectroencephal ogram (EEG) represents the spontaneous electri cal acti vi ty of the superfici al
cerebral cortex as recorded from ei ther the scal p or surface el ectrodes. The EEG si gnal ori ginates
from postsynapti c excitatory and i nhi bi tory potenti al s produced by the pyramidal cel ls l ocated in
the outer cerebral cortex. In the operating room, the EEG si gnal can often be recorded to assess
corti cal activity. Signal processi ng requires the ampli fi cati on of small vol tages (10 to 100 mV),
whi ch are 1,000 ti mes small er than ECG signal s. Conventional EEG anal ysi s uses scal p el ectrodes
positi oned at standardi zed poi nts referenced to cranial dimensi ons. The vol tage di fference between
a pai r of EEG el ectrodes i s ampli fi ed and compared with measurements usi ng a reference
el ectrode. Thi s method, di fferenti al ampli fi cati on, reduces artifacts. The resulti ng si gnal is then
passed through electroni c fi lters, whi ch reduce or remove unwanted frequencies, and is then
di spl ayed as vol tage over ti me. The EEG i s usual ly characteri zed by acti vi ty i n four frequency
bands: beta (>112 Hz), al pha (812 Hz), theta (48 Hz), and del ta (<4 Hz).
In unanestheti zed pati ents, the EEG trace demonstrates background rhythms regul ated by
pacemaker neurons of the lower brai n structures and the local el ectrical acti vi ty resulti ng from
corti cal neurons underl yi ng the acti ve electrode. Duri ng anesthesia, the background al pha rhythm
predomi nates. Wi th deeper anesthesi a or duri ng ischemi a, EEG acti vi ty general ly decreases i n both
ampli tude and frequency. A total of 50% of the brai n' s oxygen consumption has been attributed to
the energy requi rement for the generati on of EEG activity.
El ectroencephalographic monitori ng has been advocated for the intraoperati ve detection of
cerebral ischemi a duri ng caroti d endarterectomy, duri ng del i berate hypotensi on, for the
intraoperative or perioperati ve assessment of pharmacologic i nterventions, for i dentificati on of
epi l epti c foci , or for the assessment of coma or brai n death.
55

Deep anesthesi a, cerebral ischemi a, or other pathol ogi c states abol ish or reduce normal neural
EEG acti vi ty (al pha and beta rhythms), and sl ower frequencies (delta and theta) predominate.
Sleep or surgi cal anesthesi a typicall y increases ampl itude (synchroni zati on), whereas arousal
characteri sti cal ly decreases ampl itude (desynchroni zati on). Hi gh concentrati ons of i sofl urane or
desfl urane can cause peri ods of el ectrical si l ence interspersed wi th brief episodes of acti vi ty. This
pattern i s termed burst suppressi on. Si mi lar effects are seen by many i ntravenous sedati ve drugs
such as barbiturates. Increasing depth of anesthesi a often results i n EEG sl owi ng with increases i n
ampli tude, l eadi ng to burst suppressi on. At the hi ghest l evel s of anesthesi a, the EEG can become
isoel ectric, mi mi cki ng the effect of hypothermi a or brain hypoxi a. EEG i nterpretati on requi res
experi enced observers and the abi l ity to integrate the changes with anestheti c, physi ol ogic, and
surgi cal events.
Processing Electroencephalographic Data
Several si gnal -processi ng techni ques have been used to i mprove the abi l ity of cl i ni cians to
interpret changes i n the EEG and eval uate trends. The EEG si gnal i s usuall y di gi ti zed, processed,
and then graphi cal l y di spl ayed for interpretati on. Real -ti me anal ysis usi ng Fouri er transformati on
to i dentify ampli tudes and frequenci es of i nterest or a peri odi c analysi s are often performed to
convert voltage/time data to power spectral i nformati on, where power versus frequency
information is graphicall y displ ayed over epochs (e.g., the compressed spectral array).
The spectral edge frequency i s often cal cul ated and di spl ayed to summarize the changes i n the
power spectrum. The spectral edge is the frequency that is just above 95% of the power contai ned
in the raw EEG. Monitori ng the spectral edge

has been consi dered useful i n detecti on of cerebral ischemi a and anestheti c depth.
56
Other
descri ptors such as the peak power frequency or the medi an power frequency have been used to
descri be EEG data under anesthesi a.
57

The bi spectral i ndex (BIS) i s a vari able deri ved from the EEG that i s a measure of the hypnotic
effect of anesthetic agents. The BIS i s the fi rst processed EEG descri ptor that purports to predi ct
depth of consciousness. Previ ous EEG parameters, such as the spectral edge frequency, do not
change in a l inear manner wi th i ncreasing depth of anesthesi a. Furthermore, different anesthetic
agents have di fferi ng effects on the processed EEG.
The cal cul ati on of the BIS integrates four di fferent processed EEG descri ptors i nto a si ngl e
vari abl e. These four parameters were selected on the basi s of EEG data col lected from thousands
of anesthetics. The EEG data were correl ated with the cl i ni cal state of the pati ent (level of
consciousness, response to surgical inci si on). Each parameter has a parti cular stage of anesthesi a
where it performs most accuratel y. The BetaRatio parameter refl ects li ght sedati on, the
SynchFastSl ow detects surgi cal l evel s of anesthesi a, and the burst suppressi on rati o (BSR) and
QUAZI predomi nate duri ng deep l evels of anesthesi a.
58
The parameters are then ranked and
P.684
combi ned to yi eld a si ngl e number, the BIS. The range of val ves for the BIS is from 0 to 100, wi th
decreasing numbers indi cati ng deeper l evel s of sedati on or anesthesi a. BIS val ves of l ess than 60
appear to predi ct absence of consciousness.
Cli nical studi es have demonstrated that the BIS can rel i abl y predi ct the level of sedati on, l oss of
consciousness, and the probabi li ty of recal l usi ng a vari ety of anestheti c agents.
59, 60, 61, 62
The BIS
does not appear to be as rel i abl e i n predicting movement i n response to a noxi ous sti mulati on.
Motor responses to painful stimul i may be medi ated by subcorti cal structures, whi ch are not
measured by the BIS monitor. The use of the BIS can faci li tate faster emergence and i mproved
recovery from general anesthesi a by all owi ng more preci se ti trati on of anestheti c effect.
63

Other moni toring systems have been developed for cl i ni cal use that process EEG data i n order to
quantify depth of anesthesia. The Patient State Index (PSI) moni tor records the EEG from anteri or
and posteri or scal p sites. The EEG i s analyzed usi ng a mul tivariate al gori thm that quanti fi es the
most probable level of sedati on or anesthesia. PSI values range from 0 to 100, wi th l ower
numbers i ndi cati ng deeper states of hypnosi s. These PSI val ues correl ate wel l wi th l evel of
consciousness and anesthesi a, and use of PSI monitori ng may all ow for faster emergence and
recovery from anesthesia.
64
The Narcotrend moni tor classi fi es the EEG into 14 di sti nct stages from
stage A (awake) to stage F1 (i soel ectri c EEG). Decreasi ng Narcotrend stages duri ng anesthesi a
have been associated wi th decreasi ng BIS val ues.
65
Cl ini cal studi es suggest that the Narcotrend
moni tor is abl e to di sti nguish al l states of anesthesia accuratel y.
66

Evoked P ot enti al Moni t or i ng
Sti mulation of neural structures to evoke responses i s useful for moni toring the functional
integrity of brainstem, vi sual, audi tory, or peri pheral neural pathways. Evoked potenti al s (EPs)
represent smal l el ectri cal si gnal s generated i n neural pathways after peri odic stimul ati on. In the
cortex and subcortex, EPs are smal l er than the background EEG, and it is necessary to remove the
random background el ectri cal acti vi ty to record EP data. Computer si gnal averagi ng and fi lteri ng
permi ts displ ay of the EP voltages over ti me. EPs are usual l y quanti tated by the ti me from
stimul ati on (latency) and the ampli tude of the peaks generated by the neural structures of
interest. Three sensory pathways are avai l abl e for intraoperative moni toring.
67

Brai nstem audi tory evoked responses (BAERs) are moni tored by stimul ati on of the cochlea usi ng
pul sed sound waves in the ear. Three to fi ve waves are usual l y recorded usi ng el ectrodes pl aced
near the ear and cortex. BAERs are useful i n assessing brai nstem function i n comatose pati ents
and duri ng surgi cal procedures of the cerebel l opontine angl e, fl oor of the fourth ventri cl e, or
procedures i n proximity to the fifth, seventh, or eighth crani al nerves.
68
Unlike other EPs, the
BAERs are relatively resi stant to the effects of anesthesi a. A commerci all y avai l abl e audi tory
evoked potential moni tor has been developed that al l ows cl i ni cians to accurately determi ne the
depth of anesthesi a in the perioperati ve setting.
69

Vi sual evoked potenti al s (VEPs) are produced by fl ashi ng li ght to sti mulate the reti na and
recording the EPs over the occi pital cortex. VEPs assess the i ntegrity of the vi sual pathway and
have been used duri ng resecti on of pi tui tary tumors, craniopharyngi omas, or surgery in the
vici ni ty of the optic tracts. Unl ike BAERs, VEPs are techni cal l y diffi cult to obtain duri ng anesthesia,
and questi ons have arisen about thei r useful ness i n surgery.
Somatosensory evoked potenti al s (SSEPs) are produced by sti mul ati ng peri pheral nerves and
recording responses from electrodes moni tori ng the transmi ssi on of the EPs through the sensory
pathway. The nerves usual l y stimul ated are the medi an, ulnar, peroneal , or posteri or ti bi al .
Surface el ectrodes are pl aced to record the si gnal from peri pheral nerves, plexuses, nerve roots,
the dorsal col umns, the brainstem lemni scal pathways to the thal amus, and the sensory cortex.
Medi an nerve SSEPs have been used to moni tor cerebral functi on i n pati ents undergoi ng
neurosurgi cal procedures or those wi th cerebral ischemi a. In these patients, examinati on of the
ti mi ng and ampl itude of the response measured over the contral ateral scal p at 20 mil l iseconds
(N20) represents the cortical response to sti mulati on. Si mi larly, exami nation of the negati ve
waves occurri ng 11 to 14 mi l li seconds i nterrogates spi nal roots, spi nal cord, and brai nstem.
Moni tori ng the responses of upper or lower extremi ty nerves may assist i n eval uating spinal cord
functi on duri ng i nstrumentati on of the spi ne or duri ng thoracoabdomi nal surgery, where spi nal
cord ischemi a i s a possi bl e ri sk factor. Deteri orati on of spi nal cord functi on decreases the
ampli tude and increases the l atency of the SSEP waveform. Moni tori ng of SSEPs i s thought to be a
sensi ti ve indicator of the spinal cord' s functi onal integrity. Despi te the fact that SSEP moni tori ng
does not evaluate the function of the motor pathway, it appears to be useful duri ng spi nal
surgery, notabl y for correction of scoli osi s.
70
Intraoperati ve SSEPs shoul d be regarded as an
extensi on of the sensory neurologi c exami nati on duri ng anesthesia care, but may not total ly
repl ace the wake-up test. During anesthesi a, moni toring both the area of risk and the
contral ateral pathways hel ps identi fy changes resul ting from surgery as opposed to those as a
resul t of other gl obal vari abl es, such as the effect of anesthesi a.
Motor evoked potenti als (MEPs) provide a means of assessi ng descendi ng motor pathways duri ng
neurosurgi cal , orthopaedi c, or vascul ar procedures. MEPs can be obtained by transcranial
el ectrical sti mulation, transcranial magneti c sti mul ati on, or direct spi nal cord sti mulation.
71

Attenuati on of transcrani al l y eli cited MEPs by commonl y used anesthetic techni ques has l i mi ted
thei r useful ness duri ng surgery. Further investi gati on wi th MEPs i s needed to defi ne ful l y thei r use
duri ng surgery.
72

Facial nerve sti mul ation is commonly performed duri ng procedures i n the posterior fossa.
Intenti onal stimul ati on or surgi cal i rri tation of the faci al nerve can be eval uated visual ly or by
eval uating the el ectromyogram. Al though faci al nerve functi on i s rather insensiti ve to anesthetic
infl uences, muscl e rel axants need to be li mi ted to provi de adequate monitori ng condi ti ons.

TEMPERATURE MONITORING
The abil i ty to monitor body temperature i s a standard of anesthesia care. The continual
observation of temperature changes i n anestheti zed pati ents al l ows for the detecti on of acci dental
heat l oss or mali gnant hyperthermi a. Humans mai ntai n their core temperature by bal anci ng heat
producti on from metabol ism and the many environmental factors that supply heat or cool the
body. Regi onal temperature i nformation from skin, muscl e, the body cavi ti es, spi nal cord, and
brain are i ntegrated i n the central nervous system. Conceptuall y, thermoregul ati on i nvol ves the
integrati on of set poi nts, whi ch, when exceeded, tri gger temperature-di ssipati ng, temperature-
conserving, or heat-producing mechani sms. Both general and regi onal anesthesia i nhi bit afferent
and efferent control of thermoregulati on.
73, 74
In additi on, the operati ng room envi ronment and
surgi cal exposure often contri bute to excessi ve heat l osses. Heat l oss is common during surgery
because the surgical environment transfers heat from the pati ent and anesthesi a reduces heat
producti on and diminishes the capabi l i ty of pati ents to monitor and maintai n thermoregulation.
Heat i s produced as a consequence of cel lular metabol ism. In adults, thermoregul ati on i nvol ves
the control of basal metabol ic rate, muscul ar activity, sympatheti c arousal , vascul ar tone, and
hormone activation bal anced against exogenous factors that determine the need for the body to
create heat or to adjust the transfer of heat to the envi ronment.
Heat l osses may resul t from radi ati on, conduction, convecti on, and evaporati on. Radi ati on refers
to the i nfrared rays emanati ng from al l objects above absol ute temperature. Conducti on refers to
the transfer of heat from contact with objects. Convecti on refers to the transfer of heat from ai r
passi ng by objects. Evaporation represents the heat l oss resulti ng when water vaporizes. For
every gram of water evaporated, 0.58 kcal of heat is l ost.
Peri operative hypothermi a predi sposes patients to increases i n metabol ic rate (shi veri ng) and
cardi ac work, decreases in drug metabol i sm and cutaneous bl ood flow, and i mpai rments of
coagulation. Cl ini cal studi es have demonstrated that pati ents in whom i ntraoperati ve hypothermi a
devel ops are at a hi gher ri sk for devel opment of postoperati ve myocardi al ischemi a and wound
infecti on compared wi th pati ents who are normothermi c i n the peri operati ve peri od.
75, 76

Anesthesi ol ogists frequently moni tor temperature and attempt to maintai n central core
temperature at near-normal val ues i n al l pati ents undergoi ng anesthesi a.
P.685
Central core temperatures can be esti mated usi ng probes that can be pl aced i nto the bl adder,
di stal esophagus, ear canal , trachea, nasopharynx, or rectum.
77
Pul monary artery blood
temperature i s al so a good esti mate of central core temperature.
Temperature is usual l y measured usi ng el ectrical probes contai ning cal ibrated thermi stors or
thermocouples that serve as temperature transducers. Thermi stors respond to temperature
changes by changi ng thei r el ectri cal resi stance. Thermocoupl es are constructed by passi ng current
through a ci rcuit where the el ectrodes are made of two di ssi mi l ar metals. The current measured i s
di rectl y proporti onal to the temperature difference between the two metal juncti ons.
Thermocoupl e temperature probes mai ntain one junction at a known temperature and place the
second juncti on on the temperature probe ti p. Skin temperature can al so be moni tored usi ng l i qui d
crystal thermometry. Although conveni ent, temperature strips do not correl ate wi th core
temperature measurements.
78

Thermoregul atory responses are based on a physi ol ogi cal l y wei ghted average refl ecti ng changes in
the mean body temperature. Mean body temperature is estimated by the fol l owi ng equati on:
Mean temperature = 0.85 T core + 0.15 T skin
Ski n temperature moni toring has been advocated to identi fy peri pheral vasoconstri cti on but i s not
adequate to determine al terati ons i n mean body temperature that may occur duri ng surgery. Core
temperature si tes have been establi shed as rel iabl e i ndi cators of changes in mean temperature.
During routi ne noncardi ac surgery, temperature di fferences between these si tes are smal l . When
anesthetized pati ents are being cool ed, changes i n rectal temperature often l ag behi nd those of
other probe l ocati ons, and the adequacy of rewarmi ng i s best judged by measuri ng temperature at
several locati ons.
FUTURE TRENDS IN MONITORING
Diagnosti c and therapeuti c advances i n medi ci ne have had a great i mpact on the strategi es and
techniques avai labl e for i ntraoperative moni toring. Today' s anesthesi a practi ce has narrowed the
di sti ncti on between l aboratory medi ci ne and pati ent moni toring. Technol ogic advances in
i nstrument desi gn, computeri zati on, and engi neeri ng have made i t possibl e to have ready access
to serum chemi stri es, hematol ogi c profi l es, assessment of coagulation, and arteri al blood gas
measurements. Modern moni tori ng systems have the potential to transfer processed and raw data
from the operati ng room to i nformati on management systems, whi ch offer the potenti al for
creati ng meaningful paperl ess anesthesia records and enhanced archi vi ng of the conduct of
anesthesi a care as depi cted by real -ti me monitori ng trends.
The U.S. Department of Health and Human Servi ces proposed i mplementati on of pati ent record
systems i n 1996.
79
Propri etary systems for automated anesthesia records are now in the
marketpl ace. These offer fi l e shari ng so that i nformation that i s traditi onal l y viewed as pati ent
moni tori ng can al so be used for bi l l ing, orderi ng suppli es, and qual i ty i mprovement. Al though
computerizati on of the hospi tal envi ronment has direct and indi rect costs, the benefits to
physi ci ans, pati ents, insurers, and hospi tal admini strators indicate that, l i ke i n other busi ness
envi ronments, informati on management i s coming to operating room moni toring and
anesthesiol ogy.
80, 81
The cl i ni cal and admi nistrati ve data that can be obtai ned from anesthesia
work stati ons i ntegrated with hospi tal i nformati on systems shoul d enhance the qual ity of care and
improve the i ntraoperati ve moni tori ng of anestheti zed pati ents.
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> Tabl e of Contents > Secti on V - Management of Anesthesi a > Chapter 25 - Epi dural and Spi nal Anesthesi a
Chapter 25
Epidural and Spinal Anesthesia
Christopher M. Bernards
KEY POINTS
The epi dural fat and the epi dural venous pl exus do not form a conti nuous
sheet surrounding the spinal cord as is often depicted. Rather, the epi dural fat
li es in di screte pockets i n the posteri or and lateral epi dural space and the
epi dural veins travel pri mari l y i n the anteri or and l ateral epi dural space and are
normal ly absent i n the posteri or epi dural space.
Cli nici ans must devel op a three-di mensional mental picture of the spinal
anatomy so that when they contact boney structures duri ng attempted epi dural
or spinal needl e pl acement they can redi rect the needl e i n a reasoned and
systemati c manner and not subject the pati ent to random needl e pokes in an
effort to place the block.
Seri ous systemi c toxi city duri ng attempted epidural block i s al most al ways the
resul t of inadvertent l ocal anesthetic injecti on di rectly i nto the vascul ature.
Consequently, an appropri ate test dose desi gned to identi fy intravascul ar
injecti on is criti cal .
Physi cal characteri sti cs (e.g., hei ght, wei ght, cerebrospi nal fl uid [CSF] vol ume)
and age do have an effect on spi nal and epi dural bl ock characteristics. However,
the magni tude of the effects are rel ati vel y smal l and of such l ow predictive
power that these characteristics are not useful predi ctors of l ocal anestheti c
dose i n any i ndi vi dual pati ent.
The risk of hemodynamic compl icati ons of epidural and spi nal anesthesi a
increases wi th i ncreasing bl ock height.
Lidocai ne appears to be worse than other l ocal anestheti cs i n terms of the ri sk
of neurol ogical toxi ci ty (i .e., cauda equina syndrome and transi ent radi cular
irri tati on).
Recent human studi es suggest that the new preservative free formul ati on of
chloroprocai ne is safe for spinal anesthesia. Thi s drug may offer a vi abl e
al ternative to l idocai ne for short duration spi nal anesthesi a.
There are no absol ute indi cati ons for spi nal or epi dural anesthesi a. However, there are cl i ni cal
si tuati ons in whi ch pati ent preference, pati ent physi ol ogy, or the surgical procedure makes central
neuraxial bl ock the techni que of choi ce. There i s also growi ng evidence that these techni ques may
improve outcome in selected si tuati ons. Spi nal and epidural anesthesi a have been shown to bl unt
the stress response to surgery,
1
to decrease intraoperati ve bl ood l oss,
2, 3
to lower the i nci dence
of postoperative thromboemboli c events,
2, 3, 4, 5
and to decrease morbi di ty and mortali ty i n hi gh-ri sk
surgi cal pati ents.
6, 7
In addi ti on, both spi nal and epi dural techni ques can be used to extend
anal gesi a into the postoperative peri od, where thei r use has been shown

to provi de better anal gesi a than can be achi eved with parenteral opi oids.
8
In addi ti on, central
neuraxial analgesi a has become an i ndi spensabl e techni que to provi de anal gesia to nonsurgical
patients. Thus, these techni ques are an indispensabl e part of modern anestheti c practi ce, and
every anesthesi ol ogi st should be adept at performi ng them.
ANATOMY
Profi ci ency i n spi nal and epi dural anesthesia requi res a thorough understandi ng of the anatomy of
the spi ne and spinal cord. The anesthesi ol ogist must be fami l iar wi th the surface anatomy of the
spi ne but must al so devel op a mental picture of the three-dimensional anatomy of deeper
structures. In addi tion, one must appreci ate the relationshi p between the cutaneous dermatomes,
the spi nal nerves, the vertebrae, and the spi nal segment from whi ch each spi nal nerve ari ses.
Ver t ebr ae
The spi ne consi sts of 33 vertebrae (7 cervi cal , 12 thoraci c, 5 l umbar, 5 fused sacral , and 4 fused
coccygeal ) (Fi g. 25-1). Wi th the excepti on of C1, the cervi cal , thoraci c, and lumbar vertebrae
consi st of a body anteri orly, two pedi cles that project posteriorly from the body, and two lami nae
that connect the pedicl es (Fi g. 25-2). These structures form the vertebral canal , which contains
the spi nal cord, spinal nerves, and epi dural space. The l ami nae gi ve rise to the transverse
processes that project l ateral ly and the spi nous process that projects posteri orly. These bony
projecti ons serve as si tes for muscl e and l i gament attachments. The pedi cles contain a superi or
and inferior vertebral notch through which the spinal nerves exit the vertebral canal . The superi or
and inferior arti cul ar processes ari se at the juncti on of the l amina and pedi cl es and form joints
with the adjoi ni ng vertebrae. The fi rst cervi cal vertebra differs from thi s typi cal structure i n that i t
does not have a body or a spinous process.
Admi ni strati on of drugs that i mpai r coagul ation can put pati ents at i ncreased
ri sk of spinal hematoma. Our understanding of the rel ati ve ri sk of di fferent
cl asses of drugs affecti ng the cl otti ng system i s constantl y evol vi ng. Cl i ni ci ans
are directed to the consensus statement from the Ameri can Soci ety for Regi onal
Anesthesi a and Pain Medi ci ne for the most recent recommendati ons
(www.asra.com/items_of_i nterest/consensus_statements/ )
P.692
FIGURE 25-1. Posteri or (A) and l ateral (C) vi ews of the human spi nal col umn. Note the
inset (B), whi ch depi cts the vari abi l ity i n vertebral l evel at whi ch the spi nal cord termi nates.
FIGURE 25-2. Detai l of the l umbar spi nal col umn and epidural space. Note that the epi dural
veins are l argely restri cted to the anteri or and l ateral epi dural space.
The fi ve sacral vertebrae are fused together to form the wedge-shaped sacrum, which connects
the spi ne wi th the il i ac wings of the pel vi s (see Fi g. 25-1). The 5th sacral vertebra i s not fused
posteriorly, gi vi ng rise to a vari abl y shaped openi ng known as the sacral hi atus. Occasi onal l y
other sacral vertebrae do not fuse posteriorly, givi ng rise to a much larger sacral hiatus. The
sacral cornu are bony promi nences on ei ther si de of the hi atus and ai d in i dentifyi ng i t. The sacral
hi atus provides an openi ng into the sacral canal , which is the caudal termi nation of the epi dural
space. The four rudi mentary coccygeal vertebrae are fused together to form the coccyx, a narrow
triangul ar bone that abuts the sacral hi atus and can be hel pful in i dentifyi ng i t. The ti p of the
coccyx can often be pal pated i n the proxi mal gl uteal cl eft and by runni ng one's finger cephal ad
al ong i ts smooth surface, the sacral cornu can be identified as the first bony prominence
encountered.
Identi fyi ng i ndi vi dual vertebrae i s important for correctl y locati ng the desi red i nterspace for
epi dural and spi nal bl ockade. The spine of C7 is the first prominent spinous process encountered
whi l e running the hand down the back of the neck. The spi ne of T1 i s the most prominent spinous
process and i mmedi atel y fol l ows C7. The 12th thoraci c vertebra can be i denti fi ed by pal pati ng the
12th ri b and traci ng i t back to i ts attachment to T12. A l i ne drawn between the i l iac crests crosses
the body of L5 or the 4-5 interspace.
Li gaments
The vertebral bodi es are stabil i zed by fi ve l i gaments that i ncrease in si ze between the cervi cal and
lumbar vertebrae (see Fi g. 25-2). From the sacrum to T7, the supraspi nous l i gament runs between
the ti ps of the spi nous processes. Above T7 thi s li gament continues as the li gamentum nuchae and
attaches to the occipi tal protuberance at the base of the skul l . The interspi nous l i gament attaches
between the spinous processes and bl ends posteri orl y wi th the supraspi nous l i gament and
anteriorl y wi th the li gamentum fl avum. The li gamentum fl avum i s a tough, wedge-shaped l i gament
composed of el asti n. It consi sts of ri ght and l eft porti ons that span adjacent vertebral l ami nae and
fuse i n the mi dli ne to varyi ng degrees.
7, 8
The l i gamentum fl avum is thi ckest in the midl i ne,
measuri ng 3 to 5 mm at the L23 interspace of adul ts. This l i gament i s al so farthest from the
spi nal meninges in the midl i ne, measuri ng 4 to 6 mm at the L23 interspace.
9
As a result, midline
inserti on of an epidural needl e is l east l i kely to resul t in unintended meningeal puncture. The
anterior and posteri or longi tudinal li gaments run al ong the anteri or and posteri or surfaces of the
vertebral bodi es.

Epi dur al Space
The epi dural space i s the space that li es between the spinal meni nges and the si des of the
vertebral canal (Fi g. 25-3). It i s bounded crani all y by the foramen magnum, caudal l y by the
sacrococcygeal l igament coveri ng the sacral hiatus, anteri orly by the posteri or longi tudi nal
li gament, l ateral l y by the vertebral pedi cl es, and posteri orl y by both the l igamentum flavum and
vertebral lamina. The epi dural space i s not a cl osed space but communi cates with the
paravertebral space by way of the intervertebral foramina.
10
The epi dural space is shal lowest
anteriorl y where the dura may in some places fuse wi th the posteri or l ongitudi nal l i gament. The
space is deepest posteriorl y, al though the depth vari es because the space is i ntermittently
obl iterated by contact between the dura mater and the l i gamentum fl avum or vertebral l amina.
Contact between the dura mater and the pedicl es al so i nterrupts the epi dural space l ateral l y.
Thus, the epi dural space is composed of a seri es of di scontinuous compartments that become
conti nuous when the potenti al space separati ng the compartments is opened up by i njecti on of ai r
or l iquid. A rich network of val vel ess veins (Batson's pl exus) courses through the anterior and
lateral porti ons of the epidural space wi th few i f any vei ns present i n the posteri or epi dural space
(see Fi g. 25-2).
11
The epidural vei ns anastomose freel y wi th extradural vei ns, i ncl udi ng the pelvic
veins, the azygous system, and the intracrani al vei ns. The epidural space also contains lymphati cs
and segmental arteri es runni ng between the aorta and the spi nal cord.
P.693
Epidural Fat
The most ubi qui tous materi al in the epi dural space i s fat, which is pri nci pal l y l ocated in the
posterior and l ateral epi dural space (see Fi g. 25-3).
10
Interesti ngl y, the epi dural fat appears to
have cli ni cal l y i mportant effects on the pharmacology of epi durall y and i ntrathecal ly admi ni stered
drugs. For exampl e, usi ng a pi g model , Bernards et al showed that there i s a l i near rel ationship
between an opioi d's l i pid solubi li ty and i ts termi nal eli minati on hal f-ti me i n the epi dural space, i ts
mean resi dence time i n the epi dural space, and i ts concentrati on in epi dural fat.
12
In additi on, net
transfer of opi oi d from the epi dural space to the i ntrathecal space was greatest for the least l i pid
solubl e opi oi d (morphi ne) and l east for hi ghl y li pi d sol ubl e opioi ds (fentanyl , sufentani l ). In effect,
increasi ng l i pid sol ubi li ty resul ted i n opi oid sequestrati on in epidural fat, thereby, reduci ng the
bi oavai l abi l ity of drug in the underlying subarachnoi d space and spi nal ti ssue.
Epi dural fat al so appears to play a rol e i n the pharmacoki netics of epidural ly admi ni stered l ocal
anesthetics. Specificall y, sequestration in epidural fat li kel y explai ns why a hi ghly l ipi d sol ubl e
local anestheti c li ke eti docaine i s only approxi matel y equipotent wi th l idocai ne in the epi dural
space despi te the fact that eti docai ne i s roughl y seven ti mes more potent than li docai ne i n vi tro.
Because of i ts much greater l i pid solubi li ty, etidocai ne i s more l i kel y than li docaine to be
sequestered i n epi dural fat, thereby reduci ng the amount of drug avai l abl e to produce bl ock i n the
spi nal nerve roots and spi nal cord. Consi stent with this hypothesi s, Lebeaux and Tucker showed
that after admi ni steri ng 80 mg eti docaine and 50 mg l idocai ne i nto the epi dural space of sheep,
the amount of etidocai ne stil l present i n epidural fat 12 hours later was more than 100 ti mes
greater than the amount of l idocai ne.
13
Thus, sequestration in epidural fat appears to play an
important rol e i n the pharmacoki netics of l ocal anesthetics just as it does for epidural opi oids.
Meni nges
The spinal meni nges consi st of three protecti ve membranes (dura mater, arachnoi d mater, and pia
mater), whi ch are conti nuous with the crani al meninges (Fi g. 25-4).
FIGURE 25-3. The compartments of the epi dural space (stippl ed areas) are disconti nuous.
Areas where no compartments are i ndi cated represent a potenti al space where the dura
mater normal l y abuts the si des of the vertebral canal . (Repri nted wi th permi ssi on from Hogan
Q: Lumbar epidural anatomy: A new l ook by cryomi crotome secti on. Anesthesiol ogy 75:767,
1991.)
Dura Mater
The dura mater i s the outermost and thi ckest meni ngeal ti ssue. The spi nal dura mater begi ns at
the foramen magnum where it fuses with the peri osteum of the skul l , formi ng the cephal ad border
of the epidural space. Caudall y, the dura mater ends at approximatel y S2 where it fuses with the
fil um termi nal e. The dura mater extends laterall y al ong the spi nal nerve roots and becomes
conti nuous with the connecti ve ti ssue of the epineurium at approxi matel y the l evel of the
intervertebral forami na. The dura mater i s composed of randoml y arranged

coll agen fibers and elasti n fi bers arranged longi tudi nal ly and ci rcumferenti all y.
14
The dura mater i s
largel y acell ul ar except for a layer of cell s that forms the border between the dura and arachnoi d
mater.
There i s controversy regardi ng the existence and cl inical si gnifi cance of a mi dli ne connecti ve
ti ssue band, the pl i ca medi ani s dorsal is, running from the dura mater to the l i gamentum fl avum.
Anatomi c studies usi ng epi duroscopy
15
and epi durography
16
have demonstrated the presence of
the pl i ca medianis dorsal i s and have led to specul ati on that thi s ti ssue band may on occasi on be
responsi bl e for di fficul ty in i nserti ng epi dural catheters and for uni l ateral epi dural bl ock. However,
using cryomi crotome sections to investi gate the epi dural space, Hogan fail ed to fi nd evi dence of a
substantial connecti on between the dura mater and the li gamentum fl avum.
10
He speculated that
the injecti on of ei ther ai r or contrast requi red for the earl i er studi es may have compressed
epi dural contents (e.g., fat) and produced an arti fact mi micki ng a connecti ve ti ssue band. In
addi ti on, Hogan has shown i n a cl i ni cal study that there i s no si gni fi cant i mpedi ment to spread of
injectate across the mi dl ine.
17
Thus, the pl i ca medi ani s dorsal is does not appear to be cl i ni cal ly
rel evant wi th respect to cl inical epi dural anesthesi a.
FIGURE 25-4. The spi nal meni nges of the dog, demonstrati ng the pi a mater (PM) i n
apposi tion to the spi nal cord, the subarachnoi d space (SS), the arachnoid mater (AM),
trabecul ae (arrow), and the dura mater (DM). The separati on between the arachnoid mater
and the dura mater demonstrates the subdural space. The subdural space i s onl y a potenti al
space in vi vo but i s created here as an artifact of preparation. (Repri nted with permi ssi on
from Peters A, Pal ay SL, Webster H (eds): The Fi ne Structure of the Nervous System: The
Neurons and Supporti ng Cel l s. Phil adel phia, WB Saunders, 1976.)
P.694
The i nner surface of the dura mater abuts the arachnoi d mater. There is a potenti al space between
these two membranes cal l ed the subdural space (see Fi g. 25-4). Occasi onal l y a drug i ntended for
ei ther the epi dural space or the subarachnoid space i s i njected i nto the subdural space.
18
Subdural
injecti on has been estimated to occur in 0.82% of i ntended epi dural injecti ons.
19
The radi ology
li terature suggests that the inci dence of subdural i njecti on duri ng intended subarachnoi d injecti on
may be as hi gh as 10%.
20

Arachnoid Mater
The arachnoi d mater i s a deli cate, avascul ar membrane composed of overl appi ng layers of
flattened cel l s wi th connecti ve ti ssue fi bers runni ng between the cell ular layers. The arachnoi d
cel ls are interconnected by frequent ti ght junctions and occluding juncti ons. These speci ali zed
cel lul ar connecti ons li kel y account for the fact that the arachnoid mater i s the pri nci pal physi ol ogic
barri er for drugs movi ng between the epi dural space and the spi nal cord.
21

In the regi on where the spinal nerve roots traverse the dura and arachnoid membranes, the
arachnoi d mater herni ates through the dura mater i nto the epi dural space to form arachnoid
granulati ons. As wi th the crani al arachnoi d granulations, the spi nal arachnoi d granul ations serve
as a site for material i n the subarachnoi d space to exit the central nervous system (CNS).
Al though some have postulated that the arachnoi d granul ati ons are a preferred route for drugs to
move from the epi dural space to the spinal cord, the avai l abl e experimental data suggest that thi s
is not the case.
22

The subarachnoi d space l i es between the arachnoi d mater and the pi a mater and contains the CSF.
The spinal CSF is i n conti nuity with the crani al CSF and provi des an avenue for drugs i n the spi nal
CSF to reach the brai n. In addi tion, the spinal nerve roots and rootl ets run i n the subarachnoi d
space.
Pia Mater
The spinal pi a mater i s adherent to the spi nal cord and i s composed of a thin l ayer of connecti ve
ti ssue cel l s interspersed wi th col l agen. Trabecul ae connect the pi a mater wi th the arachnoi d mater
and the cell s of these two meni nges bl end together al ong the trabeculae. Unl ike the arachnoi d
mater, the pi a mater i s fenestrated i n places so that the spi nal cord i s in di rect communicati on
with the subarachnoi d space. The pia mater extends to the ti p of the spinal cord where it becomes
the fil um termi nale, whi ch anchors the spinal cord to the sacrum. The pi a mater also gi ves ri se to
the dentate l igaments, whi ch are thin connecti ve ti ssue bands extending from the si de of the
spi nal cord through the arachnoi d mater to dura mater. These li gaments serve to suspend the
spi nal cord wi thi n the meninges.
Spi nal Cor d
In the fi rst-trimester fetus, the spinal cord extends from the foramen magnum to the end of the
spi nal col umn. Thereafter, the vertebral col umn lengthens more than the spi nal cord so that at
bi rth the spi nal cord ends at about the l evel of the third l umbar vertebra. In the adul t, the caudad
ti p of the spinal cord typi cal l y l i es at the l evel of the fi rst l umbar vertebra. However, in 30% of
individual s the spinal cord may end at T12, whi le i n 10% i t may extend to L3 (see Fi g. 25-1).
23
A
sacral spi nal cord has been reported in an adult.
23
Fl exi on of the vertebral col umn causes the tip
of the spi nal cord to move sli ghtl y cephal ad.
The spinal cord gi ves rise to 31 pai rs of spi nal nerves, each composed of an anterior motor root
and a posterior sensory root. The nerve roots are i n turn composed of mul ti pl e rootl ets.

The portion of the spinal cord that gi ves ri se to al l of the rootl ets of a si ngl e spi nal nerve i s cal l ed
a cord segment. The ski n area innervated by a given spi nal nerve and i ts correspondi ng cord
segment is call ed a dermatome (Fi g. 25-5). The i ntermedi olateral gray matter of the T1 through
L2 spi nal cord segments contains the cel l bodies of the pregangl i oni c sympatheti c neurons. These
sympatheti c neurons run wi th the correspondi ng spi nal nerve to a poi nt just beyond the
P.695
intervertebral foramen where they exi t to joi n the sympatheti c chai n gangl ia.
The spinal nerves and their correspondi ng cord segments are named for the i ntervertebral foramen
through which they run. In the cervi cal regi on, the spinal nerves are named for the vertebra
formi ng the caudad hal f of the intervertebral foramen; for example, C4 emerges through an
intervertebral foramen formed by C3 and C4. In the thoracic and l umbar region, the nerve roots
are named for the vertebrae forming the cephalad hal f of the intervertebral foramen; for exampl e,
L4 emerges through an intervertebral foramen formed by L4 and L5. Because the spi nal cord ends
between L1 and L2, the thoraci c, l umbar, and sacral nerve roots run i ncreasi ngl y l onger distances
in the subarachnoi d space to get from thei r spi nal cord segment of ori gi n to the i ntervertebral
foramen through which they exi t. Those nerves that extend beyond the end of the spi nal cord to
thei r exi t si te are col l ecti vely known as the cauda equi na (see Fi g. 25-1).
TECHNIQUE
Spinal and epi dural anesthesi a shoul d be performed onl y after appropri ate moni tors are appl i ed
and i n a setti ng where equi pment for ai rway management and resuscitati on are i mmediately
avai l abl e. Before posi ti oni ng the pati ent, all equipment for spi nal bl ock shoul d be ready for use,
for exampl e, local anestheti cs mi xed and drawn up, needl es uncapped, prep sol uti on avail able,
and so on. Prepari ng al l equi pment ahead of ti me wi l l mi ni mi ze the ti me required to perform the
bl ock and thereby enhance pati ent comfort.
Needl es
FIGURE 25-5. Human sensory dermatomes.
Spinal and epi dural needles are named for the design of thei r ti ps (Fi g. 25-6). The Whi tacre and
Sprotte spinal needles have a penci l -poi nt ti p wi th the needle hole on the side of the shaft. The
Greene and Qui ncke needles have beveled ti ps wi th cutti ng edges. The penci l -poi nt needl es
requi re more force to i nsert than the bevel -ti p needl es but provi de a better tacti le feel of the
vari ous ti ssues encountered as the needl e i s inserted. In addi ti on, the bevel has been shown to
cause the needl e to be defl ected from the i ntended path as it passes through ti ssues whi le the
penci l -poi nt needl es are not defl ected.
24
Epi dural needles have a l arger di ameter than spinal
needles to faci l itate the injecti on of fluid or air when usi ng the loss-of-resistance technique to
identi fy the epidural space. In addi ti on, the larger di ameter all ows for easier insertion of catheters
into the epi dural space. The Tuohy epi dural needl e has a curved ti p to hel p control the directi on
that the catheter moves i n the epi dural space. The Hustead needl e ti p is al so curved, al though
somewhat l ess than the Tuohy needl e. The Crawford needl e ti p i s strai ght, making i t less sui tabl e
for catheter i nserti on. The outsi de di ameter of both epidural and spinal needles i s used to
determi ne thei r gauge. Larger gauge (i .e., smal l er di ameter) spi nal needl es are less l ikel y to
cause postdural puncture headaches (PDPH), but are more readi l y defl ected than smal l er gauge
needles. Epidural needl es are typicall y si zed 16 to 19 gauge and spi nal needl es 22 to 29 gauge.
Spinal needl es smal l er than 22 gauge are often easier to i nsert if an i ntroducer needl e is used.
The i ntroducer is i nserted i nto the i nterspi nous l igament in the i ntended directi on of the spi nal
needle and the spinal needle i s then

inserted through the shaft of the introducer. The i ntroducer prevents the spi nal needl e from being
defl ected or bent as i t passes through the i nterspi nous l i gament.
24
Needl es of the same outsi de
di ameter may have different insi de di ameters. Thi s i s i mportant because i nsi de di ameter
determi nes how l arge a catheter can be inserted through the needl e and determi nes how rapi dl y
CSF wi l l appear at the needl e hub duri ng spi nal needl e i nsertion. All spi nal and epi dural needles
come with a ti ght-fitting stylet. The styl et prevents the needl e from bei ng plugged wi th ski n or fat
and i mportantl y prevents draggi ng ski n i nto the epi dural or subarachnoi d spaces, where the ski n
may grow and form dermoi d tumors.
P.696
Sedat i on
If the pati ent desi res, l i ght sedation i s appropri ate before pl acement of spi nal or epi dural bl ock.
Generall y, the pati ent shoul d not be heavi ly sedated because successful spi nal and epi dural
anesthesia requi res pati ent partici pati on to mai ntain good positi on, eval uate bl ock hei ght, and
indicate to the anesthesi ologist about paresthesias i f the needle contacts neural elements. In
addition, patient cooperati on i s requi red to properly evaluate an epi dural test dose; and sedati on
with as l i ttl e as 1.5 mg midazolam plus 75 g fentanyl has been shown to reduce the rel iabi li ty of
patient reports of subjecti ve symptoms of i ntravenous l ocal anesthetic i njection.
25
Once the block
i s pl aced and adequate bl ock hei ght assured, the pati ent can be sedated as deemed appropri ate.
Spi nal Anest hesi a
FIGURE 25-6. Some of the commerci al l y avail able needles for spi nal and epi dural
anesthesia. Needl es are di sti nguished by the desi gn of thei r ti ps.
Position
Careful attenti on to pati ent posi ti oni ng i s cri tical to successful spi nal puncture. Poor positi oning
can turn an otherwi se easy spi nal anestheti c into a chal lenge for both the anesthesiol ogi st and the
patient. Spinal needles are most often inserted with the pati ent i n the l ateral decubitus positi on
and thi s technique is descri bed i n detai l l ater. However, both the prone jackkni fe and sitting
positi ons offer advantages under speci fi c ci rcumstances. The si tti ng posi ti on i s someti mes used i n
obese pati ents because i t is often easi er to identi fy the midl i ne wi th the pati ent si tti ng. In
addi ti on, the si tti ng posi ti on al l ows one to restri ct spi nal bl ock to the sacral dermatomes (saddl e
bl ock) when usi ng hyperbaric l ocal anestheti c soluti ons. Spi nal bl ock i s general l y performed in the
prone jackknife posi ti on onl y when thi s i s the posi ti on to be used for surgery. The use of
hypobari c local anestheti c sol uti ons with the pati ent i n the prone jackkni fe posi ti on produces
sacral block for peri rectal surgery.
In the l ateral decubi tus posi ti on, the patient li es wi th the operati ve side down when using
hyperbaric l ocal anestheti c sol utions and wi th the operati ve si de up when usi ng hypobaric
solutions, thus assuring that the earli est and most dense block occurs on the operative si de. The
back shoul d be at the edge of the tabl e so that the pati ent i s wi thi n easy reach. The pati ent' s
shoulders and hi ps are both posi ti oned perpendicul ar to the bed to help prevent rotation of the
spi ne. The knees are drawn to the chest, the neck i s fl exed, and the pati ent i s instructed to
acti vel y curve the back outward. Thi s wi l l spread the spinous processes apart and maximi ze the
size of the interlaminar foramen. It i s useful to have an assistant who can help the pati ent
maintai n thi s posi ti on. Usi ng the i li ac crests as a l andmark, the L23, L34, and L45 interspaces
are identi fi ed and the desi red interspace chosen for needle insertion. Interspaces above L2-3 are
avoi ded to decrease the ri sk of hitting the spinal cord with the needl e. Some fi nd i t hel pful to
mark the spi nous processes fl anki ng the desi red i nterspace wi th a skin marker. Thi s obviates the
need to rei denti fy the i ntended i nterspace after the pati ent i s prepped and draped.
The pati ent i s prepped wi th an appropri ate anti septic soluti on and draped. Al l anti septi c sol uti ons
are neurotoxi c, and care must be taken not to contami nate spi nal needl es or l ocal anesthetics wi th
the prep soluti on. How one drapes is a matter of personal preference, but the author fi nds that
preppi ng and drapi ng out a l arge area (e.g., T12-S1) with towel s is preferabl e to usi ng a
commercial one-pi ece drape wi th a l i mi ted center hol e. Drapi ng a l arge area permits easi er
identi fi cation of a rotated or i nadequatel y flexed back and al l ows one to readi l y move to another
interspace if thi s becomes necessary.
Midline Approach
For the mi dl ine approach to the subarachnoi d space, the ski n overl yi ng the desi red i nterspace is
infi ltrated wi th a small amount of local anestheti c to prevent pain when i nserti ng the spi nal
needle. One shoul d avoi d rai si ng too large a ski n wheal because thi s can obscure palpation of the
interspace, especi al l y i n obese pati ents. Additi onal l ocal anestheti c (1 to 2 mL) i s then deposi ted
al ong the i ntended path of the spi nal

needle to a depth of 1 to 2 i nches. Thi s deeper i nfil trati on provides additi onal anesthesia for
spi nal needl e i nsertion and hel ps i dentify the correct path for the spinal needl e.
The spinal needle or introducer needle i s i nserted i n the mi ddle of the i nterspace with a sl ight
cephal ad angul ati on of 10 to 15 degrees (Fi g. 25-7). The needl e i s then advanced, i n order,
through the subcutaneous ti ssue, supraspinous l igament, interspi nous l i gament, l igamentum
flavum, epi dural space, dura mater, and final l y arachnoi d mater. The l igaments produce a
characteri sti c feel as the needl e i s advanced through them, and the anesthesi ol ogi st shoul d
develop the abi li ty to distingui sh a needl e that is advanci ng through the high-resistance l i gaments
from one that i s advancing through l ower-resistance paraspi nous muscl e. Thi s wi l l al l ow early
detecti on and correcti on of needl es that are not advanci ng in the midl i ne. Penetrati on of the dura
mater produces a subtl e pop that i s most easi l y detected wi th the pencil -poi nt needl es.
Detecti on of dural penetrati on wil l prevent i nserting the needl e al l the way through the
subarachnoi d space and contacti ng the vertebral body. In addi ti on, l earni ng to detect dural
P.697
penetrati on wi l l al l ow one to i nsert the spinal needle quickl y wi thout havi ng to stop every few
mi ll i meters and remove the styl et to l ook for CSF at the needle hub.
Once the needle ti p i s beli eved to be i n the subarachnoi d space, the stylet i s removed to see if
CSF appears at the needl e hub. Wi th smal l diameter needl es (26 to 29 gauge) thi s general l y
requi res 5 to 10 seconds, but may requi re 1 minute in some pati ents. Gentl e aspi rati on may
speed the appearance of CSF. If CSF does not appear, the needl e orifice may be obstructed by a
nerve root and rotating the needl e 90 degrees may resul t i n CSF fl ow. Al ternati vel y, the needl e
orifice may not be compl etel y in the subarachnoi d space and advancing an addi ti onal 1 to 2 mm
may result i n bri sk CSF flow. Thi s is parti cul arly true of penci l-poi nt needl es, which have thei r
orifice on the si de of the needle shaft proximal to the needl e tip. Final l y, fai l ure to obtai n CSF
suggests that the needle orifice i s not in the subarachnoi d space and the needl e shoul d be
rei nserted.
If bone i s encountered duri ng needle i nserti on, the anesthesi ol ogi st must devel op a reasoned,
systemati c approach to redi recti ng the needl e. Si mpl y withdrawing the needl e and repeatedl y
rei nserti ng i t i n di fferent di recti ons is not appropri ate. When contacti ng bone, the depth shoul d be
i mmedi atel y noted and the needl e redi rected sl i ghtl y cephal ad. If bone i s agai n encountered at a
greater depth, then the needl e i s most l i kely wal ki ng down the i nferi or spi nous process and i t
should be redi rected more cephal ad unti l the subarachnoid space is reached. If bone i s
encountered agai n at a shal lower depth, then the needl e i s most l ikely walking up the superior
spi nous process and i t shoul d be redi rected more caudad. If bone i s repeatedl y encountered at the
same depth, then the needle is l ikely off the mi dli ne and walking along the vertebral l amina (see
Fi g. 25-7).
When redirecti ng a needle i t i s important to wi thdraw the ti p i nto the subcutaneous ti ssue. If the
ti p remai ns embedded i n one of the vertebral li gaments, then attempts at redi recti ng the needle
FIGURE 25-7. Mi dl i ne approach to the subarachnoi d space. The spi nal needl e i s inserted
with a sl i ght cephal ad angul ati on and should advance i n the mi dl ine wi thout contacti ng bone
(B). If bone i s contacted, i t may be ei ther the caudad (A) or the cephal ad spi nous process
(C). The needle should be redi rected sl i ghtly cephal ad and reinserted. If bone i s encountered
at a shall ower depth, then the needl e i s li kel y wal ki ng up the cephal ad spi nous process. If
bone i s encountered at a deeper depth, then the needl e i s l ikel y walking down the inferior
spi nous process. If bone i s repeatedl y contacted at the same depth, then the needl e i s li kel y
off the mi dl i ne and wal ki ng al ong the lami na. (Repri nted with permi ssi on from Mul roy MF:
Regi onal Anesthesi a: An Il l ustrated Procedural Gui de. Boston, Li ttl e Brown, 1989.)
wil l simpl y bend the shaft and not rel i abl y change needl e di recti on. When usi ng an i ntroducer
needle, it must also be wi thdrawn i nto the subcutaneous ti ssue before bei ng redi rected. Changes
in needl e di recti on shoul d be made in small i ncrements because even smal l changes i n needle
angle at the ski n may result i n fai rly l arge changes in posi ti on of the needle ti p when i t reaches
the spi nal meninges at a depth of 4 to 6 cm. Care shoul d be exercised when gri ppi ng the needl e to
ensure that i t does not bow. Inserti on of a curved needl e wi l l cause i t to veer off course.
If the pati ent experiences a paresthesi a, i t is i mportant to determi ne whether the needl e tip has
encountered a nerve root i n the epi dural space or i n the subarachnoid space. When the
paresthesi a occurs, i mmediatel y stop advanci ng the needl e, remove the styl et, and look for CSF at
the needl e hub. The presence of CSF confi rms that the needle encountered a cauda equi na nerve
root i n the subarachnoid space and the needl e tip i s i n good posi ti on. Given how ti ghtl y packed
the cauda equina nerve roots are, it i s surpri si ng that al l spinal punctures do not produce
paresthesi as. If CSF is not vi sibl e at the hub, then the paresthesi a probabl y resul ted from contact
with a spi nal nerve root traversi ng the epi dural space. This i s especi al l y true i f the paresthesia
occurs i n the dermatome correspondi ng to the nerve root that exits the vertebral canal at the
same l evel that the spi nal needl e i s inserted. In thi s case the needl e has most l i kel y devi ated from
the mi dl i ne and shoul d be redi rected toward the side opposi te the paresthesi a. Occasi onal l y, pai n
experi enced when the needl e contacts bone may be mi si nterpreted by the pati ent as a paresthesia
and the anesthesi ol ogist shoul d be alert to thi s possibi l i ty.
Once the needle is correctly i nserted i nto the subarachnoid space, i t i s fi xed i n posi ti on and the
syri nge contai ni ng local anestheti c i s attached. CSF i s gently aspi rated to confi rm that the needl e
is sti l l in the subarachnoi d space and the l ocal anestheti c sl owl y i njected (0.5 ml /s-1). After
compl eti ng the i njecti on, a smal l volume of CSF is agai n aspi rated to confi rm that the needl e ti p
remai ned i n the subarachnoid space whil e the l ocal anestheti c was deposi ted. This CSF is then
rei njected and the needl e, syringe, and any introducer removed together as a uni t. If the surgi cal
procedure i s to be performed i n the supine posi tion, the pati ent i s hel ped onto his back. To
prevent excessi ve cephal ad spread of hyperbari c local anestheti c, care shoul d be taken to ensure
that the patient' s hi ps are not rai sed off the bed as they turn.
Once the block i s placed, strict attention must be pai d to the pati ent's hemodynami c status wi th
bl ood pressure and/or heart rate supported as necessary. Bl ock hei ght shoul d also be assessed
early by pi n pri ck or temperature sensati on. Temperature sensati on i s tested by wipi ng the ski n
with al cohol and may be preferabl e to pi n pri ck because i t i s not pai nful . If, after a few minutes,
the block i s not ri sing hi gh enough or i s ri si ng

too hi gh, the tabl e may be ti l ted as appropri ate to i nfl uence further spread of hypobaric or
hyperbaric l ocal anestheti cs.
Paramedian Approach
The paramedi an approach to the epi dural and subarachnoid spaces i s useful i n si tuati ons where
the pati ent's anatomy does not favor the midl i ne approach, e.g., i nabil i ty to flex the spine or
heavil y cal ci fi ed i nterspi nous li gaments. This approach can be used wi th the pati ent i n any
posi ti on and i s probabl y the best approach for the pati ent i n the prone jackkni fe posi ti on.
The spinous process forming the l ower border of the desi red i nterspace i s identi fi ed. The needl e is
inserted ~1 cm l ateral to this poi nt and is di rected toward the mi ddl e of the i nterspace by angl i ng
it ~45 degrees cephal ad wi th just enough medi al angul ati on (~15 degrees) to compensate for the
lateral i nserti on point. The first si gni fi cant resistance encountered shoul d be the l igamentum
flavum. Bone encountered pri or to the l igamentum flavum i s usual ly the vertebral l ami na of the
cephal ad vertebra and the needl e shoul d be redi rected accordi ngl y. An alternati ve method i s to
insert the needl e perpendi cul ar to the ski n i n al l pl anes unti l the l amina is contacted. The needl e
is then walked off the superi or edge of the l ami na and i nto the subarachnoid space. The l ami na
provi des a val uabl e landmark that facil i tates correct needle placement; however, repeated needle
contact wi th the peri osteum can be pai nful .
P.698
Lumbosacral Approach
The l umbosacral (or Tayl or) approach to the subarachnoi d and epidural spaces is si mpl y a
paramedi an approach di rected at the L5-S1 interspace, whi ch i s the largest i nterl ami nar space.
Thi s approach may be useful when anatomi c constrai nts make other approaches unfeasi ble. The
pati ent may be posi ti oned l ateral ly, prone or sitting, and the needl e inserted at a point 1 cm
medial and 1 cm i nferior to the posterior superi or i l iac spi ne. The needle i s angled cephal ad 45 to
55 degrees and just medi al enough to reach the mi dli ne at the l evel of the L5 spinous process. As
wi th the paramedi an approach, the i nterspi nous l i gament i s bypassed and the fi rst si gni fi cant
resistance felt shoul d be the l i gamentum fl avum.
Cont i nuous Spi nal Anest hesi a
Inserti ng a catheter i nto the subarachnoi d space i ncreases the uti li ty of spi nal anesthesia by
permi tti ng repeated drug administrati on as often as necessary to extend the l evel or duration of
spi nal bl ock. A common and reasonabl e recommendati on for subsequent dosi ng or topping up of
conti nuous spi nal bl ocks i s to admi ni ster hal f the origi nal dose of local anestheti c when the bl ock
has reached two thi rds of its expected duration.
The techni que i s simil ar to that descri bed for si ngl e shot spi nal anesthesi a except that a needle
large enough to accommodate the desi red catheter must be used. After i nserti ng the needl e and
obtaining free-flowing CSF, the catheter i s simply threaded i nto the subarachnoi d space a distance
of 2 to 3 cm. It i s often easi er to i nsert the catheter i f i t is di rected cephal ad or caudad instead of
lateral . If the catheter does not easi ly pass beyond the needle ti p, rotating the needle 180
degrees may be hel pful or another interspace may be used. The catheter shoul d never be
withdrawn back i nto the needl e shaft because of the risk of shearing the catheter off i nto the
subarachnoi d space.
A vari ety of catheters and needles are avai labl e for conti nuous spi nal anesthesi a. Commonly, 18-
gauge epidural needl es and 20-gauge catheters are used. However, needles and catheters this si ze
carry a hi gher ri sk of PDPH, especi al l y i n young patients. Because of thi s ri sk, smal l er needl e and
catheter combi nations have been devel oped wi th catheters rangi ng i n si ze from 24 to 32 gauge.
Although small er catheters decrease the ri sk of PDPH, they have al so been associ ated wi th
mul tipl e reports of neurol ogi c i njury, speci fi cal ly, cauda equi na syndrome (see Compli cati ons). For
this reason, the United States Food and Drug Admi ni stration has advised agai nst usi ng any
catheter small er than 24 gauge for conti nuous spinal anesthesi a.
Epi dur al Anest hesi a
For the novi ce, correct placement of an epi dural needle can be techni call y more chal l enging than
spi nal needl e pl acement because there i s l ess room for error. However, wi th experi ence, epidural
needle pl acement i s often easi er than spi nal needl e pl acement because the l arger gauge needl es
used for epidural anesthesi a are l ess l ikely to be defl ected from thei r i ntended path and they
produce much better tacti l e feel of the i nterspi nous and flaval l igaments. In additi on, the l oss of
resistance technique provi des a much cl earer end poi nt when enteri ng the epi dural space than
does the subtl e pop of a spi nal needl e piercing the dura mater.
Patient preparati on, positi oning, monitors, and needle approaches for epi dural anesthesia are the
same as for spinal anesthesia. Unli ke spi nal anesthesi a, epidural anesthesi a may be performed at
any i ntervertebral space. However, at vertebral level s above the termi nation of the spinal cord,
the epidural needl e may acci dentall y puncture the spinal meni nges and damage the underl yi ng
spi nal cord. To prevent accidental meningeal puncture, the anesthesi ol ogi st must l earn to i dentify
the i nterspi nous l i gaments and the l i gamentum fl avum by thei r feel . In addi ti on, epi dural needl es
must be advanced sl owl y and, most i mportantly, under control .
After proper posi ti oni ng, steri l e ski n preparati on, and drapi ng, the desi red i nterspace i s i denti fi ed
and a local anestheti c ski n wheal i s rai sed at the poi nt of needl e i nserti on. Because epidural
needles are rel ati vely bl unt, it i s someti mes hel pful to pi erce the ski n wi th a 18-gauge
hypodermic needl e before i nserti ng the epi dural needl e. For epidural anesthesi a usi ng the mi dli ne
approach, the epi dural needle is i nserted through the subcutaneous ti ssue and into the
interspi nous l i gament. The interspi nous li gament has a characteristic gri tty feel, much li ke
inserti ng a needle into a bag of sand. Thi s i s especially true of younger pati ents. If the
interspi nous l i gament i s not cl earl y identi fi ed, then one shoul d be suspi ci ous that the needl e is not
in the midl i ne. After engagi ng the i nterspinous li gament, the needl e is advanced slowl y through it
unti l an i ncrease in resi stance i s felt. This i ncreased resi stance represents the l igamentum flavum.
The epi dural needl e must now traverse the li gamentum fl avum and stop wi thi n the epi dural space
before puncturi ng the spi nal meninges. Numerous techni ques for i denti fyi ng the epidural space
have been used successful ly; however, the l oss of resi stance to flui d has the advantage of
si mpl i ci ty, rel i abi l ity, and, most i mportantl y, a higher success rate when compared to the use of
ai r for l oss of resi stance.
26
In addition, use of flui d i nstead of ai r for l oss of resi stance decreases
the ri sk of postdural puncture headache i n the event of acci dental meni ngeal puncture.
27

A glass syri nge or a speci al l y designed l ow resistance plasti c syri nge is fi l led wi th 2 to 3 mL of
sali ne and a small (0.1 to 0.3 mL) air bubbl e. The syri nge i s attached to the epi dural needle and
the pl unger pressed unti l the ai r bubbl e i s vi si bl y compressed. If the needl e ti p i s properl y
embedded wi thi n the l i gamentum fl avum, i t shoul d be possi bl e to compress the ai r bubbl e wi thout
i njecti ng fl ui d. In thi s way the ai r bubbl e serves as a gauge of the appropri ate amount of pressure
to exert on the syri nge plunger. If the ai r bubbl e cannot be compressed wi thout i njecti ng fl ui d,
then the needle ti p i s most li kel y not i n the l igamentum flavum. In thi s case, the needl e tip may
stil l be in the

interspi nous l i gament, or i t may be off the mi dl i ne i n the paraspi nous muscl es. To di fferenti ate
between these possibi l iti es, one can careful l y advance the needl e and syri nge a few mi l li meters i n
an effort to engage the l i gamentum flavum. If it i s sti l l not possi bl e to compress the ai r bubbl e,
withdraw the needle i nto the subcutaneous ti ssue, and rei nsert i t.
Once the li gamentum fl avum i s identi fi ed, the needle i s slowl y advanced with the nondomi nant
hand whi le the dominant hand maintai ns constant pressure on the syringe pl unger (Fi g. 25-8). As
the needl e ti p enters the epidural space, there wi ll be a sudden and dramati c loss of resi stance as
the sal ine i s rapidl y injected. Sal ine i njecti on i nto the epi dural space can be moderatel y pai nful
and pati ents shoul d be forewarned. If the needle is advanci ng obl iquely through the l i gamentum
flavum, it i s possibl e to enter into the paraspi nous muscl es instead of the epi dural space. In thi s
case the loss of resistance wi ll be l ess dramati c. To hel p verify that the needl e has entered the
epi dural space, 0.5 mL of ai r can be drawn i nto the syri nge and injected. In the epi dural space
there wi l l be vi rtual ly no resi stance to ai r injecti on, whi le in the paraspinous muscl es ai r i njecti on
wil l encounter demonstrabl e resi stance.
P.699
FIGURE 25-8. Proper hand posi ti on when usi ng the loss-of-resistance technique to l ocate the
epi dural space. After embeddi ng the needl e ti p in the l i gamentum fl avum, a syri nge with 2 to
After entering the epi dural space, stop advanci ng the needl e. Because the dura mater abuts the
l i gamentum fl avum i n many pl aces, the dura may now be tented over the needl e tip and advanci ng
the needl e any farther than necessary hei ghtens the risk of accidental meningeal puncture, i.e.,
wet tap. When the syri nge i s disconnected from the needl e, i t is common to have a smal l amount
of fl ui d fl ow from the needl e hub. Thi s i s usual l y the sal i ne fl owi ng back out of the epidural space
but could be CSF i f the needl e acci dental l y entered the subarachnoi d space. CSF can often be
di sti ngui shed by the fact that CSF wi l l usual ly fl ow out in a vol ume greatl y exceedi ng that used for
the loss of resi stance, CSF wi l l be warm compared to sali ne, and CSF wil l test posi tive for gl ucose.
If a si ngl e shot technique i s to be used, then a l ocal anesthetic test dose shoul d be admi nistered
to hel p rul e out undetected subarachnoid or intravenous (i v) needl e placement. After a negati ve
test dose, the desired volume of l ocal anestheti c shoul d be admi ni stered in small i ncrements (e.g.,
5 mL) at a rate of 0.5 to 1 mL/s-1. Slow, incremental i njecti on decreases the ri sk of pai n during
injecti on and al lows detection of adverse reacti ons to acci dental iv or subarachnoi d pl acement
before the enti re dose is admi nistered.
Cont i nuous Epi dur al Anest hesi a
Use of a catheter for epidural anesthesi a affords much greater fl exi bil i ty than the si ngl e shot
technique because the catheter can be used to prol ong a bl ock that is too short, to extend a bl ock
that i s too low, or to provi de postoperati ve analgesi a. On the downsi de, catheters may mi grate
into an epidural vei n, i nto the subarachnoi d space, or out an i ntervertebral foramen. Catheter use
is also more li kel y to resul t i n uni l ateral epidural bl ock, a cl i ni cal fact shown to resul t from
catheter tips that end up i n the anteri or epidural space or migrate out an intervertebral
forami na.
17, 28
An ever-changing selecti on of epi dural catheters is commercial ly avai l abl e. They
di ffer i n diameter, sti ffness, l ocati on of i njecti on hol es, presence or absence of a styl et,
construction materi al , and the li ke. Whi chever catheter i s chosen, it i s i mportant to veri fy that i t
passes easi l y through the epidural needl e before the needle i s pl aced i n the epidural space.
Epi dural catheters are usual ly i nserted through ei ther Tuohy or Hustead needles because their
curved ti ps hel p di rect the catheter away from the dura mater. The needl e bevel shoul d be
di rected ei ther cephal ad or caudad, al though the directi on of the bevel does not guarantee that
the catheter wil l travel in that directi on. The catheter wil l typicall y encounter resi stance as i t
reaches the curve at the ti p of the needle, but steady pressure wil l usual ly result i n passage i nto
the epidural space. If the catheter wil l not pass beyond the needl e ti p, i t i s possibl e that the
needle opening i s not compl etel y i n the epi dural space or that some structure in the epidural
space is preventi ng catheter insertion (e.g., epi dural fat). In this instance, the needle can be
careful ly advanced 1 to 2 mm more or rotated 180 degrees and the catheter rei nserted. Al though
ei ther of these maneuvers may resul t i n successful catheter pl acement, they al so i ncrease the ri sk
of accidental meningeal puncture. Alternati vely, the procedure can be repeated at another
i nterspace or wi th a di fferent needl e approach, for exampl e, paramedian. Occasi onal l y a catheter
wil l advance onl y a short di stance past the needl e ti p. Thi s rai ses the possi bi li ty that the needl e
ti p i s not in the epi dural space and needs to be reposi ti oned. In this case, the catheter shoul d not
be wi thdrawn back into the epi dural needle because of the risk that the catheter tip wil l be
sheared off by the bevel 's sharp edge. Rather, the needl e and catheter shoul d be pul l ed out i n
3 mL sal i ne and an ai r bubbl e i s attached. The l eft hand rests securel y on the back and the
fingers of the left hand grasp the needl e firml y. The left hand advances the needl e slowl y and
under control by rotati ng at the wrist. The fingers of the ri ght hand maintai n constant
pressure on the syri nge pl unger but do not ai d i n advanci ng the needl e. If the needle ti p is
properl y engaged i n the l i gamentum flavum, i t shoul d be possi ble to compress the ai r bubbl e
without i njecti ng the sali ne. As the needl e tip enters the epi dural space, there wi l l be a
sudden l oss of resi stance and the sal i ne wi l l be suddenl y injected. (Repri nted wi th permi ssi on
from Mul roy MF: Regional Anesthesia: An Il l ustrated Procedural Guide. Boston, Little Brown,
1989.)
tandem and the procedure repeated.
The catheter should be advanced only 3 to 5 cm i nto the epidural space. Pl aci ng a l onger l ength of
catheter i n the epidural space increases the ri sk that it wil l enter an epidural vei n, puncture the
spi nal meninges, exit an intervertebral foramen, wrap around a nerve root, or wi nd up i n some
other disadvantageous l ocati on. Once the catheter i s appropri ately posi ti oned i n the epidural
space, the needl e i s sl owly wi thdrawn wi th one hand as the catheter is stabil i zed wi th the other.
After the needle i s removed, the l ength of catheter in the epi dural space is confi rmed by
subtracti ng the di stance between the skin and the epi dural space from the length of catheter
bel ow the ski n. Documenti ng thi s di stance i s i mportant when tryi ng to determine i f catheters used
in the postoperati ve peri od have been di sl odged.
An epi dural test dose must be admi ni stered through the catheter to test for i v or subarachnoi d
pl acement before i ncrementall y del i veri ng the enti re epidural drug dose. In addi ti on, because of
the ri sk of undetected i v or subarachnoid mi gration of the catheter over time, addi tional test
doses must be admini stered before each top-up dose is gi ven through the catheter. As wi th
conti nuous spi nal anesthesi a, a reasonable gui deline for top-up doses is to admini ster half the
initi al l ocal anestheti c

dose at an interval equal to two thi rds the expected durati on of the block.
Epi dur al Test Dose
The epi dural test dose is designed to i denti fy epidural needl es or catheters that have entered
an epidural vei n or the subarachnoid space. Fai l ure to perform the test may resul t in
intravascul ar injecti on of toxic doses of l ocal anestheti c or total spi nal bl ock. Aspi rating the
catheter or needle to check for bl ood or CSF i s hel pful i f posi ti ve, but the i nci dence of fal se-
negati ve aspi rati ons is too high to rel y on thi s techni que al one.
29

The most common test dose is 3 mL of l ocal anesthetic contai ni ng 5 mg/mL-1 epinephri ne
(1:200,000). The dose of l ocal anesthetic shoul d be suffi cient that subarachnoi d i njection wi ll
resul t in clear evi dence of spi nal anesthesi a. Intravenous i njection of this dose of epinephrine
typi cal l y produces an average 30 beats per mi nuteone heart rate i ncrease between 20 and 40
seconds after i njecti on.
30, 31
Heart rate i ncreases may not be as evi dent i n some pati ents taki ng -
blocking drugs; reflex bradycardia usual l y occurs i n these pati ents.
30, 32
In -bl ocked pati ents, a
systol i c bl ood pressure increase of 20 mm Hg may be a more reli able indicator of intravascul ar
injecti on.
30, 32

Importantl y, the sensi tivity of the standard 15 g epinephrine test dose has been shown to be
markedl y di minished by preexi sti ng hi gh thoraci c epidural anesthesi a and/or concurrent general
anesthesia.
33
Larger epi nephri ne doses may be effecti ve at detecti ng intravenous i njection in
these setti ngs, but that has not been shown experi mental ly.
Isoproterenol has al so been used to detect i ntravascul ar injecti on.
34
In addi ti on, ai r i njecti on
combi ned wi th a precordi al doppl er to detect the characteri sti c murmur has been used successful l y
to test for iv placement of epi dural catheters.
29
These techni ques have been devel oped for use i n
labori ng women where the sensi tivity of epi nephri ne as a test dose i s disturbingly l ow because
maternal heart rate i ncreases duri ng contracti ons are often as l arge as those produced by
epi nephri ne.
35
The cl inical indi cati ons for these al ternati ve tests of intravascul ar i njection awai t
addi ti onal larger studi es.
Combi ned Spi nal Epi dur al Anest hesi a
Combined spinal epi dural anesthesi a (CSEA) is a useful techni que by whi ch a spi nal block and an
epi dural catheter are pl aced si multaneously. Thi s techni que i s popul ar because i t combi nes the
rapi d onset, dense bl ock of spi nal anesthesi a wi th the fl exi bi li ty afforded by an epi dural catheter.
There are speci al epi dural needl es wi th a separate l umen to accommodate a spinal needle
avai labl e for CSEA (see Fi g. 25-6). However, the technique is easil y performed by fi rst pl aci ng a
standard epi dural needl e i n the epidural space and then inserting an appropri atel y si zed spi nal
P.700
needle through the shaft of the epi dural needl e and i nto the subarachnoi d space. The desi red local
anesthetic i s i njected into the subarachnoi d space, the spi nal needl e removed, and a catheter
pl aced in the epi dural space via the epi dural needle. The catheter can then be used to extend the
hei ght or durati on of i ntraoperative block or can be used to provide postoperative epidural
anal gesi a.
An i nteresti ng pharmacol ogi c aspect of CSEA i s the observati on that after the peak spi nal block
hei ght i s establ i shed, both sal ine and l ocal anestheti c injected i nto the epi dural space are
effecti ve at pushi ng the bl ock level hi gher.
36, 37, 38
Thi s observati on has been i nterpreted to i ndi cate
that the mechanism by whi ch the epi dural top-up increases block height is by a vol ume effect
(i .e., compressi on of the spi nal meninges forci ng CSF cephalad) as well as a local anestheti c
effect.
A potenti al risk of this technique is that the meni ngeal hol e made by the spi nal needl e may al low
dangerously hi gh concentrations of subsequently admini stered epi dural drugs to reach the
subarachnoi d space. Anecdotal case reports and i n vitro animal studi es suggest that this may be a
legi ti mate concern.
35, 39, 40, 41
Al though CSEA shows great promi se, addi ti onal prospecti ve studi es
are necessary to i denti fy the rel ati ve risks and l i mi tations of the techni que.
PHARMACOLOGY
Successful spi nal or epidural anesthesi a requires a block that is hi gh enough to bl ock sensati on at
the surgi cal si te and lasts for the durati on of the pl anned procedure. However, because vari abi l i ty
between pati ents is consi derable (Fi gs. 25-9 and 25-10), rel i abl y predicting the height and
duration of central neuraxial bl ock that wi l l resul t from a particul ar l ocal anestheti c dose i s
di fficul t. Thus, recommendations regardi ng l ocal anestheti c choi ce and dose must be vi ewed as
approxi mate gui del ines. The cl inici an must understand the factors governi ng spi nal and epi dural
bl ock hei ght and duration to i ndi vi dual ize l ocal anesthetic choi ce and dose for each pati ent and
procedure.
FIGURE 25-9. Peak spi nal bl ock hei ght fol lowi ng 10- and 15-mg doses of hypobari c,
isobaric, and hyperbari c tetracai ne solutions i njected at L3-4 wi th pati ents in the lateral
hori zontal posi tion. Note that dose has no i nfluence on bl ock hei ght and that there is
consi derable i nterindividual variabi li ty i n peak block height, especial ly wi th the hypobari c
sol uti on. (Adapted wi th permission from Brown DT, Wi l dsmith JA, Covi no BG, Scott DB: Effect
of bari ci ty on spi nal anaesthesia wi th amethocai ne. Br J Anaesth 52:589, 1980.)
Spi nal Anest hesi a
Block Height
Tabl e 25-1 li sts some common surgi cal procedures that are readi l y performed under spi nal
anesthesia and the block hei ght that is usual l y suffi ci ent to ensure pati ent comfort. Al so l i sted are
techniques that are appropriate to achi eve the desi red bl ock hei ght. The rational e for these
recommendati ons i s expl ai ned in the fol lowi ng secti on.
FIGURE 25-10. Peak epi dural bl ock hei ght fol l owi ng 20 mL of 0.75% bupivacaine and 1.5%
eti docaine injected vi a a catheter at the L1-2 interspace. Note that despi te a well -control led
technique, the i nteri ndi vi dual variabil i ty i n bl ock hei ght i s consi derabl e and demonstrates the
di fficul ty i n accuratel y predi cti ng block height i n an i ndi vi dual pati ent. (Adapted wi th
permi ssi on from Si ncl air CJ, Scott DB: Compari son of bupivacai ne and etidocai ne i n
extradural bl ockade. Br J Anaesth 56:147, 1984.)
TABLE 25-1 Representative Surgical Procedures Appropriate for Spinal Anesthesia
SURGICAL
PROCEDURE
SUGGESTED
BLOCK
HEIGHT
TECHNIQUE COMMENTS
Peri anal
Peri rectal
L1-2 Hyperbari c
solution/sitti ng
positi on
Hypobaric
solution/jackkni fe
positi on
Isobaric
solution/hori zontal
positi on
Patients must remai n in
rel ati ve head-up or
head-down posi ti on
when usi ng hypobari c
and hyperbari c sol uti ons
to mai ntai n restri cted
spread duri ng the
procedure
Lower extremity
Hip
Transurethral
resection of the
prostate
Vagi nal /cervi cal
T10 Isobaric sol uti on Hypobari c and
hyperbaric soluti ons are
al so sui tabl e but may
produce hi gher bl ocks
than necessary
Herniorraphy
Pel vi c procedures
Appendectomy
T6-8 Hyperbari c
positi on
Isobaric sol uti ons
injected at L2-3
interspace may al so be
suitable
Abdomi nal
Cesasean section
T4-6 Hyperbari c
positi on
Upper abdominal
procedures usual ly
requi re concomi tant
Baricity and Patient Position. The height of spinal block is thought to be determi ned by the
cephal ad spread of local anestheti c wi thin the CSF. Tabl e 25-2 li sts some of the many

vari abl es that have been proposed to infl uence the spread of local anestheti cs wi thin the
subarachnoi d space. Many of these vari abl es have been shown to be of negl i gibl e cl inical
importance. Of those factors that do exert si gni fi cant i nfluence on l ocal anestheti c spread, the
barici ty of the l ocal anestheti c soluti on rel ative to patient positi on i s probabl y the most i mportant.
Bari ci ty i s defi ned as the ratio of the density (mass/vol ume) of the l ocal anesthetic sol uti on
di vi ded by the

densi ty of CSF, which averages 1.0003 0.0003 g/mL-1 at 37C. Solutions that have the same
densi ty as CSF have a bari ci ty of 1.0000 and are termed i sobari c. Soluti ons that are more dense
than CSF are termed hyperbari c, whereas solutions that are l ess dense than CSF are termed
hypobaric.
general anesthesi a to
prevent vagal reflexes
and pai n from tracti on
on diaphragm,
esophagus, and the l i ke
P.701
P.702
TABLE 25-2 Factors That Have Been Suggested As Possible Determinants of Spread of
Local Anesthetic Solutions within the Subarachnoid Space
CHARACTERISTICS OF THE LOCAL ANESTHETIC
Bari ci ty
Local anesthetic dose
Local anestheti c concentration
Vol ume i njected
PATIENT CHARACTERISTICS
Age
Wei ght
Height
Gender
Pregnancy
Patient posi ti on
TECHNIQUE
Si te of i njecti on
Speed of i njecti on
Barbotage
Directi on of needl e bevel
Additi on of vasoconstri ctors
Tabl e 25-3 li sts the barici ty of l ocal anestheti c sol utions commonl y used for spi nal anesthesi a. For
practi cal purposes, sol uti ons with a barici ty <0.9990 can be expected to reli abl y behave
hypobari cal l y i n al l pati ents. Hypobaric sol uti ons are typi cal ly prepared by mixing the l ocal
anesthetic soluti on i n distil l ed water. Solutions wi th a bari ci ty of 1.0015 can be expected to
rel iabl y behave hyperbaricall y. Hyperbari c solutions are typi cal l y prepared by mixing the l ocal
anesthetic i n 5% to 8% dextrose. The barici ty of the resul tant sol uti on depends on the amount of
dextrose added; however, dextrose concentrations between 1.25 and 8% resul t i n equi valent block
hei ghts.
42, 43
Lower dextrose concentrati ons have been shown to have a concentrati on-dependent
effect on block hei ght, with 0.33% produci ng a bl ock to T9.5 on average, 0.83% produci ng a block
to T7.2, and 8% produci ng a bl ock to T3.6.
44

DIFFUSION
Adapted wi th permi ssi on from Greene NM: Di stri bution of l ocal anesthetic sol uti ons
within the subarachnoi d space. Anesth Anal g 64:715, 1985.
TABLE 25-3 Baricity of Solutions Commonly Used for Spinal Anesthesia
BARICITY
a
HYPERBARIC
Tetracai ne: 0.5% i n 5% dextrose 1.0133
Bupi vacai ne: 0.75% in 8.25% dextrose 1.0227
Li docai ne: 5% i n 7.5% dextrose 1.0265
Procaine: 10% in water 1.0104
ISOBARIC
b
Tetracai ne: 0.5% i n normal sal i ne 0.9997
Bupi vacai ne: 0.75% in sal i ne 0.9988
Bari ci ty i s i mportant in determi ni ng l ocal anesthetic spread and thus bl ock hei ght because gravi ty
causes hyperbari c sol utions to fl ow downward in CSF to the most dependent regi ons of the spi nal
column, whereas hypobari c sol utions tend to rise i n CSF. In contrast, gravity has no effect on the
di stri bution of trul y isobaric soluti ons. Thus, the anesthesi ologi st can exert consi derable infl uence
on block height by choice of anesthetic sol uti on and proper patient posi ti oni ng. Spi nal bl ock can
be restri cted to the sacral and l ow lumbar dermatomes (saddl e bl ock) by admi ni stering a
hyperbaric l ocal anestheti c sol ution wi th the pati ent i n the si tti ng posi ti on
45
or by admi ni steri ng a
hypobari c solution with the pati ent i n the prone jackknife posi ti on. Si mi l arl y, high thoracic to
mi dcervi cal level s of anesthesi a can be reached by admi ni steri ng hyperbari c sol utions with the
patient in the horizontal and Trendel enburg posi ti ons
46, 47
or by admi ni steri ng hypobaric soluti ons
with the pati ent i n a semi sitting posi tion. However, thi s use of hypobari c sol uti ons i s not
recommended because the hi gh bl ock achi eved and the di minished venous return associ ated wi th
the upright posture can lead to si gni fi cant cardi ovascul ar compromise.
The sitting, Trendelenberg, and jackkni fe positi ons have marked i nfl uences on the di stri buti on of
hypobari c and hyperbari c sol utions because these positi ons accentuate the effect of gravi ty.
However, most spinal anestheti cs are administered as hyperbari c sol utions i njected whil e pati ents
are in the hori zontal l ateral posi tion after whi ch they are turned to the horizontal supi ne posi tion.
In thi s si tuati on the i nfluence of gravity i s more subtl e because the dependent areas of the spi nal
col umn do not deviate as much from the hori zontal. Whi le the pati ent is turned laterall y, gravi ty
has a smal l but measurabl e effect on l ocal anesthetic di stributi on i n that hyperbaric sol uti ons wi ll
produce a denser, l onger lasti ng bl ock on the dependent si de, whi l e hypobari c sol utions wil l have
Bupi vacai ne: 0.5% i n sali ne 0.9983
Li docai ne: 2% i n sal i ne 0.9986
HYPOBARIC
Tetracai ne: 0.2% i n water 0.9922
Bupi vacai ne: 0.3% i n water 0.9946
Li docai ne: 0.5% in water 0.9985
a
Measured at 37C, except for hypobaric 0.5% l idocai ne measured at 25C. At 37C, thi s
solution' s bari ci ty is l ess.
b
These sol utions are sl i ghtly hypobari c but are used cl i ni cal ly as if they were i sobari c.
Data from Horl ocker TT, Wedel DJ: Density, speci fi c gravi ty, and bari city of spi nal
anesthetic soluti ons at body temperature. Anesth Anal g 76:1015, 1993; Lambert D,
Covino B: Hyperbari c, hypobari c and i sobari c spi nal anesthesi a. Resi dent Staff Physician
33:79, 1987; Greene NM: Di stri buti on of l ocal anestheti c sol utions withi n the
subarachnoi d space. Anesth Anal g 64:715, 1985; and Bodi ly N, Carpenter R, Owens B:
Lidocai ne 0.5% spi nal anaesthesia: A hypobaric sol uti on for short-stay peri rectal
surgery. Can J Anaesth 39:770, 1992.
the opposite effect.
48
Thi s makes hypobari c sol uti ons ideal for unil ateral procedures performed i n
the lateral posi ti on (e.g., hip surgery). Hyperbari c soluti ons can be used to advantage for
uni l ateral procedures performed i n the supi ne posi ti on i f the operati ve si de i s dependent duri ng
drug injecti on and the pati ent i s l eft i n the lateral posi ti on for at l east 6 mi nutes.
48
Despi te
di fferences i n bl ock densi ty and durati on, peak bl ock hei ght wi l l be comparabl e between the
dependent and nondependent si des.
When the patient is turned supine foll owi ng hyperbaric drug injecti on i n the lateral posi ti on, the
normal spinal curvature wi ll i nfluence subsequent movement of the i njected sol ution. Hyperbari c
solutions i njected at the hei ght of the lumbar lordosis wi l l tend to flow cephal ad to pool i n the
thoraci c kyphosi s and caudad to pool i n the sacrum (Fi g. 25-11). Pooli ng of hyperbari c local
anesthetic soluti ons i n the thoraci c kyphosi s has been evoked to expl ai n the cl i ni cal observati on
that hyperbari c sol utions tend to produce bl ocks with an average height in the midthoracic regi on
(see Fi g. 25-9). In addi ti on, hyperbari c sol utions have al so been observed to produce bl ocks with
a bimodal distribution, that i s, one group of pati ents wi th

bl ocks centered in the l ow thoracic region and a second group of pati ents wi th bl ocks centered in
the hi gh thoraci c regi on.
49, 50
The presumed explanation for thi s observati on i s that the lumbar
lordosis produces spl i tting of the local anestheti c sol uti on wi th some portion flowi ng caudad
toward the sacrum and the remai nder fl owi ng cephal ad i nto the thoraci c kyphosi s. The cephal ad
extent of the bl ock then depends on what fracti on of the i njected drug fl ows cephal ad. Consi stent
with thi s hypothesi s i s the fact that eli minati ng the l umbar l ordosi s by maintai ni ng the hi ps fl exed
has been shown to signi ficantl y reduce
50
or el iminate
49
the bi modal di stri buti on of bl ocks wi thout
affecti ng maximal bl ock hei ght.
Obvi ously, gravi ty i nfluences the di stri buti on of hyperbari c and hypobari c sol utions onl y unti l they
are suffi ci entl y di l uted i n CSF so that they become i sobari c. At thi s poi nt, the local anestheti c
solution no longer moves i n response to changes i n patient posi ti on and the block i s sai d to be
fixed. Interesti ngl y, the ti me requi red for a l ocal anesthetic sol uti on to become fi xed may be
consi derable. Povey et al showed that hyperbari c bupi vacai ne i njected in the sitting posi tion
produces a saddle bl ock that i s restri cted to the l umbar segments for as long as the subjects
remai ned si tti ng.
45, 46
However, even 60 mi nutes after bupivacai ne injecti on the bl ock spread to
mi dthoraci c level s after turni ng the patients supine. Si mi l arly, Bodily et al
51
found that hypobaric
li docaine admini stered i n the jackknife posi ti on rose as many as 6 dermatomes when pati ents were
P.703
FIGURE 25-11. In the hori zontal supi ne posi tion, hyperbari c local anestheti c sol uti ons
injected at the hei ght of the l umbar l ordosi s (ci rcl e) flow down the l umbar l ordosi s to pool i n
the sacrum and in the thoracic kyphosis. Pooling i n the thoraci c kyphosi s i s thought to
explai n the fact that hyperbari c sol utions produce blocks wi th an average height of T4-6.
al lowed to sit upri ght i n the recovery room as long as 60 mi nutes after l idocai ne i njecti on.
Whether i t i s al so possi bl e to affect spread so l ong after i njecti ng hyperbari c or hypobari c
solutions i n the hori zontal positi on i s uncl ear. Nonethel ess, these fi ndi ngs demonstrate that in
some si tuati ons it may be possibl e to exert i nfluence on bl ock hei ght by adjusti ng pati ent posi ti on
for at l east 60 mi nutes after local anestheti c i njecti on.
In contrast to the si tuati on wi th hyperbaric soluti ons, pati ent posi ti on has no effect on the
di stri bution of isobari c soluti ons because these sol utions are not infl uenced by gravi ty.
Consequently, i sobari c sol utions tend not to spread as far from the si te of injecti on and produce
bl ocks wi th an average hei ght i n the low thoraci c regi on (see Fi g. 25-9).
43, 52
The obvi ous caveat i s
that the l ocal anestheti c sol ution must be trul y i sobari c in the patient in whom i t i s used. Because
of the vari abil i ty i n CSF density among pati ents, it i s di ffi cul t to produce rel i abl y i sobari c l ocal
anesthetic soluti ons. Nonetheless, as i ndicated i n Tabl e 25-3, several local anestheti c sol uti ons
are used as if they were i sobari c. It i s noteworthy that whi le i sobari c sol uti ons produce an average
bl ock hei ght that i s l ower than comparabl e hyperbaric sol uti ons,
43, 52, 53, 54
the isobaric solutions
produce blocks wi th a much greater vari abi l ity in hei ght.
55, 56, 57
Logan et al have termed pl ai n
bupi vacai ne an unpredi ctabl e spi nal anestheti c agent.
55
The greater vari abi l ity in spread may
stem i n part from the fact that these sol uti ons are actuall y sl i ghtly hypobari c and thei r spread has
been shown to be affected by pati ent posi ti on.
58, 59
Temperature-rel ated changes i n bari ci ty may
al so pl ay a rol e i n the vari abi l ity in di stributi on of these nearly i sobari c sol utions. For example,
Stei nstra and van Poorten
60
have shown that the distri buti on of pl ai n bupi vacai ne i s si gni fi cantl y
al tered by changes i n temperature of the injected soluti on. In addi ti on, McClure et al
61
have
shown that increasi ng the volume and decreasi ng the concentration of isobari c tetracai ne al so
increases the vari abil i ty i n bl ock hei ght. These and other unknown factors may pl ay a rol e in the
unpredictabi l ity of these nearl y isobari c soluti ons. Al though unpredi ctabil i ty is cause for concern,
i t shoul d be poi nted out that the l ower average bl ock hei ght achieved offers potenti al advantages
for surgical procedures bel ow the umbil i cus because of the decreased incidence of cardi ovascul ar
si de effects associated wi th l ower bl ocks. The isobari c soluti on that has been shown to most
rel iabl y produce a l ow thoracic block i s 10 mg of tetracai ne crystal s di l uted i n 1- or 2-mL room
temperature sal ine and i njected i n the hori zontal posi tion.
61

Dose, Volume, and Concentration. Studi es ai med at determi ning the effect of these three
interdependent vari ables on block hei ght are di fficul t to conduct and i nterpret because i t i s not
possi bl e to change one variabl e wi thout si mul taneousl y changi ng another. Nonetheless, i t is
possi bl e to draw some concl usi ons regardi ng the effect of these vari abl es on block height. Several
studi es wi th i sobari c tetracai ne and bupi vacai ne soluti ons have found that nei ther injected vol ume
nor drug concentration affects block hei ght when dose is held constant.
61, 62, 63, 64, 65
Drug dose does
appear to pl ay a smal l rol e i n determining bl ock height wi th isobari c bupi vacaine. Two studi es
have found that 10 mg of i sobari c bupi vacai ne resul ts in significantly l ower bl ocks than does 15 or
20 mg, but there i s no difference in block height between the two hi gher doses.
66, 67
In contrast,
two studi es that exami ned the effect of different doses of isobaric tetracai ne found that doses
between 5 and 15 mg had no effect on block hei ght, produci ng bl ocks with an average hei ght of
T9-T10.
52, 68

Drug dose and vol ume appear to be relatively unimportant in predi cti ng the spread of hyperbari c
local anestheti c sol utions i njected i n the hori zontal positi on. Increasing the dose and volume of
hyperbaric tetracai ne, whi l e hol ding concentrati on constant, does not affect bl ock height when
doses between 7.5 and 15 mg are used.
52, 68, 69
Si mi larl y, increasi ng the dose and vol ume of
hyperbari c 0.5% bupi vacaine does not increase bl ock hei ght when doses between 10 and 20 mg
are used.
70, 71
However, doses of hyperbari c 0.5% bupi vacai ne <10 mg have been shown to resul t
i n bl ocks that are ~2.5 dermatomes l ower than those achi eved wi th doses >10 mg.
70
The fact that
bupi vacaine dose affects bl ock height only at the extreme low end of the usual dose range i s
consi stent wi th the experi ence wi th i sobari c bupi vacai ne reported earli er. The fact that drug dose
is relati vel y uni mportant i n determi ni ng bl ock hei ght with hyperbari c sol utions l i kel y results from
an overwhelming effect of bari city and pati ent posi ti on i n determi ni ng spread of these soluti ons.
Injection Site. The si te of injecti on can have an important effect on bl ock hei ght i n some
si tuati ons. In parti cul ar, sensory bl ock hei ght resul ting from i sobari c 0.5% bupi vacai ne i s reduced
by 2 dermatomes per i nterspace when compari ng di fferent groups of pati ents who recei ved
i njecti ons at the L2-3, L3-4, or L4-5 interspaces.
72, 73
In an even more convi nci ng study, thi s group
of i nvesti gators performed repeated bl ocks i n the same pati ent and found that by movi ng from the
L3-4 to the L4-5 i nterspace means bl ock hei ght coul d be reduced from T6 to T10 when usi ng
isobaric 0.5% bupivacaine.
74
In contrast, Sundnes et al
70
found no rel ati onshi p between injecti on
si te and bl ock hei ght when usi ng a hyperbari c bupi vacai ne sol uti on, presumabl y because of the
overwhelming effect of gravity and patient positi on on distri buti on of hyperbari c l ocal anesthetics.
Whether i sobari c and hyperbaric sol utions of other local anestheti cs wi ll behave si mi l arl y i s not
cl ear.
Patient Characteristics. In young adul ts, it was determi ned that the most i mportant vari able
governi ng block hei ght with hyperbari c local anestheti c sol uti ons may be l umbosacral CSF
volume.
75
However, it i s unclear if these findi ngs can be extrapol ated to other l ocal anesthetics or
patient ages.
Hi guchi and col l eagues performed a detai led examinati on of the effect of lumbar CSF volume, CSF
densi ty, l umbar CSF moti on, patient age, pati ent wei ght, pati ent hei ght, and pati ent body mass
i ndex (BMI) on spi nal bl ock wi th isobaric bupivacai ne.
76
Mul ti pl e li near regressi on demonstrated
that nei ther pati ent age nor hei ght correl ated wi th any cl i ni cal characteristic of spi nal block.
However, CSF volume and wei ght were correlated wi th peak bl ock hei ght. CSF vol ume was the onl y
vari abl e to correl ate wi th ti me to voidi ng. BMI was the onl y si gni fi cant predictor of time to onset
of compl ete sensory bl ock.
Although these vari ables were stati sti cal l y si gni fi cant predictors of several important aspects of
spi nal bl ock, the

coeffi ci ents of determi nati on (R
2
) were generall y smal l (average: 0.23; range: 0.08 to 0.46),
indicati ng that these vari ables account for a rel ati vel y smal l amount of the variabil i ty i n each of
the block outcomes exami ned. Cl earl y, other factors contri bute si gni fi cantl y to the cl ini cal
characteri sti cs of spi nal block wi th i sobari c bupi vacai ne.
Whil e these studies are mechani sti cal ly i mportant, their cl inical appl i cati on i s necessari l y
l i mi ted by the di ffi cul ty i n determi ni ng an i ndi vi dual pati ent's CSF vol ume, CSF density, and
vel oci ty of CSF movement.
Importantl y, several i nvestigators have found that pati ent age, wei ght, BMI, and hei ght are ei ther
not predictive of cli ni cal characteri sti cs of spi nal bl ock
77, 78, 80, 81, 82
or are of such low predictive
power as to be unrel i abl e predi ctors in any indi vi dual pati ent.
57, 72, 79, 83, 84

Onset
Most patients can sense the onset of spinal bl ock wi thin a very few mi nutes after drug injecti on
regardl ess of the local anestheti c used. However, there i s a significant di fference among drugs i n
the ti me to reach peak bl ock hei ght. Li docaine and mepi vacai ne tend to reach peak block height
between 10 and 15 mi nutes, whereas tetracai ne and bupi vacai ne may requi re >20 mi nutes before
peak block hei ght i s reached.
Duration
Spi nal bl ocks do not end abruptl y after a fi xed peri od of ti me. Rather, they recede graduall y from
the most cephal ad dermatome to the most caudad. As a resul t, surgi cal anesthesi a l asts
si gni fi cantl y longer at sacral level s than at thoraci c l evel s. Therefore, when di scussi ng the
duration of spi nal bl ock it i s necessary to di sti ngui sh between durati on at the surgical si te and the
ti me requi red for the bl ock to compl etel y resol ve. The former is important for provi di ng adequate
surgi cal anesthesi a, and the l atter is important for assuri ng a ti mel y recovery. A thorough
understandi ng of the factors that govern bl ock durati on i s necessary if the cli nici an i s to choose
techniques that result i n an appropri ate durati on of spi nal blockade.
Local Anesthetic. The pri ncipal determi nant of spi nal block durati on i s the l ocal anesthetic drug
P.704
employed. Procai ne i s the shortest acti ng l ocal anesthetic for subarachnoid use, l idocai ne and
mepivacaine are agents of intermedi ate duration, whi l e bupi vacai ne and tetracai ne are the l ongest
acti ng drugs avai l abl e for use i n the Uni ted States. Tabl e 25-4 li sts the range of ti mes required for
sensory block to regress 2 dermatomes and to completely resol ve wi th the l ocal anestheti cs most
commonly used for spinal anesthesi a. Al though drug choi ce i s the pri nci pal determi nant of bl ock
duration, other variables are responsi bl e for the wide range of bl ock duration found i n Tabl e 25-4.
Drug Dose. Increasi ng local anestheti c dose clearly increases the durati on of spi nal
bl ock.
66, 67, 69, 85, 86
For exampl e, Brown et al
52
demonstrated that durati on of sensory bl ock at L1
fol l owing 15 mg tetracai ne was ~20% greater than foll owing 10 mg. Sheskey et al
67
demonstrated
an ~40% i ncrease in bl ock duration at L2 when comparing 10 mg bupi vacai ne wi th 15 mg.
Si mi l arl y, Axel sson et al .
85
found that duration of sensory bl ock at L2 was nearl y doubl ed when
compari ng 10 mg bupivacai ne with 20 mg.
Block Height. If drug dose is hel d constant, hi gher bl ocks tend to regress faster than l ower
TABLE 25-4 Dose and Duration of Local Anesthetics Used for Spinal Anesthesia
DRUG
DOSE
(MG)
a
DURATION OF SENSORY BLOCK (MIN)
b
2-
DERMATOME
REGRESSION
COMPLETE
RESOLUTION
PROLONGATION BY
ADRENERGIC
AGONISTS (%)
c
Procai ne 50
200
3050 90120 3050
Chl oroprocai ne 30
100
3050 70150 NR
Li docai ne 25
100
40100 140240 2050
Bupi vacai ne 520 90140 240380 2050
Tetracai ne 520 90140 240380 50100
a
The l owest doses are used pri mari l y for very restri cted bl ocks, e.g., saddl e bl ock, l est
they become too di l ute to be effecti ve.
b
Durati on i s i nfl uenced by dose and bl ock hei ght. The durati on of surgi cal anesthesi a wi ll
obvi ousl y depend upon the surgi cal si te.
c
The effect of adrenergi c agoni sts depends on the dose and choice of agoni st.
Prolongation i s greatest at l umbar and sacral dermatomes and least at thoraci c
dermatomes.
NR: Not Recommended; see text for expl anati on.
bl ocks.
86
Consequentl y, i sobari c l ocal anesthetic soluti ons wi ll generall y produce l onger bl ocks
than hyperbari c sol utions using the same dose. The conventional wi sdom is that greater cephal ad
spread resul ts i n rel ati vel y l ower drug concentration in the CSF and spinal nerve roots. As a
resul t, it takes less ti me for l ocal anestheti c concentration to decrease bel ow the mi nimal l y
effecti ve concentrati on.
Adrenergic Agonists. Adrenergi c agoni sts, such as epinephrine, phenyl ephrine, and more
recentl y cl oni di ne, are added to local anestheti cs in an effort to prol ong the durati on of spi nal
anesthesia. Thei r effecti veness depends on the l ocal anestheti c wi th which they are combi ned. In
addi ti on, they are more effecti ve at prol ongi ng bl ock in the l umbar and sacral dermatomes than i n
thoraci c dermatomes.
Epi nephri ne i s typicall y administered i n doses of 0.2 to 0.3 mg and phenylephri ne in doses of 2 to
5 mg. There i s evi dence to suggest a rel ati onshi p between the dose of vasoconstri ctor added and
the durati on of spinal anesthesia; however, the relationshi p i s not strong.
87, 88, 89, 90
At the maximal
doses used cl i ni cal l y, phenyl ephri ne (5 mg) prol ongs spi nal bl ock to a greater degree than
epi nephri ne (0.5 mg).
91, 92
At lower doses, epi nephri ne (0.2 to 0.3 mg) and phenyl ephrine (2 to 3
mg) appear to be equal l y effecti ve i n prol ongi ng spi nal bl ock.
90, 93
Thus, both choi ce of adrenergic
agoni st and dose admi ni stered appear to pl ay a rol e i n determi ni ng bl ock duration.Cloni di ne has
most commonl y been added to intrathecal l ocal anesthetics i n a dose of 75 to 150 mi l li gram to
prolong spi nal block.
94, 95
At these doses, it i s at l east as effecti ve as moderate doses of
phenylephri ne and epinephri ne at prol ongi ng sensory bl ock but has been associ ated with greater
decreases in bl ood pressure i n some
94
but not all studi es.
95
Interesti ngl y, cl oni dine al so prolongs
spi nal block when administered oral ly.
96, 97, 98

Tetracai ne is the local anestheti c that i s most dramati cal l y prol onged by addi ti on of adrenergi c
agoni sts. The durati on of tetracai ne spi nal block may be i ncreased 70% to 100% at

lumbar and sacral dermatomes by additi on of phenylephri ne. Epi nephri ne may prol ong tetracai ne
spi nal anesthesi a by 40% to 60%. Cl onidi ne prolongs tetracai ne spi nal block by 50% to 70%, wi th
the larger effect occurri ng at l umbar dermatomes.
Bupi vacai ne spi nal block i s al so prol onged by adrenergi c agoni sts, al though the effect i s somewhat
less than that seen wi th tetracaine (see Tabl e 25-4). Epi nephri ne i n doses of 0.2 mg prol ongs
bupi vacaine spi nal bl ock by 20% to 30%, but onl y i n lumbar dermatomes. Larger doses of
epi nephri ne (0.3 to 0.5 mg) prol ong sensory block i n thoraci c dermatomes as wel l by 30% to 50%.
Cl oni di ne prol ongs bupivacai ne spi nal bl ock by 30% to 50% as wel l.
The effect of adrenergi c agoni sts on the duration of li docai ne spi nal bl ock is controversi al . Some
cl i ni cal studies have demonstrated that adrenergic agoni sts cl earl y prol ong l i docaine spinal
bl ock,
88, 99, 100, 101
whereas others have concl uded that adrenergi c agoni sts do not produce cli nical l y
useful prol ongati on.
102, 103
Thi s discrepancy may be expl ai ned, i n part, by the fact that spi nal bl ock
duration is so vari able that studies usi ng smal l numbers of patients may l ack suffi ci ent stati sti cal
power to detect real differences i n mean bl ock durati on between groups. Thi s probl em was
obvi ated i n an i nteresti ng study by Chi u et al
104
who used a crossover study desi gn to
demonstrate that 0.2 mg of epi nephri ne si gni fi cantl y prol onged li docai ne sensory bl ock i n l umbar
and sacral dermatomes. Thus, the avai l abl e data suggest that addi ng epi nephri ne to li docai ne wil l
resul t in a somewhat longer bl ock, at l east in l umbar and sacral dermatomes, than woul d be
achi eved i f epi nephri ne were not added.
The mechanism by whi ch adrenergic agoni sts prol ong spinal bl ock is not cl ear. Origi nal ly,
epi nephri ne and phenyl ephri ne were added to local anestheti cs with the intent of reduci ng local
spi nal cord bl ood fl ow and thereby sl owi ng the rate of drug eli mi nation from the spinal cord and
CSF. There are ani mal studi es that support thi s mechanism
105, 106
and others that do not.
107, 108

Ani mal studi es wi th cl onidi ne indicate that i t does reduce regi onal spi nal cord bl ood fl ow.
109
There
are no human studi es that have i nvestigated the effect of intrathecal adrenergic agoni sts on spinal
cord bl ood flow. However, there are human studi es that demonstrate that epi nephri ne decreases
the rate of local anestheti c cl earance from the CSF
110, 111
and also slows the rate at whi ch
subarachnoi d local anestheti c appears i n the pl asma.
99
These fi ndi ngs are consi stent wi th a
P.705
vasoconstri ctor-medi ated decrease i n drug cl earance from the spi nal cord; however, they are not
proof that thi s i s the only or even the pri ncipal mechani sm by which adrenergic agoni sts prol ong
spi nal anesthesi a.
Adrenergic agoni sts are potent anal gesic agents in thei r own right when admi ni stered into the
subarachnoi d space.
112
Anal gesi a resul ts from i nhi biti on of nociceptive afferents, an effect that i s
medi ated by sti mul ati on of -adrenergi c receptors in the spi nal cord dorsal horn. In addi tion, large
intrathecal doses of -adrenergi c agonists have been shown to produce fl acci di ty i n animal model s
by hyperpol ari zi ng motor neurons.
113
Thus, prol ongation of motor and sensory bl ock by adrenergi c
agoni sts may be due, i n part, to di rect i nhi bi tory effects of these drugs on sensory and motor
neurons.
Epi dur al Anest hesi a
Any procedure that can be performed under spi nal anesthesi a can al so be performed under
epi dural block and requi res the same bl ock hei ght (see Tabl e 25-1). As with spi nal anesthesi a,
there i s a great deal of variabi li ty among patients i n spread (see Fi g. 25-10) and durati on of
epi dural block (Tabl e 25-5). Therefore, to choose the most appropriate local anestheti c and dose
for a particul ar cl ini cal situation, the anesthesi ol ogist must be famil i ar wi th the vari abl es that
affect spread and duration of epi dural anesthesi a.
TABLE 25-5 Local Anesthetics used for Surgical Epidural Block
DRUG
a
DURATION OF SENSORY BLOCK
TWO-DERMATOME
REGRESSION
(MIN)
COMPLETE
RESOLUTION
(MIN)
PROLONGATION BY
EPINEPHRINE (%)
Chl oroprocai ne
3%
4560 100160 4060
Lidocai ne 2% 60100 160200 4080
Mepi vacai ne 2% 60100 160200 4080
Ropi vacaine
0.51.0%
90180 240420 No
Etidocai ne 1
1.5%
120240 300460 No
Bupi vacai ne
0.50.75%
120240 300460 No
a
These concentrations are recommended for surgi cal anesthesi a; more di lute
concentrations are appropriate for epi dural anal gesia.
Block Spread
Injection Site. Unli ke spi nal anesthesi a, epidural anesthesi a produces a segmental bl ock that
spreads both caudal l y and crani al l y from the si te of injecti on (Fi g. 25-12). Thus, injecti on si te i s
arguably the most important determinant of the spread of epidural block.Caudal epidural blocks
are largel y restri cted to sacral and l ow lumbar dermatomes. Low thoraci c l evels can be reached
with caudal i njections i f l arge vol umes are used (e.g., 30 mL). However, the bl ock at thoraci c
dermatomes tends to be patchy and short l ived foll owi ng caudal i njection.
114
Lumbar local
anesthetic i njections with volumes of 10 mL often extend caudad to i ncl ude al l sacral dermatomes,
al though the onset of block i n the L5 and S1 roots is often del ayed and may be patchy.
115
Twenty-
mi ll i li ter vol umes produce better quali ty sacral anesthesi a fol l owing l umbar i njecti on. The slow
onset at L5 and S1 i s thought to resul t from their l arger diameter and consequent sl ower drug
penetrati on. Lumbar i njecti ons can be extended to midthoraci c level s (T4-6) when 20-mL vol umes
of local anestheti c are used. Thoraci c injecti ons produce a symmetri c segmental band of
anesthesi a, the wi dth of whi ch depends on the dose of local anestheti c admi ni stered. When usi ng a
mi d to upper thoraci c i njecti on si te, i t i s prudent to reduce the l ocal anestheti c doses by ~30% to
50% rel ati ve to l umbar doses to prevent excessi ve cephalad spread. It is general ly not feasi bl e to
produce surgi cal anesthesia i n low l umbar and sacral dermatomes wi th mi dthoraci c or hi gher
injecti on sites. Thoracic epi dural bl ock is i deally suited for anesthesi a of the chest and abdomen.

Dose, Volume, and Concentration. Withi n the range typicall y used for surgi cal anesthesi a, drug
concentration is rel ati vel y uni mportant i n determining bl ock spread. However, drug dose and
vol ume are i mportant variabl es determining both spread and qual i ty of epi dural bl ock. If drug
concentration is hel d constant, i ncreasi ng the vol ume of l ocal anestheti c (and thereby the dose)
wil l result i n si gni fi cantl y greater average spread and greater bl ock density. However, the
rel ati onship is nonli near. For exampl e, doubl ing the vol ume and dose of 1.5% l i docaine or 0.75%
bupi vacaine from 10 mL to 20 mL has been shown to i ncrease spread by onl y three to four spi nal
segments.
115, 116
Vol ume appears to be i mportant i n determini ng block spread i ndependent of drug
P.706
FIGURE 25-12. Spread of epi dural sensory bl ock over time foll owi ng i njecti on of vari ous
local anestheti c sol utions at the L2-3 interspace. Al l sol utions contai ned epi nephri ne
1:200,000. Sensory bl ock spreads both cephal ad and caudad from the si te of injecti on wi th
ti me. Note the delay i n onset of bl ock at the L5 and S1 dermatomes wi th all sol uti ons tested.
(Repri nted with permi ssi on from Bromage PR: Epi dural Analgesi a. Phi ladel phi a, WB Saunders,
1978.)
dose, but agai n the rel ati onshi p i s nonl i near. Erdemi r et al showed that tripl i ng the injected
vol ume of l i docai ne from 10 mL to 30 mL whil e hol di ng the dose constant (300 mg) increased the
cephal ad extent of bl ock by onl y 4.3 dermatomes.
117
Thi s tendency toward greater spread i s
thought to be expl ai ned by the observati on that i ncreasi ng the vol ume of sol uti on i njected into the
epi dural space increases cephalad di stributi on.
118

Position. When using a single-shot techni que, mai ntaini ng pati ents i n the l ateral posi ti on duri ng
and after epidural i njecti on of surgi cal doses of l ocal anesthetics does not seem to have a
cl i ni cal ly i mportant effect on spread of the bl ock from si de to si de.
119
Si mi larl y, studies exami ni ng
the effect of patient position on cephal ad spread of epidural block have general l y found that the
effect of posture on spread is not cli nicall y important.
120
Interesti ngl y, Ponhol d et al
121

demonstrated that maintai ni ng a 30 degree head-up posi ti on si gni fi cantl y i ncreased the frequency
of adequate bl ock at the L5 and S1 nerve roots even though there was no effect on the cephalad
extent of anesthesi a.
Patient Characteristics
Age. Most,
115, 116, 122, 123, 124, 125
but not all ,
126
studi es that have exami ned the effect of age on
epi dural block have demonstrated greater spread i n ol der pati ents. However, the effect of age is
probabl y cl ini cal ly si gnificant onl y when compari ng adul ts whose ages differ by three or more
decades. Even so, the difference in bl ock height is not l i kely to be more than 3 or 4 dermatomes.
Greater spread in older pati ents is thought to be related to a l ess-compl i ant epidural space and
di minished abi l ity for epi dural sol uti ons to l eak out of intervertebral foramina.
118, 127
Both of these
age-rel ated changes woul d be expected to resul t i n more extensive spread of sol utions withi n the
epi dural space.
Height and Weight. The correl ati on between pati ent hei ght
115
,
116
,
125
,
126
or wei ght
125
,
126
and
spread of epi dural block i s weak and of li ttl e clinical si gni fi cance except perhaps in pati ents who
are extremel y tall , extremel y short, or morbidl y obese.
Pregnancy. Studi es examining the effect of pregnancy on spread of epi dural bl ock are confl icting.
Some studi es have demonstrated greater spread at term
128
and duri ng earl y pregnancy,
129

suggesti ng that greater spread duri ng pregnancy i s not simply the result of anatomic changes
associated wi th pregnancy. However, other studi es have not found a signi ficant difference in
spread of epi dural block between pregnant and nonpregnant women.
130, 131

Atherosclerosis. Atheroscl erosis has been suggested as an i mportant determi nant of the spread
of epi dural block.
128
However, subsequent studi es have failed to fi nd any relationship between
bl ock spread and atheroscl erosis.
116, 122, 132

Gi ven the myri ad factors that have some effect on spread of epidural anesthesi a, how shoul d
anesthesiol ogi sts choose an appropriate local anestheti c dose for a si ngl e-shot epi dural bl ock? A
useful recommendati on i s to assume that a 20-mL vol ume of al l l ocal anesthetics i ntended for
surgi cal anesthesi a wi ll produce a midthoraci c block on average after l umbar i njecti on. If there are
mul tipl e reasons to expect that the block may spread excessively i n an i ndi vi dual pati ent (e.g.,
advanced age, obesi ty, very short stature, high injecti on si te) or i f the procedure does not requi re
a hi gh bl ock, then reduce the dose accordi ngl y. If there are multi ple reasons to expect that the
spread may be reduced from the average, then i ncrease the vol ume accordingly. Obviousl y, choi ce
of the appropri ate l ocal anesthetic dose is obvi ated i f an epidural catheter i s used. In this
si tuati on, begi n

with a lower dose than one anti ci pates wi ll be needed and administer addi ti onal l ocal anestheti c as
necessary to extend the block to the desi red level.
Onset
The onset of epi dural block wi th al l local anestheti cs can usuall y be detected wi thin 5 minutes in
the dermatomes immedi ately surrounding the injecti on si te. The ti me to peak effect di ffers
somewhat among local anestheti cs. Shorter acti ng drugs generall y reach thei r maxi mum spread i n
P.707
15 to 20 mi nutes, whereas l onger acti ng drugs requi re 20 to 25 minutes. Increasi ng the dose of
local anestheti c speeds the onset of both motor and sensory block.
Duration
Local Anesthetic. As with spinal anesthesia, choice of l ocal anesthetic i s the most important
determi nant of the durati on of epi dural bl ock. Chl oroprocai ne i s the shortest duration drug used
for epi dural anesthesi a, l idocai ne and mepi vacai ne provide bl ocks of intermedi ate durati on, and
bupi vacai ne, ropi vacai ne, and eti docaine produce the longest l asti ng epidural bl ock. Tabl e 25-5
li sts l ocal anestheti cs commonl y used for epi dural bl ock and approxi mate durati on of surgi cal
anesthesia. Of note, tetracai ne and procai ne are not generall y used for epidural block because of
the poor qual i ty bl ock that these drugs produce.
Importantl y, when used epidural ly some local anestheti cs exhi bi t consi derable separation in both
the intensi ty and durati on of sensory and motor block. Eti docai ne produces the most i ntense
motor bl ock and i s unusual among local anestheti cs in that motor block may consi derably outlast
sensory block.
133
The phenomenon of the postoperati ve pati ent who i s i n pai n yet stil l unable to
move hi s or her l egs has l ed some anesthesi ol ogi sts to abandon eti docaine for epidural use. This i s
unfortunate because etidocai ne' s superi or muscle rel axation is sometimes benefi ci al
intraoperativel y. Bupivacai ne has the opposite sensori motor profi le i n that l ow concentrati ons of
bupi vacaine produce sensory block that is relatively more intense than motor bl ock. Thi s
separati on of sensory and motor bl ock underl ies the common practice of usi ng di l ute bupi vacai ne
solutions for epidural anal gesia.
Dose. Increasi ng the dose of l ocal anestheti c administered results i n i ncreased
duration
115, 134, 135, 136
and densi ty
115, 135, 136
of epidural bl ock.

Age. Studi es that have eval uated the effect of age on epidural block durati on are inconcl usi ve.
Veeri ng et al.
124
found that duration of epi dural block with pl ai n bupi vacai ne was not signi ficantl y
affected by age. Nydahl et al.
123
found that epi dural bl ock usi ng bupivacaine wi th epinephrine was
actual l y shorter i n ol der pati ents. In contrast, Park et al .
122
found that epi dural bl ock usi ng
li docaine wi th epi nephri ne was sl ightl y but significantly l onger i n ol der pati ents. Additi onal studi es
are necessary to cl arify the effect of age on durati on of epi dural bl ock.
Adrenergic Agonists. Epi nephri ne, i n a concentrati on of 5 mcg/mL (1:200,000), i s the most
common adrenergi c agoni st added to epidural l ocal anesthetics. It has been shown to prol ong the
duration of l idocai ne and mepi vacai ne epi dural bl ock by as much as 80%.
137
The mechanism by
whi ch epi nephri ne prol ongs epidural block i s not cl ear. Vasoconstri ctors have been assumed to
prol ong bl ock by produci ng l ocal vasoconstri cti on and thus decreased l ocal anesthetic cl earance
from the epidural space. The fact that epi nephri ne reduces peak pl asma concentrati ons of some
local anestheti cs fol l owing epidural i njecti on i s consi dered to be supportive evi dence of thi s
mechanism. However, iv infusion of epinephrine al so decreases peak plasma concentrati on of
epi durall y administered local anestheti cs, presumabl y by i ncreasing thei r vol ume of di stri buti on.
138

Thus, i t i s uncl ear what rol e l ocal vasoconstri cti on pl ays i n epi nephri ne' s abi l i ty to prol ong
epi dural block. As discussed earli er for spi nal anesthesi a, prolongation of motor and sensory bl ock
may be due, i n part, to di rect i nhi bitory effects of epi nephri ne on sensory and motor neurons.
Epi nephri ne does not si gni fi cantl y prol ong the durati on of anesthesi a when added to concentrated
solutions of bupivacaine,
139, 140
eti docaine,
135, 140
or ropi vacai ne
141
that are generally used for
surgi cal anesthesi a. However, epinephrine does appear to prol ong anal gesi a and i mprove the
quali ty of block when added to more di l ute sol uti ons of these l ocal anestheti cs, such as those used
for l abor anal gesia.
142, 143, 144

Summar y
The extent and duration of both spi nal and epi dural block are influenced by a number of vari ables,
some of whi ch are under the control of the anesthesi ol ogi st. Understandi ng the i mpact of these
vari abl es wi ll al low the anesthesi ol ogi st to rati onal l y select the most appropri ate drug and dose for
any cl i ni cal si tuati on. However, even the most experi enced anesthesi ol ogist wi ll sti ll have bl ocks
that are not adequate for the pl anned procedure. The frequency of fai l ed bl ocks can be kept to a
mi ni mum i f the cl i ni cian ai ms to produce blocks that are a li ttl e higher and a l i ttl e l onger than
seems necessary. It i s often easi er to deal wi th a bl ock that i s too hi gh or too l ong than to cover
up for a block that is too l ow or too brief.
PHYSIOLOGY
Neur ophysi ol ogy
The physi ology of local anestheti c neural bl ockade i s di scussed i n detai l i n Chapter 17. Thi s
secti on bri efly presents aspects of the physi ol ogy of neural blockade that are unique to spi nal and
epi dural anesthesi a.
Site of Action
The site of acti on of spi nal and epidural anesthesi a is not preci sel y known. Fol lowi ng epi dural
administrati on, l ocal anestheti c is found i n the spinal nerves withi n the epidural space, i n spi nal
nerve rootl ets withi n the CSF, and i n the spinal cord. Simil arl y, fol l owing i ntrathecal
administrati on i n ani mals, l ocal anestheti c is found i n al l si tes between the spinal nerve rootl ets
and the i nteri or of the spi nal cord.
145, 146
Thus, neural bl ockade can potential ly occur at any or al l
poi nts al ong the neural pathways extending from the si te of drug administrati on to the i nteri or of
the spi nal cord.
In an i nteresting study i n humans, Boswell et al demonstrated that pati ents are abl e to feel
paresthesi as duri ng di rect el ectri cal stimul ati on of the spinal cord under spinal anesthesi a.
147

Corti cal evoked potential s from direct spi nal cord sti mulati on were al so maintai ned under spinal
anesthesia, al though ampl i tudes were decreased. In contrast, paresthesi as and corti cal evoked
potential s from ti bi al nerve sti mulation were abol i shed by spi nal anesthesi a. These i nvestigators
concl uded that neural pathways wi thi n the spi nal cord were l argely intact during spinal anesthesi a
and that the spi nal nerve rootlets were the pri nci pal si te of neural bl ockade.
The site of epi dural bl ock is l ess well l ocal ized. Monkey studi es suggest that epidural bl ock occurs
largel y at sites wi thin the spi nal meni nges, including the cauda equi na nerve roots, dorsal root
entry zone, and the long tracts of spinal cord whi te matter.
148
However, these findi ngs are not
enti rely consi stent with the segmental onset of epidural anesthesi a (see Fi g. 25-12) or wi th the
l i mi ted segmental bl ocks that can be produced wi th

smal l doses of l umbar epidural l ocal anestheti cs i n humans. These cli nical observations are most
readi l y expl ai ned by bl ock of the segmental spinal nerves as they traverse the epidural or
paravertebral spaces. In reali ty, epi dural bl ock l ikely occurs at both extradural and subdural si tes
with extradural radi cul ar bl ock predomi nati ng early and subdural spi nal bl ock predomi nati ng l ater.
Thi s supposi ti on i s consi stent with human studi es by Urban who ri gorously exami ned the anatomi c
pattern of anal gesi a that occurred duri ng onset and regressi on of epi dural block.
149
He concl uded
that l ocal anesthetics ini ti all y acted on radi cular structures fol lowed l ater by acti ons wi thi n the
spi nal cord.
Interesti ngl y, human studies demonstrate that somatosensory evoked potenti al s are mai ntained
duri ng epidural anesthesi a, al though ampl i tudes are decreased and l atenci es i ncreased. Thi s
contrasts wi th spi nal bl ock i n whi ch evoked potenti al s are compl etel y el imi nated and supports the
cl i ni cal i mpression that epi dural bl ock i s general ly less dense than that achieved wi th spinal
anesthesia.
Differential Nerve Block
Differenti al bl ock refers to a cl inicall y important phenomenon in whi ch nerve fi bers subserving
di fferent functions di splay varyi ng sensi tivity to local anestheti c bl ockade. In vivo sympatheti c
nerve fi bers appear to be bl ocked by the lowest concentration of local anestheti c foll owed i n order
by fibers responsible for pain, touch, and motor function. Thi s observation has led to the wi dely
P.708
hel d bel i ef that di fferences i n sensi tivity to l ocal anesthetic bl ockade is explai ned sol el y by
di fferences i n fiber di ameter, with smal ler di ameter neurons exhibi ting greater sensi ti vi ty than
larger di ameter neurons. Whil e the mechani sm for di fferenti al block i n spi nal and epi dural
anesthesia i s not known, it i s clear that fi ber diameter is not the onl y, or perhaps not even the
most important, factor contri buting to differenti al bl ock.
150, 151
Di fferenti al block i s al so discussed
i n Chapter 17.
Differenti al bl ock occurs wi th both peri pheral nerve blocks and central neuraxial bl ocks. In the
peri pheral nervous system, di fferential block is a temporal phenomenon wi th sympatheti c block
occurri ng first fol l owed in ti me by sensory and motor bl ock. In contrast, wi th spi nal and epidural
anesthesia differenti al block i s mani fest as a spati al separati on i n the modal i ti es blocked. This i s
seen most cl early wi th spinal anesthesia where sympatheti c block may extend as many as 2 to 6
dermatomes higher than pi n-pri ck sensation,
152
whi ch in turn extends 2 to 3 dermatomes hi gher
than motor bl ock. Thi s spati al separation i s bel ieved to resul t from a gradual decrease i n local
anesthetic concentrati on withi n the CSF as a function of distance from the si te of i njecti on. Wi th
epi dural anesthesi a, si mil ar zones of differenti al sensory and sympatheti c bl ock are found.
153

Perhaps the most troublesome consequence of di fferential bl ock i s the occasi onal patient who has
intact touch and propri oception at the surgi cal si te despi te adequate bl ockade of pai n sensati on.
Even the most stoi c pati ents are l ikely to find thi s unpl easant and may lie in fear that the
procedure wil l soon become painful . In no i nstance shoul d the anesthesi ol ogi st downpl ay the
di stress this may cause patients. Reassurance and judici ous sedati on as necessary are usual l y
sufficient to overcome this problem.
Another i mportant neurophysi ologi c aspect of central neuroaxial block i s that i t produces
sedati on,
154
potenti ates the effect of sedati ve hypnoti c drugs,
155, 156, 157
and markedl y decreases
minimum al veolar concentration (MAC).
158
The mechanism(s) underl yi ng these effects is not
known but deafferentati on, that i s, the l oss of ascendi ng sensory i nput to the brai n, i s commonl y
invoked as causati ve.
Car di ovascul ar P hysi ol ogy
Cardi ovascul ar si de effects, princi pall y hypotensi on and bradycardi a, are arguabl y the most
important and most common physi ol ogi c changes during spinal and epidural anesthesi a.
Understandi ng the homeostati c mechani sms responsibl e for control of bl ood pressure and heart
rate i s essenti al for understandi ng and treati ng the cardiovascular changes associ ated wi th spi nal
and epidural anesthesi a.
Spinal Anesthesia
Bl ockade of sympatheti c efferents is the pri nci pal mechani sm by which spi nal anesthesi a
produces cardi ovascul ar derangements. As woul d be expected, the i ncidence of si gni fi cant
hypotensi on or bradycardia is general ly rel ated to the extent of sympatheti c bl ockade, whi ch i n
turn paral l el s bl ock hei ght.
159, 160
However, the severi ty of cardi ovascul ar changes has been shown
not to correl ate wi th peak bl ock hei ght i n one study
161
and to correlate poorl y in another (Fi g. 25-
13).
159
Additi onal ri sk factors associ ated wi th hypotensi on i ncl ude age >40 to 50 years, concurrent
general anesthesi a, obesity, hypovol emi a, and addi ti on of phenylephri ne to the local
anesthetic.
159, 162

Hypotensi on duri ng spi nal anesthesi a is the resul t of both arterial and venodi l ati on. Venodi lati on
increases volume i n capaci tance vessel s, thereby decreasi ng venous return and right-si ded fi l li ng
pressures.
161, 163, 164, 165
Thi s fall i n prel oad i s thought to be the pri nci pal cause of decreased cardi ac
output duri ng hi gh spi nal anesthesi a. Arterial dil ati on duri ng spi nal anesthesi a resul ts in
si gni fi cant decreases in total peripheral resi stance (Fi g. 25-14).
164, 166
Thus, the hypotension that
accompani es 30% to 40% of spi nal anestheti cs may be the result of reducti ons i n afterl oad,
reductions i n cardi ac output, or both (see Fi g. 25-14).
FIGURE 25-13. The rel ati onshi p between peak bl ock height and change i n systoli c bl ood
pressure (SBP) during spinal anesthesia. Al though there i s a statistical l y si gni fi cant
correlation between block height and decrease i n systoli c blood pressure, the i nteri ndi vi dual
vari abi l ity i s so great that the relationshi p has li ttl e predictive value. Thi s i s refl ected i n the
R
2
of 0.07 for the li near regressi on l ine. (From Carpenter RL, Capl an RA, Brown DL et al :
Inci dence and ri sk factors for si de effects of spi nal anesthesi a. Anesthesi ology 76:906,
1992.)
Heart rate does not change si gni fi cantl y duri ng spi nal anesthesi a in most pati ents (see Fi g. 25-
14). However, cl i ni cal ly si gnifi cant bradycardi a occasional ly occurs wi th a reported i nci dence of
10% to 15%. As wi th hypotensi on, the ri sk of bradycardi a increases wi th i ncreasing block
hei ght.
159
Addi ti onal

ri sk factors associ ated with bradycardi a i ncl ude age younger than 50 years, ASA 1 physi cal status,
and concurrent use of bl ockers.
159, 162
The mechanism responsibl e for bradycardi a i s not cl ear.
Bl ockade of the sympathetic cardi oaccel erator fi bers ori gi nati ng from T1-4 spi nal segments i s
often suggested as the cause. The fact that bradycardi a is more common with hi gh bl ocks supports
this mechanism. However, significant bradycardi a sometimes occurs with blocks that are
seemi ngl y too low to bl ock cardioaccelerator fibers. Di mi ni shed venous return has al so been
proposed as a cause of bradycardia duri ng spi nal anesthesi a. Intracardi ac stretch receptors have
been shown to reflexivel y decrease heart rate when fi l l i ng pressures fal l .
167
Consistent wi th thi s
mechani sm, Jacobsen et al demonstrated a si gni fi cant reducti on i n left ventri cul ar vol umes and
FIGURE 25-14. The cardi ovascul ar effects of spi nal and epi dural anesthesi a i n vol unteers
wi th T5 bl ocks. The effects of spinal anesthesi a and epi dural anesthesia wi thout epinephrine
were generall y comparabl e and are both qual i tati vel y and quanti tati vel y different from the
effects of epi dural anesthesi a wi th epinephrine. (Modi fi ed from Boni ca JJ, Kennedu WF Jr,
Ward RJ, Tol as AG: A comparison of the effects of hi gh subarachnoi d and epi dural anesthesi a.
Acta Anaesthesi ol Scand [Suppl ] 23:429, 1966.)
P.709
heart rate during hypotensi ve epi sodes in two pati ents during epi dural anesthesi a.
168
They
concl uded that central volume depl eti on el i ci ted a vagal l y medi ated refl ex slowi ng of heart rate.
Simil arl y, Baron et al demonstrated that vagal acti vi ty i s enhanced by decreased venous return
duri ng epidural anesthesi a.
169
However, thi s mechani sm does not operate at all ti mes i n al l
patients. Anzai and Ni shi kawa demonstrated si gni fi cant heart rate i ncreases i n 40 pati ents who
had their fi l l ing pressures suddenl y decreased by body til t duri ng spi nal anesthesi a.
165
In real i ty,
both bl ockade of cardi oaccel erator fi bers and decreased fi l l ing pressures as wel l as other
unrecogni zed factors l ikel y contri bute to bradycardi a during spinal anesthesi a.
Al though bradycardi a i s usuall y of moderate severity and wel l tol erated, there have been reports
of sudden, unexpl ai ned, severe bradycardi a and asystol e duri ng both spi nal and epi dural
anesthesia.
170, 171
In additi on, mul ti pl e case reports document that spi nal anesthesi a can also
produce second- and thi rd-degree heart bl ock
172, 173, 174
and that preexi sti ng fi rst-degree bl ock may
be a ri sk factor for progressi on to hi gher grade bl ocks duri ng spi nal anesthesi a.
172
These reports
document the need for conti nued vi gi l ance wi th prompt and, i f needed, aggressi ve treatment of
the cardiovascul ar changes that accompany central neuraxial bl ockade.
Epidural Anesthesia
The hemodynami c changes produced by epi dural anesthesi a are largel y dependent on whether or
not epi nephri ne is added to the l ocal anestheti c sol ution (see Fi g. 25-14).
175
Hi gh epi dural bl ock
with nonepi nephri ne-contai ning sol uti ons resul ts i n decreased stroke volume, cardi ac output, total
peri pheral resi stance, and arterial pressure. The magnitude of these changes is general l y l ess than
that seen wi th comparabl e level s of spi nal block.
175
As with spinal anesthesia, these hemodynami c
changes are beli eved to resul t from venous and arteri al di l ation i nduced by sympatheti c bl ockade.
In contrast, when epi nephri ne-contai ning sol utions are used for epi dural anesthesi a, stroke
vol ume and cardi ac output increase si gni fi cantl y (see Fi g. 25-14).
175
However, peri pheral
resistance fal l s

dramati cal l y, resul ti ng in a decrease i n arteri al pressure greater than that seen with
nonepi nephrine-contai ning sol utions. -2adrenergi c-mediated vasodi latati on produced by low
doses of absorbed epi nephri ne accounts for the greater decrease i n peripheral vascul ar resi stance
and bl ood pressure. Decreased peri pheral resi stance may al so contribute to the marked i ncrease in
cardi ac output. However, epinephrine-induced venoconstriction with a resul tant i ncrease i n venous
return may al so pl ay an i mportant rol e i n i ncreasi ng cardi ac output.
176

Treating Hemodynamic Changes
Treatment of hypotension secondary to spinal and epi dural bl ock must be ai med at the root
causes: decreased cardiac output and/or decreased peri pheral resi stance. Bol us crystall oid
administrati on has often been advocated as a means of restori ng venous return and thus cardiac
output duri ng central neuraxi al bl ockade. However, the effecti veness of thi s therapy i n
normovol emi c pati ents is controversi al . Prehydrati ng pati ents with 500 to 1,500 mL of crystal l oi d
does not rel i abl y prevent hypotensi on, but it has been shown to decrease the i nci dence of
hypotensi on duri ng spi nal anesthesi a i n some,
177, 178
but not all , studi es.
160
Si mi l arl y, prehydrati on
with crystal l oi d has been shown not to be effecti ve i n preventi ng hypotension during spinal
anesthesia for cesarean secti on.
179
Thus, al though judi cious crystal l oi d prel oadi ng of pati ents
before central neuraxial bl ocks may benefi t some pati ents, this practi ce cannot be rel ied on to
prevent cl ini cal ly si gnificant hypotension in al l or even most pati ents. The reason for this i s that
increasi ng preload can only i ncrease stroke vol ume, whi ch has l imited abil i ty to restore bl ood
pressure if heart rate or systemi c vascular resistance remai ns l ow. In thi s regard col loi ds offer an
interesti ng al ternati ve to crystal l oi ds for prel oading before central neuraxial bl ocks. Marhofer and
coll eagues have shown that 500 mL 6% hetastarch actual l y i ncreases systemi c vascul ar resi stance
index (SVRI) i n elderly pati ents havi ng spi nal anesthesi a, whi l e 1,500 mL crystal loi d si gnifi cantly
decreases SVRI.
180

Vasopressors are a more rel i abl e approach to treating hypotensi on secondary to central neuraxi al
bl ockade. Drugs wi th both - and -adrenergi c activity have been shown to be superi or to pure -
P.710
agoni sts for correcti ng the cardiovascular derangements produced by spinal and epidural
anesthesia.
181, 182
Ephedri ne i s the drug most commonl y used to treat hypotensi on. Ephedrine
bol uses of 5 to 10 mg i ncrease blood pressure by restori ng cardi ac output and peri pheral vascul ar
resistance. Dopami ne, in l ow to moderate doses, has also been shown to correct the hemodynamic
changes i nduced by central neuraxi al block.
183, 184
Dopami ne may be preferabl e to ephedri ne for
long-term i nfusion because tachyphyl axis can devel op to repeated ephedri ne bol uses. Pure -
adrenergi c agoni sts, most commonl y phenyl ephri ne, are al so used to correct hypotension during
spi nal anesthesi a. However, -agoni sts i ncrease blood pressure largel y by increasi ng systemi c
vascul ar resi stance, sometimes at the expense of further decreasi ng cardi ac output.
182
In addi ti on,
phenylephri ne bol uses have been shown to produce transient left ventri cul ar dysfuncti on duri ng
epi dural anesthesi a with nonepi nephri ne-contai ning l ocal anestheti cs.
185
A potenti al , but as yet
unstudi ed, rol e for -agoni sts may be to treat hypotension that occurs duri ng epidural anesthesi a
with epinephrine-contai ning l ocal anesthetics. Because the pri nci pal derangement i n this si tuati on
is a marked decrease i n systemi c vascul ar resistance, -agoni sts may be an appropri ate choi ce for
treating hypotension in thi s setting.
Deci di ng when to treat hemodynamic derangements during spi nal and epidural anesthesi a is
perhaps more difficult than deci ding how to treat them. There are currentl y no studi es that cl earl y
define the l ower l i mi t of acceptabl e blood pressure or heart rate for any group of patients. In the
absence of such data, several authors have recommended treating bl ood pressure i f i t decreases
more than 25% to 30% bel ow baseli ne or i n normotensive pati ents, if systoli c pressure fall s below
90 mm Hg. Recommendations regarding bradycardi a suggest i ni ti ati ng treatment i f heart rate fall s
bel ow 50 to 60 beats/minutes-1. These recommendations are reasonabl e, although not uni versall y
appl icable. Ul ti matel y, anesthesi ol ogi sts must decide what i s an acceptabl e bl ood pressure and
heart rate for an i ndi vi dual patient based on that pati ent's underlying medi cal condi tion.
Respi r at or y P hysi ol ogy
Spinal and epi dural blocks to midthoracic l evel s have l i ttl e effect on pul monary function in
patients without preexi sting l ung di sease. Drugs used peri operati vel y for sedation duri ng spinal or
epi dural block l ikely have a larger i mpact on pul monary functi on than the bl ock per se. In
parti cul ar, l ung volumes, resting minute venti l ation, dead space, arteri al bl ood gas tensi ons, and
shunt fracti on show l i ttl e or no change during spinal or epidural anesthesi a. Interesti ngl y, the
ventil atory response to hypercapni a is actual l y increased by spinal and epi dural block.
186, 187

Hi gh bl ocks associ ated with abdomi nal and i ntercostal muscl e paralysi s can impai r venti l atory
functi ons requi ri ng acti ve exhal ati on. For exampl e, expi ratory reserve vol ume, peak expi ratory
flow, and maximum minute ventilation may be signi fi cantl y reduced by hi gh spi nal and epidural
bl ocks. The negati ve i mpact of hi gh bl ocks on active exhal ati on suggests caution when usi ng
spi nal or epi dural anesthesia i n patients with obstructive pul monary di sease who may rely on thei r
accessory muscles of respi ration to mai ntain adequate venti lation.
Patients with hi gh spi nal or epi dural bl ocks may complai n of dyspnea despi te normal or elevated
mi nute ventil ati on. This l i kely results from the patient' s inabi l ity to feel the chest wall move whi l e
breathing. Thi s i s understandabl y fri ghteni ng to the pati ent, but reassurance i s usuall y effecti ve in
al leviating thei r fear. The anesthesi ol ogi st must be alert to the possi bi li ty that the compl ai nt of
dyspnea stems from i nci pient respiratory fail ure secondary to respi ratory muscle paral ysi s. A
normal speaki ng voi ce, as opposed to a fai nt gaspi ng voi ce, suggests venti l ati on i s normal .
Gast r oi nt est i nal P hysi ol ogy
The gastroi ntesti nal effects of spi nal and epidural anesthesi a are largel y the resul t of sympathetic
bl ockade. The abdominal organs derive thei r sympatheti c i nnervati on from T6-L2. Bl ockade of
these fibers resul ts i n unopposed parasympatheti c acti vi ty by way of the vagus nerve.
Consequently, secreti ons increase, sphincters relax, and the bowel becomes constricted. Some
surgeons bel ieve this i mproves surgi cal exposure. Nausea i s a common compl i cation of spi nal and
epi dural anesthesi a. The etiology is unknown but an increased i ncidence of nausea duri ng spi nal
anesthesia i s associ ated wi th bl ocks hi gher than T5, hypotensi on, opi oi d premedi cation, and a
hi story of moti on si ckness.
159, 162

Endocr i ne- Met abol i c P hysi ol ogy
Surgery produces numerous endocri ne and metabol ic changes, including i ncreased protei n
cataboli sm and oxygen consumpti on as wel l as increases i n ci rcul ati ng concentrati ons of
catechol amines, growth hormone, renin, angi otensi n, thyroi d-stimul ati ng hormone, -endorphi n,
gl ucose, and free fatty acids, among others.
1
These endocri nemetaboli c changes have coll ecti vel y
been termed the surgi cal stress response.

The mechanisms responsi ble for the stress response are compl ex and incompletely understood.
However, afferent sensory information from the surgical si te pl ays an important role i n ini ti ati ng
and mai ntai ni ng these changes.
1
Not surpri si ngly, spinal and epi dural anesthesi a have been shown
to i nhibi t many of the endocri nemetaboli c changes associ ated wi th the stress response. The
inhi bitory effect is greatest with lower abdomi nal and l ower extremi ty procedures and l east with
upper abdomi nal and thoracic procedures.
1
The salutary effect of spinal and epidural anesthesi a is
bel i eved to resul t from blockade of the afferent sensory informati on that helps i niti ate the stress
response.
Although some aspects of the surgi cal stress response may be benefi cial , i t i s general l y viewed as
mal adapti ve and possi bl y a contri butor to postoperati ve morbi di ty and mortal ity.
1
Despi te the
abi li ty of central neuraxi al block to decrease the stress response, there i s as yet no cl ear evi dence
that thi s resul ts in decreased morbi di ty or mortali ty.
COMPLICATIONS
Backache
Although postoperati ve backache occurs fol l owing general anesthesi a, it i s more common foll owi ng
epi dural and spinal anesthesi a.
188
Compared with spi nal anesthesi a, back pai n fol l owi ng epi dural
anesthesia is more common (11% versus 30%) and of l onger durati on.
189
Importantl y, back pai n
has been ci ted i n one study as the most common reason for pati ents to refuse future epidural
bl ock.
189
The eti ol ogy of backache i s not cl ear, al though needle trauma, l ocal anesthetic i rri tation,
and li gamentous strai n secondary to muscl e rel axati on have been offered as expl anati ons.
P ost dur al P unct ur e Headache
Postdural puncture headache i s a common compl i cation of spi nal anesthesi a wi th a reported
inci dence as hi gh as 25% i n some studi es. The risk of PDPH i s l ess wi th epi dural anesthesia, but it
occurs in up to 50% of young patients following acci dental meni ngeal puncture wi th l arge di ameter
epi dural needl es. The headache i s characteri sti cal ly mi l d or absent when the patient is supi ne, but
head elevation rapidl y leads to a severe fronto-occi pi tal headache, whi ch again i mproves on
returni ng to the supi ne positi on. Occasi onall y cranial nerve symptoms (e.g., di plopl ia, ti nni tis) and
nausea and vomi ti ng are also present. The headache i s bel i eved to resul t from the l oss of CSF
through the meningeal needl e hol e resul ting i n decreased buoyant support for the brai n. In the
upri ght positi on the brai n sags i n the cranial vaul t putting tracti on on pai n-sensi ti ve structures.
Tracti on on crani al nerves is bel ieved to cause the crani al nerve pal sies occasi onall y seen.
The i nci dence of PDPH decreases with increasi ng age (Fi g. 25-15) and wi th the use of smal l
di ameter spi nal needl es wi th noncutti ng ti ps.
190, 191
Inserting cutti ng needl es with the bevel
al igned parall el to the l ong axi s of the meni nges has al so been shown to decrease the incidence of
PDPH.
191, 192
Some authors have suggested that paral l el insertion spreads dural fi bers, whereas
perpendi cul ar i nserti on cuts the fi bers resul ting i n a l arger meni ngeal hol e. However, the col l agen
fi bers of the dura mater are arranged randomly; therefore, as many fi bers wil l be cut with paral l el
inserti on as wi th perpendi cular insertion. A more li kel y explanation arises from the fact that the
dura mater is under l ongitudi nal tension. Thus, a sl it-li ke hole oriented perpendi cul ar to this
longi tudi nal tensi on wi l l tend to be pul led open whil e a hol e ori ented paral l el to thi s tensi on wil l be
P.711
pul led cl osed. Some studi es have suggested that women are at greater ri sk of devel opi ng PDPH.
However, if age di fferences are accounted for, there does not appear to be a gender di fference i n
the i nci dence of PDPH.
191
Fol kl ore asi de, remaining supi ne fol l owing meningeal puncture does not
decrease the i ncidence of PDPH. Fi nall y, use of fl uid, instead of ai r, for loss of resi stance during
attempted epi dural anesthesia does not al ter the ri sk of accidental meningeal puncture, but does
markedl y decrease the risk of subsequentl y devel opi ng PDPH.
27
PDPH usual l y resol ves
spontaneously in a few days to a week for most patients. However, there are reports of PDPH
persisting for months fol lowi ng meni ngeal puncture. Ini tial treatment is appropriatel y conservati ve
if this meets the patient' s needs. Bed rest and analgesi cs as necessary are the mai nstay of
conservati ve treatment. Caffei ne has al so been shown to produce short-term symptomati c
rel ief.
193

Epidural Blood Patch. Pati ents who are unabl e or unwil l ing to awai t spontaneous resol uti on
shoul d be offered epi dural bl ood patch. Epi dural bl ood patch i s bel i eved to form a cl ot over the
meni ngeal hole, thereby preventi ng further CSF l eak whi l e the meni ngeal rent heal s. Ten to 20 mL
of autol ogous bl ood i s asepti cal l y i njected i nto epi dural space at or near the i nterspace at whi ch
the meni ngeal puncture occurred. Thi s i s effecti ve i n rel i eving symptoms wi thi n 1 to 24 hours i n
85% to 95% of pati ents; ~90% of pati ents who fai l an i ni ti al blood patch wil l respond to a second
patch. The most common si de effects of blood patch are backache and radi cul ar pai n, al though
transi ent bradycardia and cranial nerve palsi es have also been reported.
The timing of epi dural bl ood patch has been controversi al . Earl y studi es suggested that
prophyl acti c bl ood patch i n patients at hi gh ri sk for PDPH was i neffecti ve. Thi s l ed several authors
to suggest that bl ood patch shoul d not be performed before pati ents devel op symptoms of PDPH.
Subsequent studi es, which used l arger vol umes of bl ood i n the epi dural space (15 to 20 mL), have
shown that prophylacti c blood patch is effective in preventi ng PDPH i n pati ents i n whom the
meni nges were acci dental l y punctured duri ng attempted epidural anesthesi a.
194, 195
Prophyl acti c
bl ood patch i s not appropri ate for most patients but i s worth consi deri ng in hi gh-ri sk outpati ents
for whom a return tri p to the hospi tal for epi dural bl ood patch woul d be di ffi cul t.

Epi dural ly admi ni stered fi bri n glue has been shown to be an effecti ve al ternati ve to bl ood
FIGURE 25-15. The i nci dence of postdural puncture headache decreases as pati ent age
increases. When usi ng beveled needles, the inci dence i s hi gher than average at any given
age i f the needl e i s inserted perpendi cul ar to the spi nal meni nges and l ower i f inserted
paral l el to the spinal meni nges. (Modi fi ed from Lybecker H, Mll er JT, May O, Ni el sen HK:
Inci dence and prediction of post-dural puncture headache: A prospective study of 1021 spinal
anesthesias. Anesth Anal g 70:389, 1990.)
P.712
administrati on for treatment of PDPH.
196
Whether i t i s superi or to bl ood requi res further study but
it may be an attracti ve al ternative for some patients. In the future it may be necessary to drop
the term bl ood patch in favor of meni ngeal patch.
Hear i ng Loss
Lamberg et al demonstrated that a transi ent (1 to 3 days) mil d decrease i n heari ng acui ty (greater
than 10 dB) i s common after spi nal anesthesi a wi th an i nci dence of roughl y 40% and a 3:1
female:mal e predomi nance.
197
Si mi larl y, Glteki n et al
198
demonstrated a 45% i nci dence of
heari ng impai rment i n subjects undergoi ng pri locai ne spi nal anesthesi a but a much l ower incidence
(18%) in pati ents havi ng bupi vacai ne spi nal anesthesi a. The mechani sm of heari ng loss in these
studi es is uncl ear, but the marked female predomi nance, the absence of PDPH, and the di fference
in i ncidence between pri l ocai ne and bupi vacai ne suggest that CSF leak i s not the cause.
Syst emi c Toxi ci t y
Systemi c toxici ty of l ocal anesthetics i s di scussed i n detai l in Chapter 17. Systemi c toxi ci ty does
not occur wi th spinal anesthesi a because the drug doses used are too l ow to cause toxi c reacti ons
even if i njected intravenously. Both CNS and cardiovascular toxi city may occur duri ng epidural
anesthesia. CNS toxi city may result from l ocal anestheti c absorpti on from the epi dural space but
more commonl y occurs fol l owi ng accidental intravascul ar i njecti on of l ocal anesthetic. In contrast,
cardi ovascul ar toxi city from epi dural local anestheti cs can only occur uni ntended i ntravascular
injecti on because the plasma concentrati ons of local anestheti cs requi red to produce seri ous
cardi ovascul ar toxi ci ty are very hi gh. An adequate IV test dose and i ncremental i njection of local
anesthetics are the most i mportant methods to prevent both CNS and cardi ovascul ar toxici ty
duri ng epidural anesthesi a.
Tot al Spi nal
Total spi nal anesthesia occurs when l ocal anestheti c spreads hi gh enough to bl ock the enti re
spi nal cord and occasi onall y the brai nstem duri ng either spinal or epidural anesthesi a. Profound
hypotensi on and bradycardi a are common secondary to compl ete sympatheti c blockade.
Respi ratory arrest may occur as a result of respi ratory muscle paral ysi s or dysfuncti on of
brainstem respi ratory control centers. Management incl udes vasopressors, atropine, and fl ui ds as
necessary to support the cardi ovascul ar system, pl us oxygen and control l ed venti lation. If the
cardi ovascul ar and respiratory consequences are managed appropri atel y, total spi nal bl ock wil l
resol ve without sequelae.
Neur ol ogi c I nj ur y
Seri ous neurol ogic i njury i s a rare but wi dely feared compl icati on of epidural and spi nal
anesthesia. Multi ple large series of spi nal and epidural anesthesi a report that neurol ogic i njury
occurs i n ~0.03% to 0.1% of al l central neuraxi al bl ocks, al though in most of these seri es the
bl ock was not cl earl y proven to be causati ve.
199
Persi stent paresthesi as and l i mi ted motor
weakness are the most common i njuri es, al though parapl egi a and di ffuse i njury to cauda equina
roots (cauda equi na syndrome) do occur rarel y. Injury may resul t from direct needle trauma to
the spinal cord or spinal nerves, from spinal cord i schemi a, from accidental i njecti on of neurotoxic
drugs or chemi cal s, from i ntroducti on of bacteri a into the subarachnoi d or epidural space, or very
rarel y from epi dural hematoma.
199

Importantl y, l ocal anestheti cs i ntended for epidural and i ntrathecal use can themsel ves be
neurotoxi c i n concentrati ons used cl i ni cal l y.
200
In parti cul ar, hyperbari c 5% li docai ne has
been i mpl icated as a cause of mul tipl e cases of cauda equi na syndrome foll owi ng subarachnoi d
injecti on through smal l -bore (mi crospi nal ) catheters during conti nuous spinal anesthesi a.
201

Hyperbaric sol uti ons i njected through these hi gh-resistance catheters have been shown to produce
very li ttl e turbul ence and thus poor mixing of the local anesthetic within CSF.
202
Nerve i njury i s
bel i eved to resul t from pooli ng of toxi c concentrati ons of undil uted l i docai ne around dependent
cauda equi na nerve roots. Consequently, the U.S. Food and Drug Admi ni strati on has banned the
use of these smal l -gauge catheters for conti nuous spi nal anesthesi a. Although the combi nati on of
mi crospi nal catheters and high concentrati ons of l idocai ne have cl early been i mpl i cated i n causing
cauda equi na syndrome, this compl icati on has al so occurred when using l arger (20 gauge)
catheters,
201
2% l idocai ne,
203
and 0.5% tetracaine.
201
A common thread in all of these reports has
been the apparent mal distri buti on of the l ocal anestheti c wi thin the CSF. Mal di stributi on shoul d be
suspected whenever spi nal block i s unexpectedl y restri cted and maneuvers, such as al tering
patient posi ti on or drug bari ci ty, shoul d be empl oyed to i mprove drug di stri buti on before
addi ti onal drug is i njected through a conti nuous spinal catheter. If these maneuvers fai l to
i mprove drug di stri buti on, an alternati ve anestheti c techni que shoul d be empl oyed.
The mechanism by whi ch l ocal anesthetics produce cauda equi na syndrome i s not yet cl ear;
however, in vi tro evi dence suggests that l ocal anestheti cs produce exci totoxic damage by
depol arizing neurons and increasi ng intracel l ul ar cal cium concentrations.
204
It i s al so uncl ear as
yet whether adjuncts added to l ocal anesthetics, for exampl e, epinephrine, contri bute to cauda
equina syndrome. However, based on animal studi es, i t has been argued that epi nephri ne should
not be added to i ntrathecal li docai ne.
205
Rather, i f a prol onged durati on of spi nal anesthesi a i s
necessary, then a l onger acti ng drug l ike bupi vacai ne shoul d be used.
Transient Neurologic Symptoms (TNS). In addi tion to cauda equi na syndrome, the occurrence
of transi ent neurol ogi c symptoms (TNS) or transi ent radi cul ar i rri tation (TRI) has al so emerged as
a concern fol lowi ng central neuraxial bl ockade. TRI is defi ned as pai n, dysesthesi a, or both in the
legs or buttocks after spi nal anesthesi a and was fi rst proposed as a recogni zabl e enti ty by
Schneider.
206
Al l l ocal anestheti cs have been shown to cause TRI al though the ri sk appears to be
greater wi th l idocai ne than other l ocal anestheti cs.
207, 208, 209, 210, 211, 212, 213

In a large epidemiologi c study of nearl y 2,000 pati ents, Freedman et al characterized the cli nical
pi cture of TRI.
214
They found that pati ents recei vi ng l i docai ne were si gnifi cantly more l i kel y to
develop TRI than were pati ents receiving spinal tetracai ne or bupi vacai ne al though TRI di d occur
with these latter two drugs as wel l. Additi onal risk factors for TRI i ncl uded surgery i n the
li thotomy posi ti on when l idocai ne, but not when bupivacai ne or tetracaine, was used, and
outpati ent status; obesi ty was a borderl i ne ri sk factor. Variabl es shown not to increase the risk of
TRI i ncl uded l i docai ne dose, type of spi nal needl e, addi tion of epinephrine to l i docaine,
paresthesi a, hypotensi on, and bl ood ti nged CSF among others. In a separate study, Sakura has
shown that the additi on of phenyl ephri ne i s a ri sk factor for TRI when usi ng 0.5% tetracai ne for
spi nal anesthesi a.
215

Pai n from TRI was not tri vi al , with the majori ty of pati ents rating i t as moderate (VAS = 4 to
7/10). The pai n usual l y

resol ved spontaneousl y withi n 72 hours but a very few pati ents requi red 6 months.
214

The mechanism responsible for TRI is unknown; however, i t woul d be i nappropri ate to concl ude
that TRI is si mpl y a mil der mani festation of cauda equi na syndrome. Di fferences in cl inical
presentation, ri sk factors, and so on suggest that these are not si mply two poi nts al ong a
conti nuum of the same process.
Chl or opr ocai ne
Chl oroprocai ne was i ntroduced i nto cl i ni cal practice i n 1951 and was used for spi nal anesthesi a
begi nni ng i n that year. In the early 1980s, however, cli ni ci ans reported multi ple cases of
neurol ogical injury fol l owi ng intrathecal i njecti on of chl oroprocai ne. Importantl y, the
chloroprocai ne sol ution avai l abl e at the ti me contained either methylparaben as an anti microbi al
or bi sulfite as an antioxi dant. Subsequent animal studi es demonstrated that bi sulfite and
metabi sul fi te at l ow pH were capable of causi ng neurologi cal injury, but that plai n chl oroprocai ne
was not. Nonethel ess, concern about the potential for chloroprocai ne-mediated neurotoxi city l ed
to i ts nearly compl ete abandonment as a spi nal anestheti c. Thi s occurred despite the fact that the
U.S. Food and Drug Administrati on had concl uded that chl oroprocaine was not more neurotoxic
than l i docai ne, bupi vacaine, or mepivacaine. Thi s abandonment of chl oroprocai ne for spi nal use
was faci li tated by the cl i ni cal i mpressi on that li docai ne was a safer alternati ve for short durati on
P.713
spi nal anestheti cs.
However, we now recognize that l i docaine is not wi thout ri sk of neurol ogi cal toxici ty. Thi s
observation, coupl ed wi th the fact that a preservati ve-free chl oroprocai ne formulation is now
avai labl e, has l ed to a reeval uati on of chl oroprocai ne as a short-acti ng spi nal anestheti c. In 2004,
Kouri and Kopacz compared the block characteri stics of 40 mg pl ai n 2% li docai ne wi th 40 mg plai n
2% preservative-free chl oroprocai ne i n humans usi ng a double-bl i nd, randomi zed crossover study
desi gn.
216
They found that both drugs produced i denti cal average block heights (T8), but that
chloroprocai ne resul ted in more rapid resol uti on of sensory block (103 13 mi nutes versus 126
16 mi nutes.) and faster attai nment of di scharge cri teria (104 12 mi nutes versus 134 14
mi nutes). In additi on, seven of ei ght vol unteers experi enced TNS fol lowi ng intrathecal l idocai ne
whi l e none experi enced TNS foll owing 2% chl oroprocai ne. In other studies from the same research
group, chl oroprocai ne spi nal bl ock height and durati on were shown to be posi ti vel y correl ated wi th
chl oroprocai ne dose
217
and additi on of dextrose was shown not to al ter spi nal bl ock characteri sti cs
except that it i ncreased postvoi d bl adder vol ume.
218
Thi s group al so performed studi es to
determi ne the effect of epi nephri ne and fentanyl as block-prolongi ng adjuvants to spi nal
chloroprocai ne. Vath and Kopacz found that the addi tion of 20 g fentanyl to 40 mg chloroprocai ne
increased average peak bl ock hei ght (T5 versus T9), prol onged the time for sensory block
regression to L1 (78 7 mi nutes versus 53 19), and modestly i ncreased the ti me to complete
regression (104 7 mi nutes versus 95 9 mi nutes).
219
Interesti ngl y, Smi th et al . found that
epi nephri ne (0.2 mg) increased chl oroprocaine bl ock duration but that i t' s use was associated wi th
a hi gh incidence of myalgi a, arthral gi a, mal ai se, and anorexi a that l asted up to 48 hours.
217
The
authors had no expl anati on for the epi nephri ne-associated si de effects, but recommended agai nst
its use wi th intrathecal chl oroprocaine.
Thus, these studi es, coupl ed wi th concerns about the potenti al for li docai ne-mediated
neurotoxi ci ty, rai se the possi bil i ty that chloroprocai ne wi ll reenter the mai nstream as a spi nal
anesthetic, especi all y for ambulatory anesthesi a. Additi onal , l arger studies demonstrati ng
chloroprocai ne' s safety wi ll help to clarify thi s drug' s role i n spi nal anesthesi a.
Importantl y, as of thi s wri ting, chl oroprocai ne i s not speci fi cal ly indi cated for spi nal anesthesia,
therefore, i ts use i s off-label. But then so to i s the use of mul tipl e drugs that are routi nel y
administered i ntrathecal l y, including pl ain bupi vacai ne, fentanyl , and sufentani l .
Spi nal Hemat oma
Spinal hematoma i s a rare but potenti al l y devastati ng compl i cation of spi nal and epi dural
anesthesia, with an i nci dence estimated to be l ess than 1 in 150,000. Pati ents most commonl y
present wi th numbness or lower extremity weakness, a fact that can make earl y detecti on di ffi cul t
in pati ents receiving peri operati ve spi nal local anestheti cs for pain control. Earl y detecti on i s
criti cal because a del ay of more than 8 hours i n decompressing the spi ne reduces the odds of good
recovery.
220

Coagul ati on defects are the principal risk factor for epi dural hematoma. This raises the
legi ti mate questi on as to how to treat pati ents who are or who wil l be anticoagulated. Thi s
issue has been addressed i n a Consensus Statement from the American Soci ety for Regi onal
Anesthesi a and Pai n Medi ci ne
221
and the recommendati ons presented here are taken from thi s
consensus statement. In bri ef, patients taking nonsteroidal anti -infl ammatory drugs wi th
anti pl atelet effects (e.g., cycl ooxygenase-1 inhi bi tors) or recei vi ng subcutaneous unfracti onated
hepari n for DVT prophylaxi s are not vi ewed as bei ng at i ncreased ri sk of spi nal hematoma.
In contrast, other cl asses of anti pl atelet drugs, l ike thi enopryi di ne derivatives (e.g., ti clopi dine,
cl opi dogrel ) and GP IIb/IIIa antagoni sts (e.g., abci xi mab, epti fi bi ti de, ti rofi ban) have a more
potent effect on pl atel et aggregati on and neuraxi al bl ock should general ly not be performed i n
patients taki ng these or si mi lar medi cations. Further, the consensus statement recommends that
ti cl opi di ne be di sconti nued for 2 weeks and cl opi dogrel for 1 week before performi ng central
neuraxial bl ocks. The GP IIb/IIIa antagoni sts have a shorter durati on of acti on, thus i t i s
recommended that abci xi mab shoul d be di scontinued 24 to 48 hours before central neuraxi al bl ock
and epti fi bi ti de, and ti rofi ban 4 to 8 hours beforehand.
Patients recei vi ng fracti onated l ow-mol ecul ar wei ght hepari n (e.g., enoxapri n, dal tepari n,
ti nzapari n) are consi dered to be at i ncreased ri sk of spi nal hematoma. Pati ents recei ving these
drugs preoperati vel y at thromboprophylacti c doses shoul d have the drug hel d for 10 to 12 hours
before central neuraxial bl ock. At hi gher doses, such as those used to treat establi shed DVT,
central neuraxi al block shoul d be del ayed for 24 hours after the l ast dose. For patients i n whom
low-mol ecul ar-weight hepari n is begun after surgery, si ngl e-shot central neuraxi al bl ocks are not
contrai ndi cated provi ded that the first low-mol ecul ar-weight hepari n dose i s not admi nistered until
24 hours postoperatively i f usi ng a twi ce dai l y dosing regi men and 6 to 8 hours i f usi ng a once-
dai ly dosi ng regi men. If an i ndwell i ng central neuraxi al catheter is i n place, i t should not be
removed unti l 10 to 12 hours after the l ast low-mol ecul ar- weight hepari n dose and the
subsequent doses shoul d not begin unti l at l east 2 hours after catheter removal .
Patients who are ful l y anti coagulated (i.e., have el evated PT or PTT) or who are receiving
thrombolyti c or fi brinol yti c therapy are consi dered to be at i ncreased risk of spi nal hematoma.
These pati ents should not recei ve central neuraxial bl ock except i n very unusual ci rcumstances
where other opti ons are not vi able.
Importantl y for those patients who may have an epi dural or intrathecal catheter pl aced, its
removal is nearl y as great a ri sk for spi nal hematoma as i ts i nserti on and the ti mi ng of removal
and anti coagul ati on shoul d be coordi nated. Al so, drugs/regi mens not consi dered to put patients at
increased ri sk of neuraxial bleedi ng when used alone (e.g., mi ni dose

unfracti onated heparin and NSAIDS) may i n fact i ncrease ri sk when combi ned. Thi s discussi on i s
necessari ly abbrevi ated and the reader who confronts these i ssues cl ini call y shoul d revi ew the
compl ete consensus statement.
CONTRAINDICATIONS
The onl y absol ute contrai ndicati on to spi nal or epi dural anesthesia is patient refusal . However,
several preexi sti ng condi ti ons i ncrease the rel ati ve risk of these techniques and the
anesthesiol ogi st must careful l y wei gh the expected benefi ts before proceedi ng. Some condi tions
that i ncrease the apparent ri sk of central neuraxi al bl ock i nclude the fol lowi ng:
1. Hypovol emi a or shock i ncrease the risk of hypotension.
2. Increased i ntracrani al pressure i ncreases the risk of brain herniation when CSF is lost
through the needl e, or i f a further increase i n intracrani al pressure fol lows i njection of large
vol umes of sol ution into the epidural or subarachnoi d spaces.
3. Coagulopathy or thrombocytopenia increase the risk of epidural hematoma.
4. Sepsi s increases the risk of meningiti s.
5. Infecti on at the puncture site i ncreases the ri sk of meningiti s.
Preexi sti ng neurol ogic di sease, particul arl y diseases that wax and wane (e.g., mul ti pl e scl erosis),
have been considered a contrai ndi cati on to central-neuraxial bl ock by some authors. However,
there i s no evi dence to suggest that spinal or epi dural anesthesi a alters the course of any
preexi sti ng neurologi c di sease. Recommendations to avoid regi onal anesthesi a i n these pati ents
stem l argel y from a medicol egal concern that the anestheti c may be i ncorrectl y bl amed for any
subsequent worseni ng of the pati ent' s preexi sti ng condi tion. Al though thi s i s a l egi ti mate concern,
it i s not a reason to avoi d central-neuraxial bl ock i f this i s an otherwise appropri ate choi ce.
SPINAL OR EPIDURAL ANESTHESIA?
Spinal and epi dural anesthesi a each have advantages and di sadvantages that may make one or
the other techni que better sui ted to a particul ar patient or procedure. Controll ed studi es
P.714
compari ng both techni ques for surgi cal anesthesi a have consistently found that spinal anesthesia
takes less time to perform, produces more rapi d onset of better qual ity sensori motor block, and is
associated wi th l ess pai n duri ng surgery. Despi te these i mportant advantages of spi nal anesthesi a,
epi dural anesthesi a offers advantages, too. Chief among them are the l ower risk of PDPH, l ess
hypotensi on i f epi nephri ne is not added to the l ocal anesthetic, the abi l ity to prol ong or extend the
bl ock vi a an i ndwel l ing catheter, and the opti on of usi ng an epi dural catheter to provi de
postoperative anal gesia.
References
1. Kehl et H: The stress response to surgery: Rel ease mechani sms and the modi fying effect of
pai n rel ief. Acta Chir Scand Suppl 550:22, 1988
2. Modi g J, Borg T, Karlstrm G, Mari puu E, Sahl stedt B: Thromboembol ism after total hi p
repl acement: Rol e of epi dural and general anesthesi a. Anesth Anal g 62:174, 1983
3. Thornburn J, Louden J, Vall ance R: Spinal and general anesthesi a in total hip repl acement:
Frequency of deep vei n thrombosi s. Br J Anaesth 52:1117, 1980
4. Christopherson R, Beattie C et al : Peri operati ve morbidi ty i n pati ents randomi zed to
epi dural or general anesthesi a for l ower extremi ty vascular surgery. Anesthesi ol ogy 79:422,
1993
5. Rosenfel d B, Beatti e C, Chri stopherson R et al : The effects of di fferent anestheti c regi mens
on fi bri nol ysi s and the devel opment of postoperative arteri al thrombosi s. Anesthesi ology
79:435, 1993
6. Yeager M, Glass D, Neff R, Bri nck-Johnsen T: Epi dural anesthesi a and analgesia i n hi gh-ri sk
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> Tabl e of Contents > Secti on V - Management of Anesthesi a > Chapter 26 - Peri pheral Nerve Bl ockade
Chapter 26
Peripheral Nerve Blockade
Michael F. Mulroy
KEY POINTS
GENERAL PRINCIPLES
Regi onal anesthesia of the extremi ti es and of the trunk i s a useful al ternative to general
anesthesia i n many si tuati ons. Peripheral nerve blocks have attracted renewed i nterest because of
thei r sal utary role in reducing postoperati ve pain
1
and shorteni ng outpati ent recovery.
2

Local Anest het i c Dr ug Sel ect i on and Doses
The pharmacol ogy of l ocal anestheti cs is revi ewed at l ength in Chapter 17. Al though hi gh
concentrations of drug are needed to produce rapi d onset of anesthesi a in the epi dural space,
lower concentrations (e.g., 1% to 1.5% l idocai ne, 0.25% to 0.5% bupivacai ne) are more
appropri ate on peri pheral nerves because of concerns about local and systemi c toxi city. Local
toxi ci ty of these anestheti cs appears to be concentrati on dependent.
3

Lower concentrati ons are also i ndi cated when l arger vol umes are requi red to anestheti ze
poorl y l ocal ized peri pheral nerves or to bl ock a seri es of nerves. The use of a hi gh-
Peri pheral nerve bl ocks provide longer and more local i zed pain reli ef than
neuraxial techni ques whil e al so avoi di ng the side effects of systemic medicati on.
Larger vol umes of local anestheti c may increase the success potenti al of
peri pheral bl ocks, but the total mil l igram dosage must be l i mi ted to avoi d
systemi c toxi city because of slow absorption. Hi gher concentrati ons of local
anesthetics on peripheral nerves wi ll i ncrease the degree of motor bl ockade, but
larger volumes of more dil ute soluti ons can be used with less ri sk of toxi city.
Nerve bl ocks associ ated with bony or vascul ar landmarks are more reli able and
easy to perform than those that depend on surface landmarks al one.
Several peri pheral nerve bl ocks are acceptabl e al ternatives to neuraxi al
techniques in the anticoagulated pati ent.
Peri pheral nerve stimul ators are useful tools to faci l itate nerve blockade, but
they do not eli mi nate the risk of nerve i njury. In the adult pati ent,
responsi veness must be maintai ned to al l ow reporti ng of nerve contact or pai n
on injecti on.
concentration solution may be useful to i ncrease motor bl ockade but i ncreases the total mi l li gram
dose of l ocal anestheti c.
The absorpti on of drug and the durati on of anesthesi a vary wi th the dose, drug, location injected,
and presence of vasoconstrictors. The hi ghest blood levels of l ocal anestheti c occur after
intercostal blockade, foll owed by epidural , caudal , and brachi al pl exus bl ockade. Si mi l arl y, the
durati on depends on the bl ood suppl y of the area of i njecti on. Equi valent doses of l ocal anestheti c
may produce onl y 3 to 4 hours of anesthesia when placed in the epidural space, but 12 to 14
hours i n the arm and 24 to 36 hours when pl aced on the sci ati c nerve. In general , the addi ti on of
epi nephri ne 1:200,000 to 1:400,000 i s advantageous in prol onging the duration of blockade and in
reduci ng systemi c bl ood l evels of l ocal anestheti c. Its use i s not appropri ate i n the vi ci nity of
termi nal bl ood vessel s, such as in the di gi ts or peni s, or when usi ng an intravenous (IV) regional
technique. The recommended doses and drugs i n thi s chapter assume the addi tion of epi nephri ne
to the sol uti on. In general , the recommendati ons wil l be for an effecti ve vol ume for a sensory
bl ock: the fi nal choi ce of drug, vol ume, and concentrati on wil l be the determinants of the durati on
of bl ock and the degree of motor bl ockade.

Ner ve Local i zat i on
The bl ockade techni ques associ ated with rel iabl e proxi mi ty of nerves to bones or arteri es are
the easi est techni cal ly to perform (e.g., intercostal , axi ll ary). Less rel i abl e l andmarks, such
as the psoas compartment or obturator foramen, requi re ei ther large vol umes of l ocal anesthetic
solution or the establ ishment of a di sti nct local izati on of the desi red nerve to provide adequate
anesthesia. Paresthesias are the tradi tional si gn of successful l ocali zation, but the use of electri cal
sti mul ati on has gai ned populari ty with the devel opment of improved equipment.
4
A l ow-current
el ectri cal i mpul se appl i ed to a peri pheral nerve produces sti mul ati on of motor fi bers and i denti fi es
the proxi mi ty of the nerve wi thout actual needle contact or patient discomfort. Because the nerve
stimul ator does not techni cal ly contact the nerve, i ts use may reduce the chance for nerve injury,
al though it sti l l may occur and paresthesi as have been eli cited wi th thi s techni que before motor
responses. A famil i ari ty wi th anatomy and techni que is sti l l necessary to bring the needl e i nto
proxi mi ty to the nerve. The i deal stimul ator should have a vari able-amperage output. Thi s al l ows
a hi gh current to be del i vered i n the expl orati on phase and then a progressivel y lower current to
document proxi mi ty of the nerve. The accuracy of the l ocali zati on can be improved by the use of
insulated needl es. Current fl ow can al so be improved by usi ng the positi ve (red) pole of the
stimul ator as the ground (or reference) electrode and the negati ve (black) lead as the connecti on
to the needl e i tsel f. Whereas 1 to 2 mA can be used to produce the first motor twitch, actual
injecti on of anestheti c shoul d be del ayed unti l sti mulation i s produced by as l i ttle as 0.3 to 0.5
mA. At that poi nt, 2 to 3 mL of l ocal anestheti c should be suffi cient to abol i sh motor twi tch,
i ndi cati ng that i t i s appropri ate to i nject the remai nder of the proposed dose.
Seeking a sensory paresthesia wi th the needle remai ns an acceptabl e al ternative, though there i s
potential for i ntraneural i njection if paresthesi as are obtai ned. This i s usual ly signal ed by a
compl ai nt from the pati ent of a cramping or achi ng pai n duri ng the i ni ti al injecti on. If this
occurs, the needl e shoul d be i mmedi atel y withdrawn by a few mi ll i meters and a smal l test
injecti on repeated. Even wi thout i ntraneural injecti on, resi dual neuropathy of peri pheral nerves
appears more li kel y i f paresthesi as are obtai ned. A thi rd probl em wi th thi s techni que i s the
inevitable associated discomfort; pati ent educati on and sedati on must be handl ed appropri atel y.
Another al ternati ve i s the use of ul trasound gui dance to l ocal ize nerves, especi al l y i f l ocated near
an artery (axi ll ary or femoral). These techniques show promi se, but require more complex
equipment and experi ence. The choi ce of l ocali zation technique depends on many factors,
especial ly the experi ence and trai ni ng of the operator.
Equi pment
Although reusabl e syri nges and needl es can be manufactured to a hi gher standard, their cost and
concern about i nfecti on general l y l ead to a preference for disposable equi pment. There i s a large
P.719
number of hi gh-qual i ty di sposabl e ki ts avail able on the market, and many of the major
manufacturers customi ze thei r packages at the request of l arge insti tutions wil l ing to commi t to
purchasi ng a suffici ent vol ume. The use of disposable trays places the burden of steril i zati on on
the manufacturer, al though the l iabi li ty for checking the steri l i ty of contents always remai ns wi th
the user.
Needl es used for regional techni ques are often modi fi ed from standard i njecti on needl es. For
peri pheral bl ockade, the short bevel or B bevel is often used to reduce the potenti al for injury
to nerves. Other modificati ons, such as the penci l -poi nt insulated needl e, have been i ntroduced
in attempts to reduce nerve i njury.
Speci al syri nges are also useful for performi ng peri pheral nerve bl ockades. Pl asti c and gl ass are
equal l y useful . Wi th respect to size, a 10-mL syri nge is usual l y a good compromise. Large vol umes
are often required for peri pheral nerve bl ockade, so that 3- and 5-mL syringes are rarel y
adequate. Larger than 10-mL vol ume often presents such bulk and wei ght that fi ne control is
hampered. If a larger syringe i s used, i t i s usual l y advi sabl e to attach i t to the needle by a short
length of extension tubing. The use of fi nger rings (the control syri nge) is hel pful in controll i ng
injecti on, facil i tating aspi rati on, and al l owing the operator to refi ll the syri nge with one hand (Fi g.
26-1). Luer-Lok adapters for the syri nge-hub connecti on are al so advantageous. Although fri cti on
fittings produce tight seal s, the amount of force required for attachi ng or removing the syri nge
may di spl ace a needle that has been meti cul ousl y maneuvered i nto the appropri ate cl ose contact
wi th a nerve.
Continuous Catheters
A recent additi on to the armamentari um of the regi onal anesthesi ol ogi st is continuous-infusi on
catheters adapted for peri pheral nerve bl ockade. Ki ts are avai l abl e that incl ude a standard
pol yami de catheter, such as previ ousl y used for epidural analgesi a, combi ned with a Tuohy needle
for insertion that has been modified to include nerve sti mul ati on capabil i ty. These ki ts al low the
l ocal i zati on of a peri pheral nerve wi th an el ectrical current and the threadi ng of a catheter to l i e
conti guous to that nerve to provi de prol onged postoperati ve analgesi a. Further enhancements
incl ude the development of sti mulating catheters, whi ch i ncl ude an el ectrode i n the catheter ti p
that al l ows more preci se local i zati on of the catheter as it i s advanced al ongsi de the nerve.
FIGURE 26-1. The three-ri ng (control ) syri nge. Use of this adaptati on to the pl unger of a
standard 10-mL syringe all ows greater control of i njecti on, easi er aspirati on, and the
opportunity to refil l the syringe wi th one hand. Pl asti c adapters are avai l abl e for disposabl e
syri nges as demonstrated. (Reproduced wi th permission from Mul roy M: Handbook of
Regi onal Anesthesi a. Phi l adel phi a, Lippi ncott Wi l li ams & Wi l ki ns, 2002.)
Catheter infusi ons provi de prol onged postoperati ve analgesi a fol l owing major joi nt repl acement,
as wel l as si gni fi cant anal gesi a of an extremi ty foll owing short-stay orthopedic surgery.
1
Standard
precauti ons are requi red to preserve the steril i ty of the catheter and the i nserti on si te, but
compl i cati ons have been rare wi th these techni ques and new devi ces. There are a number of
conti nuous-infusi on devi ces now avai l abl e, both in i npati ent and outpati ent confi gurati on, whi ch
al low del i very of di l ute local anestheti c concentrati ons for as l ong as 72 hours after surgery.
These devi ces range from simple pressure i nfusi on plasti c apparatuses that del i ver a fi xed fl ow
rate to many that can be preprogrammed to vari abl e fl ow rates and include a pati ent-control led
suppl emental bol us

feature. The sel ecti on of the i deal catheter and i nfusion device combi nati on for a speci fic patient
and si tuati on requi res i ndi vi dual revi ew of the avai l abl e opti ons.
The selecti on of anti septi c sol utions i s usual ly a l ocal preference. Chlorhexadine, alcohol, and
organic i odi ne preparations are current standards for skin asepsi s. For major deep nerve blockade,
a wide area of ski n preparation i s more desi rabl e, and the borders of the cl ean area can be
extended by drapi ng on four si des with steri l e towel s. Regional anesthesi a does not require the
same degree of steril e preparati on and gowni ng as i ndi cated for surgery, but strict attention to
asepsi s i s desi rabl e to reduce the chance of infecti on.
Common Compl i cat i ons
Systemi c toxici ty of l ocal anesthetics i s not the most common but is the most seri ous concern.
5

Thi s syndrome and the probl ems of all ergy and other uni que toxi citi es are addressed i n Chapter
17. Central nervous system exci tation and myocardi al depressi on are the two most common
hazards associ ated wi th hi gh bl ood l evel s of local anestheti cs. No peripheral nerve bl ockade usi ng
si gni fi cant quantiti es of local anestheti c shoul d be performed wi thout oxygen and appropri ate
resusci tati on equi pment immedi ately avai l abl e. This i ncl udes bl ockades usi ng smal l quanti ties of
anesthetic near cerebral vessels, such as stel l ate gangl i on or cervical pl exus blockade. With
peri pheral nerve bl ockade, careful use of a test dose and smal l i ncremental i njecti ons are
appropriate if i ntravascular injecti on i s a ri sk. Toxi ci ty can al so occur owi ng to slow absorpti on of
hi gh doses. Pati ents should be observed careful l y for 20 to 30 minutes foll owi ng injecti on because
peak level s occur at this ti me.
Whil e compl icati ons of peri pheral bl ockade appear l ess frequent than after neuraxial blockade,
peri pheral nerve damage does appear to be a frequent cause for fil i ng of a mal practi ce clai m.
6

Peri pheral neuropathy usual l y results from intraneural local anestheti c i njecti on or needl e trauma,
al though there are other causes.
7
Careful attention should be pai d to posi ti oni ng the pati ent wi th
numb extremiti es. Postoperative foll ow-up i s important in confi rming that neurol ogic function has
returned to normal . If a defi ci t i s detected, earl y neurol ogic assessment i s cri ti cal i n determi ni ng
whether a preexi sti ng neuropathy was involved. Fortunatel y, most of these syndromes resol ve
uneventful l y, but ful l recovery of some peri pheral i njuri es requires several months as a resul t of
sl ow regenerati on of i njured peri pheral nerves. Sympatheti c concern and i nvol vement of the
anesthesiol ogi st i n arrangi ng physi cal therapy duri ng recovery hel p reduce pati ent di ssati sfaction.
Other mi nor compl i cations such as pai n at the site of i njecti on and local hematoma formati on
are not uncommon but are usuall y of short durati on and respond to reassurance by the
anesthesiol ogi st. Hematoma around a peri pheral nerve i s not of the same significance as that i n
the epidural or subarachnoi d space. Agai n, expressed concern and hel p with local therapy and
anal gesi cs al l evi ate pati ent di ssati sfacti on.
PATIENT PREPARATION
P at i ent Sel ect i on
In general , al l patients schedul ed for extremi ty, thoraci c, abdomi nal , or peri neal surgery shoul d
be consi dered candi dates for peripheral regi onal anesthetic techni ques. These can be used as the
only anestheti c, as a suppl ement to provi de analgesia and muscle rel axation al ong with general
P.720
anesthesia, or as the initi al step for provisi on of prol onged postoperati ve anal gesia such as with
intercostal blockade or conti nuous peri pheral nerve catheters. Adamant refusal of regi onal
anesthesia by a pati ent i s a contrai ndi cati on to the procedure. However, patient refusal i s
frequently a relative refusal. If the patient' s real objections are to bei ng awake or bei ng
aware, thi s can be managed by the use of sedati ves and amnesti c drugs. Other contraindicati ons
incl ude local i nfection and severe systemi c coagul opathy. The presence of preexi sti ng neurol ogi c
di sease i s often discussed. Some data are avai labl e in the case of spi nal anesthesi a, but the use of
peri pheral nerve bl ockade i n this si tuati on i s uncl ear. Al though some physi ci ans avoi d any
procedure that may confuse the picture of postoperati ve neuropathy, others beli eve that i f there is
a cl ear di fference in the potential injury and the preexisting di sease, regi onal techni ques are
appropriate. There are no cl ear answers i n this regard, and ful l pati ent educati on and cooperation
are most appropri ate. Fi nall y, the l evel of pati ent anxi ety i s an important consi derati on. Extreme
apprehensi on regardi ng surgery necessitates heavy sedation, and the advantages of regional
anesthesi a i n provi di ng rapi d recovery, al ertness, and protecti on of ai rway refl exes may be
negated. The use of regional anesthesi a in these si tuati ons i s a matter of judgment and
experi ence.
P r emedi cat i on and Sedat i on
The best preparati on for a regional techni que is careful pati ent educati on. Supplemental
medicati on i s also useful . In addi tion to the general comments about premedi cati on di scussed i n
earli er chapters, regional anesthesi a techni ques have speci al requirements. First, sedati on must
be adjusted to the required l evel of pati ent cooperati on. Wi th ei ther the eli citati on of a
paresthesi a or electri cal sti mulation technique, medi cati on must be l i ght enough to al low the
patient to i dentify and report nerve contact. Al though a mil d dose of opi oid (50 to 100 g of
fentanyl or equival ent) wi l l hel p ease the di scomfort of nerve local i zati on, patient responsi veness
must be mai ntai ned. Thi s does not precl ude the use of an amnestic agent. Smal l doses of propofol
or mi dazol am may provi de excel lent amnesia at level s of consciousness that sti ll al low
cooperati on.
Moni t or i ng
Although current di scussi ons of moni tori ng typi cal l y i ncl ude mechani cal and el ectri cal
devices, repeti ti ve assessment of the pati ent' s mental status when receiving l ocal anesthetics
is of paramount importance. The anesthesi ologist must maintai n frequent verbal contact with
these pati ents and i deall y have an uni nvol ved assi stant avail able to assess the level of
consciousness at al l ti mes. There are no electri cal or mechanical devi ces that detect ri sing bl ood
level s of l ocal anesthetic; close observation for peak l evel s owing to i v (withi n 2 mi nutes) and
subcutaneous (~20 minutes) absorption is essential. An el ectri cal or mechanical pul se counter i s
appropriate to detect the pulse ri se seen with epinephrine when i t is i ncl uded in a test dose. Pul se
moni tori ng is al so useful as an indicator of systemi c toxi city with bupi vacai ne. A basel i ne bl ood
pressure should be obtai ned whenever any sympatheti c bl ockade i s performed and at frequent
intervals thereafter. Beyond these specifi c comments, the standards for moni tori ng and record
keepi ng on any pati ent undergoi ng regi onal anesthesi a are the same as for pati ents undergoi ng
any general anesthetic.
Di schar ge Cr i t er i a
Concern is occasi onall y expressed about di scharging pati ents from postanesthesi a care uni ts when
an extremi ty i s sti l l anesthetized. If regional anesthesi a is admini stered to provide

prol onged anal gesi a, numbness may be expected to persist for 10 (with intercostal anesthesi a) to
24 (wi th sci atic blockade) hours after bupi vacai ne or ropi vacai ne administration. Patients with
numb extremiti es have been successful ly discharged from the postanesthesia care unit to the
floors as long as thei r mental al ertness is adequate. Outpatients may be di scharged home wi th
numb arms or l egs (or even wi th continuous peri pheral nerve infusions) as l ong as the patient is
rel iabl e and adequate instructi on about ambul ati on and care of the i nsensiti ve extremity is
P.721
provi ded.
SPECIFIC TECHNIQUES
The remai nder of thi s chapter i s devoted to the detai ls of the performance of speci fi c types of
bl ockade, arranged by secti ons of the body. No attempt has been made to descri be every regi onal
techni que practi ced, but to focus on those of cl ini cal usefulness to the anesthesi ol ogist.
Head and Neck
Regi onal anesthesia of the head and neck has limi ted surgi cal appl i cation. Concern about control
and mai ntenance of the airway makes many anesthesi ol ogi sts uncomfortable with regi onal
techniques when i ntraoperati ve ai rway i ntervention i s awkward. Tri gemi nal nerve bl ockade and
occi pi tal nerve bl ockade are used for di agnosti c or neurol yti c bl ockade for chronic pai n syndromes.
Cervi cal pl exus bl ockade i s useful for some surgi cal procedures on the neck, and topi cal regi onal
ai rway anesthesi a is effective i n reduci ng the subjecti ve di scomfort and hemodynami c responses
to tracheal i ntubation.
Trigeminal Nerve Blockade
Sensory and motor nerve function of the face is provi ded by the branches of the fi fth crani al
(tri gemi nal ) nerve. The roots of thi s nerve ari se from the base of the pons and send sensory
branches to the large gasseri an (or semil unar) gangl ion, which li es on the superi or margi n of the
petrous bone just inside the skul l above the foramen oval e. A smal ler motor fi ber nucl eus l ies
behind i t and sends motor branches to one terminal nerve, the mandi bul ar. The three major
branches of the tri gemi nal each have a separate exi t from the skul l (Fi g. 26-2). The uppermost
ophthal mi c branch passes through the sphenoi dal fissure i nto the orbit. The mai n termi nal fi bers
of this nerve, the frontal nerve, bifurcate into the supratrochlear and supraorbi tal nerves. These
two branches traverse the orbi t along the superi or border and exi t on the front of the face i n the
easil y pal pated supraorbital notch for the former and al ong the medi al border of the orbi t for the
latter.
The two major branches of the tri gemi nal nerve are the mi ddl e (maxi l l ary) and l ower
(mandibular). The maxi l lary nerve contai ns onl y sensory fi bers and exi ts the skul l through the
foramen rotundum. It passes beneath the skul l anteri orly through the sphenomaxil l ary fossa. At
this point, i t l i es medi al to the l ateral pterygoid plate on each side. At the anterior end of thi s
channel , i t agai n moves superi orly to reenter the skul l in the i nfraorbi tal canal i n the fl oor of the
orbit. In the sphenomaxi l lary fossa, i t branches to form the sphenopalatine nerves and to give off
the posteri or dental branches. The anteri or dental nerves ari se from the mai n trunk as i t passes
through the infraorbi tal canal. The terminal i nfraorbi tal nerve emerges from the foramen of the
same name just bel ow the eye and lateral to the nose and gi ves off the termi nal pal pebral , nasal ,
and l abi al nerves. The mandi bul ar nerve i s the third and l argest branch of the trigeminal , and the
only one to recei ve motor fibers. It exi ts the skul l posteri or to the maxi l lary nerve through the
foramen oval e. At thi s poi nt, i t is just posterior to the l ateral pterygoi d pl ate of the sphenoi d
bone. The motor nerves separate i nto an anteri or branch i mmedi atel y below the foramen oval e.
The mai n branch continues as the i nferior al veolar nerve medi al to the ramus of the mandi ble.
Thi s nerve curves anteriorl y to foll ow the mandibl e and exits as a termi nal branch through the
mental foramen. The mental nerve provi des sensati on to the l ower l i p and jaw.
Gasserian Ganglion Blockade
Ideall y, the simplest blockade of the tri gemi nal nerve i s performed in the central gangl ion. It i s
FIGURE 26-2. Lateral vi ew of major branches of the trigeminal nerve. Each major branch
exits the skull by a separate foramen. The ophthal mi c branch travels i n the orbi t. The
maxi ll ary and mandi bul ar branches emerge from the skull medial to the lateral pterygoid
pl ate, whi ch serves as the l andmark for thei r identi fi cati on. (Reproduced wi th permission
from Mul roy M: Handbook of Regi onal Anesthesi a. Phi l adel phi a, Li ppincott Wi l l iams & Wil ki ns,
2002.)
used for treatment of di sabl i ng trigeminal neuralgi a. Thi s bl ockade i s technical l y the most di ffi cul t
and has the most undesi rabl e potenti al for the compl i cati ons; i t i s usual l y performed by
neurosurgeons under fluoroscopi c gui dance and wi l l not be descri bed i n detai l here.
Superficial Trigeminal Nerve Branch Blockade
Fortunatel y, most anestheti c appl i cations of tri gemi nal bl ockade can be more easi l y performed by
injecti on of the i ndi vi dual termi nal superfi ci al branches. This i s rel ati vel y si mpl e because the three
superfi cial branches and their associ ated forami na al l l ie in the same sagi ttal pl ane on each side of
the face (Fi g. 26-3). Each of these forami na i s readil y pal pable, and these nerves can be easi ly
bl ocked wi th superfi ci al injecti ons of smal l quanti ties of l ocal anesthetic. Although the bony
landmarks are usual l y suffi cient themselves, paresthesias are desi rable before al cohol i njecti on.
Each of these blocks can be performed wi th

the pati ent i n the supine posi ti on. The procedure for bl ockade fol l ows:
1. The supraorbi tal notch i s easi ly pal pated al ong the medi al superi or ri m of the orbit, usual l y
2.5 cm from the midl i ne. Two to 3 mL of local anestheti c i njected immedi atel y i n the vi ci ni ty
of the notch produces anesthesi a of the i psi l ateral forehead. Anesthesi a of the
supratrochlear nerve by superfi ci al infi ltrati on of the medi al aspect of the orbital ri m is
P.722
FIGURE 26-3. Terminal branches of the tri gemi nal nerve. Each of the three termi nal
branches (the supraorbi tal , i nfraorbital, and mental ) exits i ts respecti ve bony canal i n the
same sagi ttal pl ane, approxi matel y 2.5 cm from the midl i ne. The infraorbi tal canal is angl ed
sl i ghtly cephal ad, whil e the mental canal can be entered i f the needl e is di rected medi all y
and sl i ghtl y caudad. (Reproduced with permission from Mul roy M: Handbook of Regi onal
Anesthesi a. Phi l adel phi a, Li ppincott Wi l li ams & Wil ki ns, 2002.)
needed if the band of anesthesia i s to cross the mi dl ine.
2. The i nfraorbital foramen li es below the inferi or orbi tal ri m i n the same pl ane at
approxi mately the same di stance from the midl i ne as the supraorbi tal notch (usuall y 2.5
cm). If the foramen cannot be pal pated directl y, i t can be sought by gentl y probi ng wi th a
smal l -gauge needl e. Thi s needl e shoul d be i ntroduced through a ski n wheal approximatel y
0.5 cm bel ow the expected openi ng, because the canal angles cephalad from this point
toward the orbi tal fl oor. Again, i njection of a smal l quanti ty of l ocal anesthetic immedi atel y
in the vicini ty of the foramen produces anesthesi a of the middl e thi rd of the ipsi lateral face.
3. The mental nerve al so emerges approximately 2.5 cm from the mi dl ine, usual ly mi dway
between the upper and l ower borders of the mandibl e. The mental canal angles medi all y and
inferi orl y so that, in thi s case, needl e insertion should start approxi matel y 0.5 cm above and
0.5 cm l ateral to the anti cipated l ocati on of the ori fi ce if i t cannot be pal pated di rectl y. In
ol der patients, resorpti on of the superi or margi n of the mandibular bone wi l l make the
foramen appear to l i e more superi orl y al ong the ramus. Again, 2 mL of local anesthesi a
injected i nto the canal produces anesthesi a of the mandibul ar area.
Maxillary Nerve Blockade
If anesthesi a i n superi or dental nerves i s al so requi red or i f superfici al i nfraorbital nerve bl ockade
does not produce adequate anesthesia, proxi mal block of the maxi l l ary nerve i s requi red. Thi s can
be performed by a l ateral approach to the sphenopalatine fossa. The procedure for blockade
fol l ows:
1. The pati ent l i es supi ne wi th a small towel under the occi put and the head turned sl ightl y
away from the si de to be bl ocked. The zygomatic arch is marked al ong i ts course, and the
patient is asked to open and close the mouth slowly so that the curved upper border of the
mandi ble can be identi fi ed. The lowest poi nt of the mandi bul ar notch i s palpated, and an X
is marked at this spot, whi ch i s usual ly at the mi dpoi nt of the zygoma. A skin wheal i s raised
at the X after the appropri ate ski n preparati ons.
2. Wi th the patient' s jaw i n the open posi tion, a 7.5-cm needl e i s introduced through the X
and di rected 45 degrees cephal ad and sl i ghtl y anteri or. Thi s di recti on should be toward the
imagi ned posterior border of the globe of the eye.
3. The needl e shoul d contact the pterygoi d pl ate. It i s then wi thdrawn and redi rected sl i ghtl y
anterior unti l it succeeds in passi ng beyond the pterygoi d pl ate. At thi s poi nt, the nerve
should li e approxi matel y 1 cm deeper. A paresthesi a i n the nose or the upper teeth confi rms
the nerve local i zati on.
4. Anesthesi a can be achieved by i njecting 5 mL into the fossa, either on obtai ni ng the
paresthesi a or bl i ndl y by advanci ng 1 cm beyond the plate. The major compli cati on of
concern i s spread of the anestheti c to adjacent structures, especial ly to the nerves i n the
orbit.
Mandibular Nerve Blockade
Thi s nerve can al so be bl ocked for inferi or dental pain. It is the only branch where anesthesi a
carri es the ri sk of l oss of motor (masti cation) functi on. The procedure for bl ockade fol l ows:
1. Head positi on and l andmarks are the same as those descri bed for the maxi l lary nerve
bl ockade.
2. A 5-cm needl e i s i ntroduced through the ski n wheal and di rected medi al l y but sl i ghtly
posterior and wi thout the cephal ad angul ati on required for maxil l ary nerve anesthesi a. Thi s
leaves the needl e approxi matel y perpendi cul ar to the ski n i n al l pl anes.
3. When the pterygoi d pl ate i s contacted, the needl e is redirected posteri orl y until i t passes
beyond the pl ate. It shoul d contact the nerve 0.5 to 1 cm deep to thi s poi nt.
4. Paresthesi a of the jaw or cheek confirms i denti fi cati on of the nerve. Fi ve to 10 mL of
solution i njected i ncremental l y at this poi nt shoul d produce anesthesi a of the terminal
branches. If paresthesias are essenti al, expl orati on shoul d be carri ed gentl y cephal ad and
caudad from the i ni tial poi nt where the needl e passes posteri or to the plate. As wi th
maxi l l ary bl ockade, paresthesi as can be pai nful to the pati ent, and the use of an assistant to
secure the head i s occasi onal l y necessary. Faci al nerve anesthesi a can occasional ly be seen
when large volumes are i njected to bl ock the mandi bular nerve. Thi s i s of li ttl e consequence
unl ess neurol yti c agents are used. A more seri ous compli cati on i s the possibi l ity of
intravascul ar injecti on i n this highl y vascularized area. Injecti on shoul d be performed
incrementall y wi th small quanti ties and

there shoul d be constant observati on for si gns of central toxici ty.
Cervical Plexus Blockade
Sensory and motor fi bers of the neck and posteri or scal p ari se from the nerve roots of the second,
third, and fourth cervi cal nerves. Thi s cervi cal plexus i s uni que in that the sensory fi bers separate
from the motor fi bers earl y in thei r course and can be bl ocked separatel y. Classi c pl exus
anesthesia al ong the tubercl es of the vertebral body produces both motor and sensory blockade.
The transverse processes of the cervi cal vertebrae form pecul i ar el ongated troughs for the
emergence of thei r nerve roots. These troughs l ie immedi atel y lateral to a medi al openi ng for the
cephal ad passage of the vertebral artery. The trough at the termi nal end of the transverse process
di vi des i nto an anteri or and a posteri or tubercl e, whi ch can often be easi l y pal pated. These
tubercles also serve as the attachments for the anteri or and mi ddle scal ene muscl es, whi ch thus
form a compartment for the cervical pl exus as wel l as for the brachi al pl exus i mmedi atel y bel ow.
The compartment at this l evel i s less developed than the one formed around the brachi al pl exus.
The motor branches (i ncl udi ng the phreni c nerve) curl anteri orl y around the lateral border of the
anterior scalene and proceed caudad and medi al l y toward the muscl es of the neck. They give
anterior branches to the sternocl eidomastoi d muscl e as they pass behi nd i t. The sensory fi bers, as
menti oned, al so emerge behi nd the anteri or scalene muscl e but separate from the motor branches
and conti nue l aterall y to emerge superfi ci al l y under the posteri or border of the
sternocl ei domastoid muscl e. They provi de sensory anesthesi a to the anteri or and posteri or ski n of
the neck and shoulder.
Anesthesi a of either the superfi cial cervi cal nerves or the cervi cal pl exus i tsel f can be used for
operations on the l ateral or anteri or neck such as thyroi dectomy and carotid endarterectomy. In
carotid surgery, l ocal infi l trati on of the caroti d bi furcati on may be necessary to bl ock refl ex
hemodynamic changes associ ated with glossopharyngeal sti mul ati on.
1. The pati ent i s placed supi ne with a smal l towel under the head, wi th the head turned sl i ghtly
to the si de opposi te the one to be bl ocked.
2. The mastoi d process i s identi fi ed and marked. The transverse processes can often be
pal pated. If not, the most prominent tubercl e, that of C6, i s marked, and a l ine i s drawn
between it and the mastoid process (Fi g. 26-4).
3. The cervi cal processes shoul d be fel t approxi matel y 0.5 cm posteri or to the li ne drawn
between the mastoi d and the si xth cervical tubercl e. The second vertebral process should l i e
approxi mately 1.5 cm bel ow the mastoi d itself. (There is no process for the first vertebra.)
4. The thi rd and fourth processes l ie approxi mately 1.5 cm bel ow their respecti ve superi or
nei ghbors.
P.723
5. Ski n wheal s are raised at the three X marks that have been placed over the transverse
processes.
6. A 3.75-cm needl e i s i ntroduced perpendi cul ar to the ski n and di rected posteri or and sl i ghtl y
caudad at each X unti l it rests on the transverse process. It i s important to mai ntai n a
caudad di recti on to avoi d entry directl y i nto the i ntervertebral forami na. The needl e is
wal ked caudad. It shoul d sl ip off the bone i f it i s trul y on the process rather than conti nuing
to contact bone if it i s on the vertebral body. It i s i mportant to contact the transverse
process as far l ateral ly as possi bl e to avoid any contact of the needle wi th the vertebral
artery (Fi g. 26-5).
7. A syri nge is connected to the needl e, and 5 mL of local anestheti c sol uti on i s deposi ted al ong
the transverse process. Anesthesi a in the di stribution of the nerve should follow within 5
minutes.
FIGURE 26-4. Superfi ci al landmarks for cervical plexus bl ockade. A l i ne i s drawn from the
mastoi d process to the promi nent tubercl e of C6. The transverse processes of C2, C3, and C4
li e 0.5 cm posterior to thi s l ine and at 1.5-cm i nterval s bel ow the mastoi d. (Reproduced wi th
permi ssi on from Mulroy M: Handbook of Regional Anesthesi a. Phi l adel phi a, Li ppi ncott
Wi l li ams & Wil ki ns, 2002.)
The major potential compli cati on of thi s procedure i s i ntravascular injecti on i nto the vertebral
artery. If the needl e is advanced too far medi al l y into the vertebral foramen, epidural or even
subarachnoi d anesthesi a may be produced. Thi s i s more l i kel y i n the cervi cal region because of
longer sleeves of dura that accompany these nerve branches.
Phrenic nerve blockade occurs with deep cervi cal pl exus anesthesia. Thi s blockade i s not i ndi cated
i n any pati ent who depends on the diaphragm for ti dal venti lati on, nor i s bi l ateral bl ockade
desi rabl e in most pati ents. Recurrent l aryngeal nerve or vagal bl ockade can also occur because of
di ffusion of the l ocal anesthetic. Thi s i s a troubl esome but not serious compl icati on. It may
interfere with the abil i ty to eval uate vocal cord functi on fol lowi ng thyroi d surgery.
Superficial Cervical Plexus Blockade. Thi s i s performed i n the same posi ti on as deep cervi cal
pl exus bl ockade and resul ts i n anesthesi a only of the sensory fi bers of the pl exus. The procedure
for bl ockade fol l ows:
1. An X i s made al ong the posteri or border of the sternocl eidomastoi d muscle at the level of
C4. Thi s usual l y corresponds wi th the juncti on of the external jugul ar vei n as i t crosses the
posterior border of the muscl e (Fi g. 26-6).

2. A skin wheal i s rai sed at thi s mark, and superfi ci al local anestheti c infi ltration is performed
al ong the posteri or border of the sternocl eidomastoi d muscl e 4 cm above and bel ow the l evel
of the X. Ten to 12 mL of local anestheti c sol uti on usual ly provi des sensory anesthesi a of
the anteri or neck and shoul der.
FIGURE 26-5. Anatomy of deep cervi cal pl exus bl ockade. The transverse processes l ie under
the lateral border of the sternoclei domastoi d muscl e, each wi th a di stal trough or sul cus that
defines the path of nerve exi t. (Reproduced with permission from Mul roy M: Handbook of
Regi onal Anesthesi a. Phi l adel phi a, Li ppi ncott Wil l iams & Wi lkins, 2002.)
P.724
FIGURE 26-6. Superfi ci al cervi cal plexus bl ockade. The sensory fibers of the pl exus al l
emerge from behi nd the l ateral border of the sternocl ei domastoi d muscl e. A needle i nserted
at its mi dpoint, usual ly where the external jugular vei n crosses the muscle, can be di rected
superi orl y and i nferi orl y to block all these terminal branches. (Reproduced wi th permi ssi on
from Mul roy M: Handbook of Regi onal Anesthesi a. Phi l adel phi a, Li ppi ncott Wil l iams & Wi lkins,
Occipital Nerve Blockade
The ophthalmi c branch of the tri gemi nal nerve provi des sensory innervati on of the forehead and
anteri or scal p, but the remai nder of the scalp is innervated by fi bers of the greater and l esser
occi pi tal nerves, termi nal branches of the cervi cal pl exus. These nerves can be bl ocked by
superfi cial injecti on at the poi nt on the posteri or skull where they emerge from bel ow the muscl es
of the neck (Fi g. 26-7). Anesthesi a is rarel y used for surgi cal procedures; i t is more often appl i ed
as a di agnosti c step in evaluati ng head and neck pai n compl ai nts. The procedure for bl ockade
fol l ows:
1. The bl ock i s performed i n the sitting posi tion, wi th the pati ent leani ng the head forward to
expose the promi nent nuchal ri dge of bone at the posteri or base of the skul l .
2. The external occi pi tal protuberance i s identi fi ed i n the mi dl ine, and a mark i s pl aced l ateral
to thi s promi nence al ong the nuchal li ne at the lateral border of the insertion of the erector
muscles of the neck, usual l y 2.5 cm from the mi dli ne. The branches of the greater occi pi tal
nerve usual ly pass l ateral ly from behi nd the muscl e to cross the nuchal l i ne at thi s poi nt.
3. After ski n preparati on, a smal l needle is i ntroduced through the mark to the depth of the
skul l itsel f. A ridge of 1 to 4 mL of l ocal anestheti c (1% l i docaine or equi val ent) is then
deposited across the path of the emerging nerves just above the l evel of the bone.
Paresthesi as are occasi onal l y encountered but are not essential for obtai ni ng si mpl e ski n
anesthesia.
4. If more anteri or anesthesia of the scalp i s requi red, the lesser occipi tal nerve branches are
al so bl ocked by advanci ng the needle subcutaneousl y from this point in an anterior directi on
2002.)
FIGURE 26-7. Occi pi tal nerve bl ockade. The greater and l esser branches of the occi pi tal
nerve emerge from under the muscles at the l evel of the nuchal ri dge on the posterior scalp.
They can be easi l y bl ocked by a subcutaneous ridge of anesthetic sol ution. (Reproduced with
toward the mastoi d process. A band of anestheti c sol ution i s deposi ted al ong the l i ne
between the skin entry and the mastoid. A l arger vol ume (6 to 8 mL) is required.
Compli cati ons of this technique are rare. Care must be taken not to advance the needl e anteri orly
under the skull , as the foramen magnum mi ght be entered uni ntenti onal l y wi th a l ong needl e.
Local hematoma may be produced wi th the superfici al i njecti on, but thi s i s only a temporary
problem.
Ai r way Anest hesi a
Mani pulation of the ai rway ei ther duri ng l aryngoscopy or duri ng tracheal i ntubation i s often
associated wi th l aryngospasm, coughi ng, and undesi rabl e cardiovascular refl exes (see al so
Chapter 22). The anesthesiologi st can abol i sh or blunt these refl exes by anestheti zi ng one or al l of
the sensory pathways i nvol ved. The nasal mucosa i s i nnervated by fibers of the sphenopalatine
gangl i on, a branch of the mi ddl e di vi si on of the fi fth crani al nerve. These branches l i e on the
lateral wal l of the nasal passages on each si de, under the mucosa just posteri or to the mi ddl e
turbi nate (Fi g. 26-8). The branches of these fibers conti nue caudad to provi de sensory i nnervation
to the superi or porti on of the pharynx, uvul a, and tonsi ls. Anesthesi a of the maxi l lary branch of
the tri gemi nal nerve i s possi bl e but not a practi cal sol uti on for ai rway anesthesi a. Transmucosal
topical appl i cation of local anestheti c i s more appropri ate. Bel ow the sphenopal ati ne fi ber
di stri bution, sensory i nnervation of the oral pharynx and supragl otti c regi ons i s provi ded by
branches of the gl ossopharyngeal nerve. These nerves li e laterally on each side of the pharynx
submucosal l y i n the regi on of the posteri or tonsi l lar pi ll ar. Direct submucosal injecti on can be
performed but carri es the ri sk of uni ntenti onal i ntravascul ar i njecti on i nto several blood vessel s in
this area. Topical anesthesi a of the termi nal branches i n the mouth and throat is again an easi er
approach, but deep injecti on of the glossopharyngeal nerve may be requi red to bl ock the gag
refl ex compl etel y. The larynx i tself i s innervated by the superi or l aryngeal branch of the vagus
nerve in the area above the vocal cords. Thi s branch l eaves the mai n vagal trunk i n the caroti d
sheath and passes anteriorl y. Its i nternal branch penetrates the thyrohyoid membrane and di vi des
to provi de the sensory fi bers to the cords, epigl ottis, and arytenoids.

P.725
FIGURE 26-8. Nasal ai rway anesthesi a. Cotton pl edgets soaked with anesthetic are inserted
al ong the i nferi or and mi ddl e turbi nates to produce anesthesia of the underlying
sphenopal ati ne gangl i on by transmembrane diffusi on of the soluti on. Wi de pl edgets al so are
needed to provide maximal topical anesthesia and vasoconstri cti on of the nasal mucosa.
(Reproduced wi th permi ssi on from Mul roy M: Handbook of Regi onal Anesthesi a. Phi ladel phi a,
Lippi ncott Wil l iams & Wi lkins, 2002.)
The recurrent l aryngeal nerve provides i nnervation to the areas below the vocal cords, i ncl udi ng
motor i nnervati on for al l but one of the intri nsi c l aryngeal muscles. The trachea i tsel f is
innervated by the recurrent laryngeal nerve. Topical anesthesia i s agai n the si mplest approach to
this nerve.
Airway anesthesi a can be performed by anestheti zi ng one or all of these sensory di stri buti ons. Ful l
anesthesia faci li tates procedures such as nasal i ntubati on or fi beropti c l aryngoscopy. Airway
anesthesia bel ow the vocal cords i s best avoi ded i f there i s concern about potenti al pul monary
aspirati on of gastri c contents. Topical postpharyngeal anesthesi a may al so abl ate protective
laryngeal refl exes.
Many pati ents fi nd i t more comfortabl e to be semi upri ght or si tti ng when topi cal anesthesi a i s
sprayed i nto the posteri or pharynx. These posi ti ons al l ow them greater ease i n swal lowi ng excess
sol uti ons and may reduce gaggi ng. In whatever posi ti on chosen, there shoul d be a fi rm support
behind the head to reduce i nvol untary withdrawal moti ons by the patient, whi ch might disl ocate
needl es bei ng used for i njecti ons.
1. For nasal mucosal anesthesi a, cotton pl edgets soaked wi th anestheti c sol ution are i ntroduced
through the nares and passed al ong the turbi nates al l the way to the posteri or end of the
nasal passage (see Fi g. 26-8). A second set of pl edgets i s i ntroduced with a cephal ad
angul ati on to fol l ow the mi ddl e turbi nate back to the mucosa overl yi ng the sphenoid bone.
Thi s pledget is the more criti cal because anesthesi a in thi s mucosal area i s most l ikely to
anesthetize the branches of the sphenopalati ne gangli a as they pass al ong the l ateral wal l of
the ai rway. Bi lateral anesthesi a is preferable, even i f a nasal tube is to be inserted only on
one si de; bi l ateral bl ockade of the sphenopal ati ne fibers al so produces posteri or pharyngeal
anesthesia caudad to thi s l evel. The pl edgets shoul d be all owed to remain i n contact wi th the
nasal mucosa for at least 2 to 3 mi nutes to al l ow adequate di ffusi on of local anestheti c.
Cocaine i n a 4% sol ution has been the tradi ti onal topi cal anestheti c for thi s appli cation
because of i ts uni que vasoconstri cti ve properti es. Al ternate soluti ons have been
recommended, pri mari l y a mixture of 3% to 4% l idocai ne and 0.25% to 0.5% phenylephri ne.
2. Topi cal anesthesi a to the posteri or pharynx can be performed whi l e the nasal appl icators are
i n pl ace. Thi s can be done with a commercial spray or with an atomi zer fi l led with a 4%
solution of li docaine. (A higher concentrati on of l ocal anesthetic i s requi red to penetrate
mucosal membranes.) For effecti ve anesthesia i n the posteri or pharyngeal wal l, topical
appl icati on is performed in two stages. Fi rst, the tongue itself is sprayed wi th a local
anesthetic, and the pati ent i s encouraged to gargle and swal l ow the resi dual l i qui d i n the
mouth. The numb tongue is then grasped wi th a gauze pad wi th one hand whi l e the spray
device i s inserted into the mouth with the other. The pati ent i s then encouraged to take
rapi d deep breaths (pant l i ke a puppy) whi l e the spray i s appli ed on i nspi ration. The
inspi ratory flow of gases shoul d be enough to draw the l i docaine sol ution into the posterior
pharynx and even to the vocal cords themsel ves. If superi or laryngeal nerve blockade has
been performed before this, i t i s li kel y that the aerosol wi l l be carri ed i nto the trachea itsel f.
Agai n, a few minutes are needed for adequate onset of topi cal anesthesi a in the pharynx.
Topi cal anesthesi a is l ess effecti ve i f there are copi ous secretions. Premedi cation wi th an
anti choli nergic i s frequentl y benefici al .
3. Superi or l aryngeal nerve blockade can al so be performed whi l e the nasal pl edgets are i n
pl ace (Fi g. 26-9). Thi s nerve is blocked bi laterall y by i dentifyi ng the superi or ala of the
thyroi d carti l age, whi ch usuall y li es just i nferi or to the posterior portion of the hyoi d bone on
each si de. A 5-mL syringe wi th a 1% l i docai ne sol ution wi th a 23-gauge, 1.75-cm needl e i s
used. The i ndex fi nger of one hand retracts the ski n of the neck caudad down over the
thyroi d carti l age; the needle i s i nserted unti l i t rests on the superi or margi n of the carti l age.
The tension on the ski n i s then rel eased and the needl e is withdrawn sl i ghtly and all owed to
wal k superi orl y off the cartil age. The needle is then rei nserted and passed through the
thyrohyoi d membrane, whi ch is percei ved as a discerni bl e resi stance. After careful
aspirati on, 2.5 mL of sol uti on i s injected i nto the space bel ow the membrane. This procedure
i s repeated on the opposi te si de. Thi s bl ockade can be

performed as part of total ai rway anesthesi a or i t can be used i ndependentl y to provi de
increased acceptance of i ndwel l i ng endotracheal tubes i n the i ntensi ve care uni t.
4. The gl ossopharyngeal nerve can be bl ocked by a di rect injecti on into the base of the anteri or
tonsi ll ar pi l lar if persi stent gagging i s a probl em. The tongue i s retracted medi all y wi th a
gloved finger or a tongue blade to expose the base of the anteri or pi l lar. A l ong 25-gauge
(spinal) needl e is i nserted 0.5 cm subcutaneousl y into the base of the pi ll ar 0.5 cm lateral to
the base of the tongue. After careful aspi rati on, 2 mL of 1.5% li docai ne i s i njected, and the
procedure i s repeated on the opposite si de. Thi s produces anesthesi a of the l ingual branch
(base of the tongue) and may even anesthetize the pharyngeal and tonsi l l ar branches by
di ffusion. Thi s al l ows laryngoscopy wi th l ess gaggi ng and hemodynami c response.
5. Tracheal anesthesi a can be performed by a di rect transcricoi d (transtracheal ) injecti on.
Thi s is accompl ished by rai sing a small ski n wheal over the cri cothyroi d membrane. A 20-
gauge iv catheter i s then inserted gently through thi s ski n wheal and through the membrane.
Entry i nto the trachea can be confi rmed by the abil i ty to aspirate air through the catheter.
The steel stylet i s then removed, and the plastic catheter is l eft i n the trachea. A syri nge
with 4 mL of 4% l idocai ne i s attached to the catheter, and the l ocal anesthetic i s sprayed
into the trachea duri ng i nspi ration. The fl ow of ai r usual ly carri es the l ocal anesthetic
di stal ly; the resul tant cough conti nues to spread the anestheti c more proxi mall y up to the
undersi de of the vocal cords and the l arynx.
6. After each of these steps has been compl eted, the pl edgets can be removed from the nasal
passages and nasal i ntubati on performed. If tracheal or l aryngeal anesthesi a has been
omi tted because of concern about aspi ration, there shoul d be some pharmacol ogi c
interventi on to reduce the cardi ovascul ar response to the passage of the tube i nto the
trachea. This can be faci li tated by pretreatment wi th i v -adrenergi c-bl ocking drugs, by
administrati on of sedation, or by admi nistrati on of propofol i mmedi atel y after the ai rway i s
secured.
P.726
Compli cati ons of these techniques are rare. Systemic toxici ty from the l ocal anesthetics i s a
di sti nct possi bil i ty because of the large quantiti es of drug requi red to produce suffici ent mucosal
anesthesia. If al l four stages of ai rway anesthesi a are undertaken, the total mil l igram doses
appl ied usuall y exceed the maxi mal recommended dose for peri pheral i njection. Fortunatel y, the
mucosal absorpti on is l ess than the peripheral absorption, but close attention to the patient' s
mental status and preparati on for treatment of toxici ty are necessary. Aspi rati on of gastri c
contents is al so a possi bil i ty when the protective refl exes of the ai rway are i nterrupted.
Upper Ext r emi t y
The i nnervation of the upper extremity i s conveni entl y derived from fi ve cl osel y approxi mated
nerve roots, extendi ng from C5 to T1 (the brachial plexus). These roots undergo a seri es of
mergers and di vi si ons that produce the termi nal nerves of the arm and hand. The pl exus branches
are cl ose enough to each other to al low rel iabl e anesthesi a to be achieved at several points
associated wi th consi stent bony or vascul ar l andmarks.
In thei r proximal course, the nerve roots l i e in a wel l demarcated fasci al envelope formed by the
anterior fasci a of the mi ddle scalene muscl e and the posteri or fascia of the anteri or scal ene. These
muscles attach to the posteri or and anteri or tubercles of the transverse processes of the cervi cal
vertebrae from which the nerves emerge. The tubercle can be used as a fai thful landmark to gui de
local izati on of the nerve, and the fasci al planes serve to keep anestheti c sol uti on i njected between
them close to the nerve bundle. The fasci a extends outward for a vari abl e di stance from the
lateral border of the muscl es to encl ose the nerves i n a sheath, whi ch can extend below the
cl avicl e. Thi s encl osed bundl e passes over the first ri b just behi nd the mi dpoi nt of the cl avi cl e
(and just posteri or to the inserti on of the anterior scalene on the ri b), where i t i s joined by the
subcl avi an artery. At the mi dpoi nt of the ri b, the pl exus has consoli dated i nto onl y three trunks;
these rapi dl y subdi vi de i nto the termi nal branches. The muscul ocutaneous nerve is the fi rst major
branch to l eave the compani onshi p of i ts partners as i t passes i nto the body of the
coracobrachi ali s muscl e hi gh i n the axi l la. As the i ndi vi dual nerves form, separate compartments
in the sheath are formed by devel opi ng septa, and bl ockade of al l the nerves with a si ngl e
injecti on i s not rel iabl e below the cl avi cl e.
Al though many approaches to the brachi al pl exus have been descri bed, there are basicall y four
anatomic l ocations where anesthetics are placed: (1) the i nterscal ene groove near the transverse
processes, (2) the subclavi an sheath at the fi rst ri b, (3) near the coracoi d process in the
infraclavi cul ar fossa, and (4) surrounding the axi l lary artery in the axi l la. Because of the speci fi c
confi gurati on of the nerves at each of these levels, the anesthesi a produced i s di fferent with each
approach and appl i cabl e to di fferent si tuati ons.
8
Interscal ene i njection at the level of the si xth
cervi cal transverse process produces extensi on of the blockade to the l ower fi bers of the cervi cal
pl exus and i s ideall y sui ted for shoul der operati ons and upper arm procedures. It frequentl y
spares the l owest branches of the plexus, the C8 and T1 fi bers, whi ch i nnervate the caudad
(ulnar) border of the forearm. Bl ockade at the l evel of the fi rst rib i s most rel iabl e in produci ng
anesthesia of all four terminal nerves of the forearm and hand. Injecti on i n the infracl avicul ar
fossa produces excel l ent anesthesi a of the entire arm and hand, although mul ti pl e injecti ons may
be requi red. The axi l lary techni que i s si mpl er but carries the risk of mi ssi ng the muscul ocutaneous
and medi al antebrachi al cutaneous nerves that depart the sheath hi gh i n the axi ll a, and thus
mi ght produce i nadequate anesthesi a of the forearm. The choi ce of the appropri ate approach
depends not onl y on the pati ent' s anatomy but also on the si te of surgery.
The terminal branches can al so be anestheti zed by l ocal anestheti c injecti on along their peripheral
FIGURE 26-9. Superior laryngeal nerve bl ockade. The needle is advanced superiorl y off the
lateral wing of the thyroi d carti lage to drop through the thyrohyoi d membrane. (Reproduced
with permission from Mul roy M: Handbook of Regi onal Anesthesi a. Phi l adel phi a, Lippi ncott
courses as they cross the joint spaces, or by the i njecti on of a di l ute l ocal anesthetic sol uti on
intravenously bel ow a pneumati c tourni quet on the upper arm (intravenous regi onal, or Bi er
bl ock).
Brachial Plexus Blockade: Interscalene Approach
Local i zati on of the nerves uses a combi nati on of the muscul ar and bony l andmarks surroundi ng the
nerves.
9
The use of l ong-acti ng local anestheti cs wi ll provide anal gesi a for 12 to 14 hours. For
longer analgesia, i nserti on of a conti nuous catheter is effective for procedures such as shoul der
rotator cuff repairs,
10
al though securi ng the catheters i n the mobi l e neck ti ssues i s a chall enge.

1. The pati ent i s posi ti oned supi ne with the head turned to the side opposite that to be
bl ocked. A smal l towel i s pl aced under the occi put. The arm on the side to be bl ocked i s hel d
at the si de, and the pati ent i s asked to hold the shoul der down by pretendi ng to reach for
the hi p.
2. The l ateral border of the sternocl ei domastoi d muscl e i s identi fi ed and marked, and the
patient is then asked to rai se the head sl i ghtl y i nto a sniffi ng positi on. Thi s tenses the
scal ene muscl es behind the sternocl ei domastoi d muscl e, and the groove between the
anterior and mi ddl e scalene i s pal pated by roll i ng the fi ngers posteriorl y off the l ateral
border of the sternocl eidomastoid muscl e. Thi s groove i s marked al ong i ts enti re extent, as

hi gh up as possi bl e. The patient then rel axes the muscl es of the neck, and the l evel of the
cricoid carti lage i s marked. The i ndex fi nger then gentl y pal pates i n the groove at the level
of the cri coi d (Fi g. 26-10). The prominent transverse process of C6 can often be felt di rectly.
3. After asepti c ski n preparation, a skin wheal i s rai sed i n the groove at the level of the cricoid.
A 22-gauge, 3.75-cm needl e i s i ntroduced through the wheal perpendi cul ar to the skin i n al l
pl anes so that i t is directed medial ly, caudad, and sl i ghtl y posteri orl y (Fi g. 26-11).
4. The needl e i s advanced unti l the tubercl e is contacted or nerve local i zati on i s eli cited (Fi g.
26-12). If bone i s contacted before nerve, the needl e i s wi thdrawn and redirected i n smal l
steps in an anteroposteri or pl ane unti l the nerves are i dentified.
5. Once the nerve i s l ocated (usuall y a motor response i n the del toi d or bi ceps, or a
paresthesi a to the thumb or upper arm), the needle is fixed in this posi tion wi th one hand
whi l e 25 to 30 mL of l ocal anesthetic sol ution is i njected. Careful aspi ration is performed
first, and the i ni tial injecti on i s performed i n smal l i ncrements to detect intraneural or
intraarterial pl acement of the needl e. A l arger vol ume (30 to 40 mL) is required i f greater
spread i s desired, such as to the cervi cal pl exus or i nferi orl y to the C8 to T1 fi bers.
6. If a catheter i s to be i nserted, the needle entry poi nt may be moved a centimeter cephalad
and the correspondi ng angle of i nserti on i s a li ttl e steeper and more tangential to the course
of the plexus. The opening of the ti p of the i ntroduci ng needl e shoul d be di rected l ateral ly.
After the catheter i s i ntroduced a few centi meters beyond the ti p, the proxi mal end may be
secured more firml y by tunnel ing 3 to 4 cm bel ow the ski n by passi ng i t back through an
intravenous catheter that has been introduced subcutaneousl y near the entry si te. Securing
catheters in the freel y mobi le neck i s a chal l enge.
7. If arm surgery requi ri ng a tourni quet i s pl anned, a subcutaneous ri ng of anestheti c across
the axil l a is usual l y requi red to bl ock the superfici al i ntercostobrachial fi bers crossi ng from
the chest wal l into the axil l a.
P.727
FIGURE 26-10. Superfi ci al landmarks for i nterscalene brachi al pl exus bl ockade. The
sternocl ei domastoid muscle is i denti fi ed, and the anteri or scal ene muscle i s found by movi ng
the fi ngerti ps over the lateral border of the l arger muscl e whil e i t i s sl i ghtl y tensed. The
groove between the anteri or and mi ddl e scal ene muscl es can usuall y be fel t easil y, al ong
with the tubercl e of the si xth cervi cal vertebra, whi ch li es at the l evel of the cricoid carti lage.
(Reproduced wi th permi ssi on from Mulroy M: Handbook of Regional Anesthesi a. Phil adel phi a,
Lippi ncott Wi ll i ams & Wi l ki ns, 2002.)
FIGURE 26-11. Hand position for interscal ene bl ockade. The needl e i s di rected medi al l y and
caudad i nto the interscal ene groove whi le one hand exerts constant control of the depth by
resti ng on the clavi cle. (Reproduced wi th permi ssi on from Mulroy M: Handbook of Regi onal
Compli cati ons from this approach are related to the structures located i n the vi ci ni ty of the
tubercle. The cupola of the lung i s close and can be contacted i f the needl e i s di rected too far
caudad. Pneumothorax shoul d be consi dered i f cough or chest pai n is produced whi l e expl ori ng for
the nerve. If the needl e i s al l owed to pass di rectly medi al l y, i t may enter the i ntervertebral
forami na, and i njection of local anestheti c may produce spinal or epidural anesthesi a. The
vertebral artery passes posteriorl y at the l evel of the si xth vertebra to l ie i n its canal i n the
transverse process; direct i njecti on i nto thi s vessel can rapi dly produce central nervous system
toxi ci ty and convul si ons.

Careful aspirati on and i ncremental injecti ons are hel pful in avoidi ng both of these potential
problems.
Even wi th appropri ate i njection, the l ocal anesthetic soluti on spreads to conti guous nerves. This
produces cervi cal pl exus bl ockade wi th high vol umes, i ncl udi ng the motor fi bers to the di aphragm,
whi ch may be a probl em i n pati ents wi th respi ratory i nsuffi ci ency. A Horner' s syndrome i s common
because of spread to the sympatheti c chai n on the anteri or vertebral body.
Neuropathy of the C6 root i s a potential probl em because the needl e may uni ntenti onal l y pi n the
nerve root against the tubercle and predi spose to intraneural injecti on. The needle should be
withdrawn sl i ghtly i f the first injecti on produces the characteri sti c crampy pai n sensati on.
Inadequate anesthesi a is most l ikel y to occur i n the ul nar distri buti on. As menti oned previ ousl y,
thi s may be reduced by the use of hi gher volumes.
FIGURE 26-12. Needl e di recti on for interscal ene bl ockade. The needle is al ways kept in a
45-degree caudad directi on; medi al i nserti on all ows the point to pass i nto the intervertebral
foramen and produces epidural , spinal , or intra-arterial injecti on of anestheti c. Note the
rel ati on of the vertebral artery and the nerve roots to the transverse processes. (Reproduced
with permission from Mul roy M: Handbook of Regi onal Anesthesi a. Phi l adel phi a, Li ppi ncott
P.728
Brachial Plexus Blockade: Supraclavicular Approach
The descripti on of the approach to the brachi al pl exus at thi s level i s ori gi nall y attri buted to
Kul enkampff. Current techniques avoi d medi al directi on of the needle, as ori gi nall y descri bed,
whi ch may contact the pleura.
1. The pati ent l i es i n the same posi ti on as for i nterscalene blockade, wi th the i psil ateral arm
hel d at the si de and pul l ed downward to exaggerate the landmarks of the cl avicl e and the
neck muscl es.
2. The outli ne of the clavi cle i s drawn on the skin, as well as the interscal ene groove (as
descri bed previousl y). The mi dpoi nt of the cl avi cl e i s marked. An X is pl aced posteri or to
this midpoi nt i n the i nterscalene groove, usual ly 1 cm behi nd the cl avicl e. On the thin
patient, the pul sati on of the subcl avi an artery can be appreci ated i n the groove or just
anterior to it.
3. After asepti c preparati on, a ski n wheal is raised at the mark, and a 3.75-cm, 22-gauge
needle attached to a 10-mL syringe i s introduced in the sagi ttal plane and advanced caudad
unti l the fi rst ri b i s contacted (Fi g. 26-13). It i s important that the di rection of the needl e
remai n perpendi cul ar to the ri b, whi ch usual l y requi res that the syri nge remai n paral l el to
the axis of the head and neck. If the rib is not contacted, careful expl orati on shoul d be
carri ed out fi rst laterall y to the mark and, last of al l , medi all y. The greatest danger of
contacting the pl eura occurs when probi ng medi al l y.
4. If a nerve response is not obtai ned on needle inserti on, expl orati on i s conti nued unti l the ri b
is i dentified. A 5-cm needl e may be needed to reach the rib in the heavi er pati ent. Once the
ri b i s contacted, the needl e is wal ked i n an anteroposteri or pl ane unti l a nerve response i s
found. Agai n, the needl e i s kept i n the sagi ttal pl ane on the dorsal surface of the ri b duri ng
exploration. If the needl e advances beyond the anteri or or posteri or border of the rib as i t
curves medial ly at these two poi nts, i t is si mply redi rected in the opposi te di recti on unti l the
ri b i s found agai n. Medial di recti on i s avoi ded. Whi l e expl ori ng al ong the di recti on of the ri b,
the needl e shoul d be wi thdrawn almost to the skin before redirection for each pass. If i t is
l i fted onl y a few mi l l i meters from the ri b, i t may simply push the nerve bundl e ahead of i t
without making contact.
5. If no nerve response i s obtained, the artery can be used as a landmark. Once it i s entered
with the needl e, a seri es of injecti ons posteri or to i t can be used to produce a wal l of 40
mL of anestheti c sol uti on i n this area.
6. An al ternate approach i s to i ntroduce the needle just above the cl avi cl e from the anterior
surface of the body, and advance i t di rectl y posteri or, fol lowi ng a l i ne that woul d be
traversed by a pl umb bob toward the fl oor (assumi ng the pati ent i s supine). If no nerve
response i s encountered, the syri nge and needl e are withdrawn and rotated caudal l y i n smal l
increments and advanced agai n. Theoreti cal l y, the needle wi ll encounter the nerves before
contacting the ri b or the pl eura. The safety of thi s approach may be i mproved by starti ng
with an even greater cephalad angul ation, 40 degrees off the verti cal .
11

7. If a nerve response is produced during the course of expl oration, the anestheti c sol ution is
injected whi le the needle is fi xed in posi ti on. Twenty-five to 40 mL of l ocal anestheti c wil l
produce adequate analgesi a. Mul ti pl e nerve responses are not requi red.
8. If a tourni quet i s to be used, a ri ng of subcutaneous anesthesi a shoul d be i nfi l trated al ong
the axil l a to bl ock the sensory fi bers from the chest wal l that cross here to i nnervate the
i nner aspect of the upper arm.
Pneumothorax is the most seri ous compl i cation of this techni que. Al though i t i s rare i n
experi enced hands, i t does occur more frequentl y with thi s approach to the brachi al pl exus than
with any other approach. Thi s may li mit the use of this techni que, particul arl y i n outpatients, i n
whom the insertion of a chest tube would then requi re hospi tal izati on. Other compl i cations of
peri pheral bl ockade of the brachi al pl exus do not occur wi th any greater frequency with this
bl ockade than wi th other methods of blockade.
Brachial Plexus: Infraclavicular Block
Approachi ng the brachi al pl exus in the i nfracl avi cul ar area at the poi nt where the plexus passes
bel ow the coracoi d process appears to have a l ower ri sk of pneumothorax (Fi g. 26-14). Here the
pl exus consi sts of three cords, wi th the musculocutaneous nerve already departed from the
bundl e. Nerve l ocal i zati on i s more chal l engi ng than wi th other techni ques because of the depth
from the skin, but the approach i n the i nfracl avi cular area offers the potential of excell ent
anal gesi a of the enti re arm with only two separate i njecti ons, and al so all ows for the introducti on
for conti nuous catheters to provi de prol onged postoperati ve pai n rel ief. The origi nal description of
this

procedure was a complex one that was l i mi ted in i ts accuracy; more recent anatomi c and
radi ographi c studi es have provi ded a si mpler approach,
12
as fol l ows:

FIGURE 26-13. Hand position for supracl avi cul ar bl ockade. The needl e i s di rected caudad
behind the mi dpoi nt of the cl avi cl e i n the interscal ene groove. Agai n, control of depth i s
maintai ned by the hand resti ng on the cl avicl e. The syri nge i s kept i n the sagi ttal pl ane
paral l el to the pati ent' s head to prevent medi al angulation, whi ch woul d increase the chance
of pneumothorax. (Reproduced with permission from Mul roy M: Handbook of Regi onal
P.729
1. Patient is pl aced i n the supi ne positi on wi th the arm at the si de. The coracoi d process is
pal pated bel ow the clavi cle and marked wi th a ci rcl e. A li ne is drawn 2 cm medi al l y and then
extended 2 cm i nferi orl y from thi s poi nt, and an X is pl aced on the skin.
2. After ski n preparati on and ski n wheal , a 10-cm needl e i s i nserted directl y perpendi cul arly
through the X and advanced through the pectoral is muscl e, searching for a nerve response.
The fi rst response obtained i s usual ly the musculocutaneous nerve. Thi s nerve can be
bl ocked by an injecti on of 5 mL of l ocal anesthetic. For compl ete anesthesia of the hand, a
separate response in the hand i tsel f needs to be obtained. When movement or sensati on i n
the hand is el ici ted, a further 25 mL of l ocal anestheti c can be injected, presumabl y within
the neurovascul ar sheath at thi s poi nt. The sheath usual ly li es just caudad to the
muscul ocutaneous nerve. The artery may be al so identi fi ed easi l y at thi s poi nt, and careful
aspirati on i s required to prevent intravascul ar i njecti on.
3. If a response i s not el ici ted before contact i s made wi th bone (usuall y the scapul a
posteriorly), then the needle i s wi thdrawn to near the skin and rei ntroduced wi th a sli ghtl y
di fferent angulation, usual ly i n a caudad di rection. Several passes may be requi red because
the nerves li e at an average depth of 5 cm from the skin. At thi s poi nt, smal l changes i n
needle angul ati on may produce wi de variations i n the location of the tip of the needl e.
4. If a catheter i s to be threaded, it shoul d be onl y in response to nerve l ocali zation i n the
hand i tsel f. The tip of the Tuohy needl e shoul d be directed l ateral l y to al l ow the catheter to
FIGURE 26-14. Infracl avicul ar approach. The nerves and trunks of the brachi al pl exus li e
basicall y al ong a strai ght l ine that can be projected from the lateral tubercle of the C6
vertebral body to the axi l l ary artery i n the axi l l a. At the mi dpoi nt of thi s l i ne, the plexus
consi sts of three trunks, wi th the muscul ocutaneous nerve potenti al l y having already
departed from the neurovascul ar bundl e. Thi s mi dpoi nt l i es bel ow the cl avicl e and l ateral to
the ri b cage. The nerves can be i denti fi ed by drawi ng a l i ne endi ng 2 cm medi al l y from the
cricoid process and 2 cm inferi orl y. A needl e i nserted di rectl y posterior at thi s point should
contact the nerves at a depth of between 5 and 10 cm. (Reproduced wi th permission from
Mul roy M: Handbook of Regional Anesthesi a. Phi l adel phi a, Li ppi ncott Wil l iams & Wi lkins,
2002.)
run i n the directi on of the nerves. It shoul d be advanced onl y a short distance beyond the
ti p of the needl e because of the ri sk of puncturi ng the artery at thi s level . The catheter can
be secured to the skin and remain i ndwel l ing for several days.
13

Compli cati ons of this technique include hematoma formation and nerve i njury. The ri sk of
pneumothorax is minimi zed by avoi ding any medi al devi ati on of the needl e point.
Brachial Plexus: Axillary Technique
The axi ll ary technique carri es the l east chance of pneumothorax and thus may be a preferred
technique for the outpatient. The nerves are anestheti zed around the axi ll ary artery, where they
have regrouped i nto thei r termi nal branches. Because of the observation that the si ngl e sheath
may be broken up i nto separate compartments by fascial septa surroundi ng i ndi vi dual nerves i n
the axil l a, local anestheti c shoul d be i njected at mul ti pl e sites in the axi ll a in contrast to the
si ngl e i njections possi ble wi th proxi mal approaches. Another obstacl e to the si ngl e-injecti on
technique at thi s l evel is the earl y departure of the muscul ocutaneous branch from the sheath
hi gh i n the axil l a.
1. The pati ent l i es supi ne wi th the arm extended 90 degrees from the si de and flexed at the
el bow. Extensi on beyond 90 degrees potenti al l y compresses the axi ll ary artery because of
the pressure from the head of the humerus and may make i denti fi cati on of the l andmarks
more di ffi cul t. A pi l l ow under the forearm al so reduces rotation of the shoul der joi nt, whi ch
can obscure the pul se.
2. The axi ll ary artery i s marked as hi gh i n i ts course i n the axil l a as i s practi cal . It i s usuall y
felt i n the i ntramuscul ar groove between the coracobrachial is and the tri ceps muscl es. It
al so passes between the insertions of the pectoral i s major and the latissimus dorsi muscl es
on the humerus.
3. After asepti c preparati on, a ski n wheal is raised over the proxi mal portion of the artery. The
i ndex and mi ddl e fi ngers of the nondomi nant hand straddl e the artery just bel ow thi s poi nt,
both l ocal izing the pul sati on and compressing the neurovascul ar bundle bel ow the i ntended
si te of i njecti on (Fi g. 26-15).

4. Common Approaches
A) Direct Nerve Localization. The traditi onal method i s to i denti fy each of the nerves
with either a paresthesi a or nerve stimul ator technique. Ideal ly, the nerves serving the
area of proposed surgery are sought fi rst. The medi an and the muscul ocutaneous
nerves l i e on the superi or aspect of the artery (as vi ewed by the operator), whereas
the ul nar and radi al nerves l i e bel ow and behi nd the vessel (Fig. 26-16). A three-ring
syri nge i s especi al l y useful in thi s techni que to al l ow aspi rati on duri ng the nerve
search, to hel p i denti fy the potenti al for switchi ng to a transarteri al approach i f the
artery i s entered. When a nerve response i s obtained, 5 to 10 mL are injected, taki ng
precauti ons to avoi d intraneural injecti on. Firm pressure is mai ntained on the di stal
sheath to encourage the soluti on to move central ly from the point of injecti on,
hopeful ly to i ncl ude the poi nt of ori gin of the muscul ocutaneous nerve. Wi th the
mul tipl e-injecti on techni que, other nerve responses shoul d be el i ci ted wi thi n 5 mi nutes
of the ori ginal i njection. Beyond this ti me, spread of the soluti on may produce
hypesthesi a of the other nerves, whi ch prevents thei r i denti fi cation. The second nerve
response should be sought on the side of the artery opposi te the ori ginal one. Whi le
some have had success i n patients i n si mpl y injecti ng a l arge vol ume on a singl e-nerve
response, most practi tioners have found the need to i denti fy at l east two or three
separate nerves to ensure success.
Alternati vel y, all four major peri pheral nerves may be sti mulated and anestheti zed
lower in the arm, at the juncti on of the upper and mi ddl e thi rd of the humerus
P.730
(midhumeral approach
14
). At this point, the medi an nerve is sti mulated subcutaneousl y
near the artery, the ul nar nerve is deeper and medi al to the artery, the
muscul ocutaneous nerve i s under the biceps and 2 to 4 cm away from the artery, and
the radi al nerve i s behi nd the humerus.
B) Peri vascul ar i nfil trati on. Usi ng the same approach with a shorter, smal ler gauge
needle, 5 to 10 mL of l ocal anestheti c is i njected cl osel y on each si de of the artery,
using mul ti pl e passes with a movi ng needle not seeki ng nerve responses, producing a
wal l of sol ution that i ntercepts the paths of each of the branches. After i ni tial
infi ltration, sensation or motor functi on i s tested in the peripheral nerve di stributi on
within 5 minutes. If anesthesi a is not present, rei njection of the area is again
performed wi th mul ti pl e passes. Thi s approach i s si mpl er and can be performed
rapi dl y, but requi res cl ear i denti fi cation of the pul se.
C) Transarteri al . Another si mpl e al ternative i s to del iberately enter the artery wi th the
needle. The needl e is advanced through the vessel until aspi rati on confirms that i t has
passed just posteri or; at thi s point, half the anestheti c sol uti on i s injected
incrementall y wi th careful attenti on to avoi d i ntravascular placement. The needl e is
then wi thdrawn back through the vessel until aspi rati on confirms that i t i s just anterior
to the artery. The other hal f of the soluti on i s injected. Thi s technique is si mpl e and
effecti ve and should be kept in mind as an al ternative if the vessel is uni ntentional ly
entered duri ng ei ther of the aforementi oned techni ques.
5. If forearm anesthesi a is requi red, supplementary anesthesi a of the musculocutaneous nerve
may be obtai ned by i njecti ng an additi onal 5 to 10 mL of anesthetic soluti on i nto the body of
the coracobrachial is muscl e. This muscl e can be easi l y grasped between the thumb and
forefi nger, and the entry into i ts fasci al compartment i s readil y identi fi ed. Al ternativel y a
di rect nerve response can be el ici ted with a sti mul ator. Thi s step may be requi red even if 40
mL of sol uti on i s used i n the peri vascul ar injecti on because the muscul ocutaneous nerve may
be spared as often as 25% of the time even wi th thi s or l arger vol umes. A suppl emental
subcutaneous i njection of 5 mL i nferi or to the artery i s al so requi red to anestheti ze the
medial antebrachi al cutaneous nerve.
6. If a conti nuous techni que is desi red, a catheter can be threaded centrall y after nerve
local izati on, or si mpl y after identi fyi ng the sheath by percei vi ng the characteri sti c fasci al
pop on entry that i s more easil y appreci ated with the l arger bl unter needles used for
catheter i nserti on. Securi ng the catheter in the axi ll a i s chal l engi ng, and may requi re
immobil i zati on of the arm.
The compli cati ons of the axil l ary approaches to the brachial pl exus are mi nimal compared wi th
those of the more proxi mal approaches. The probl em of neuropathy i s the foremost consi derati on,
and the rel ati ve ri sk wi th various techni ques remai ns controversi al . Hematoma can occur i f the
vessel i s punctured, but thi s is rarel y a probl em. The use of smal l -gauge needl es may reduce this
possi bi li ty. The advantages of any one techni que i n reduci ng compl icati ons remai ns uncl ear, and
the success rate of the vari ous techni ques i s vari abl e and appears to depend on personal
famil i ari ty.
Intravenous Regional Anesthesia (Bier Block)
The simplest techni que of arm anesthesi a i s the i njecti on of l ocal anestheti c into the venous
system bel ow an occl udi ng tourni quet.
1. A small -gauge (20 or 22) i v plasti c catheter i s i nserted i n the arm to be bl ocked on the
dorsum of the hand. It i s taped fi rml y i n place, and a hepari n port or small syringe i s
attached and sali ne is i njected to mai ntai n patency. A pneumati c tourniquet i s appl i ed over
the upper arm.
2. The arm i s el evated to promote venous drainage. An el asti c bandage may be appl i ed to
produce further exsangui nation. After exsangui nati on, the tourni quet i s i nfl ated to 300 mm
FIGURE 26-15. Hand position for axillary blockade. Two fingers of equal l ength straddl e the
artery whi le the needl e i s introduced al ong i ts l ong axi s wi th a central angul ati on. The
pal pati ng fingers serve not only to i denti fy the vessel but al so to compress the peri vascul ar
sheath and encourage the spread of anestheti c sol ution central l y. (Reproduced wi th
permi ssi on from Mulroy M: Handbook of Regi onal Anesthesi a. Phi l adel phi a, Li ppincott
FIGURE 26-16. Needl e posi tion for axil l ary i njecti on. The median (M) and muscul ocutaneous
nerves l i e on the superi or side of the artery (A), al though the latter may have already
departed the axil l ary sheath at the l evel of i njecti on. The ul nar nerve (U) l i es inferi or, and
the radi al nerve (R) i s i nferi or and posteri or. V, vei n.
Hg or 2.5 ti mes the pati ent's systol i c

bl ood pressure and i s tested for adequate occlusi on of the radi al pulse.
3. The arm i s returned to the hori zontal positi on, a 50-mL syringe wi th 0.5% l i docai ne is
attached to the previousl y i nserted cannula, and the contents are i njected. The forearm
di scol ors, and the patient percei ves a transient pi ns and needl es sensati on as anesthesi a
ensues over the fol l owing 5 mi nutes. Epinephrine shoul d not be added to the l ocal anestheti c
solution.
4. For short procedures, the cannul a can be removed at this point. If surgery may extend
beyond 1 hour, the cannul a can be l eft in pl ace and rei njected after 90 mi nutes.
5. Beyond 45 minutes of surgery, many patients experi ence discomfort at the l evel of the
tourni quet. Special doubl e-cuff tourni quets are avai l abl e for this bl ockade to al l evi ate thi s
probl em. The proxi mal cuff i s i nfl ated fi rst, al lowi ng anesthesia to be i nduced i n the area
under the distal cuff. If discomfort ensues, the distal cuff i s infl ated over the anestheti zed
area of ski n, and the uncomfortable proximal cuff i s rel eased. Thi s step i s cri ti cal because
the major risk of thi s procedure i s premature rel ease of sol ution into the ci rculati on. If a
double cuff is used, both cuffs shoul d be tested before starting and the proper sequence for
infl ati on and defl ati on meticul ousl y fol lowed. The potenti al for l eakage of anestheti c i nto the
ci rculati on i s greater with these narrower cuffs used in the double setup. Because the
shifti ng process al so increases the potenti al for uni ntentional rel ease of anestheti c, the use
of a si ngl e, wi der cuff may be better for short procedures.
6. If surgery i s completed i n l ess than 20 mi nutes, the tourni quet i s l eft i nfl ated for at least
that total peri od of ti me. If 40 mi nutes has elapsed, the tourniquet can be defl ated as a
si ngl e maneuver. Between 20 and 40 mi nutes, the cuff can be deflated, rei nflated
i mmedi atel y, and fi nal l y defl ated after 1 minute to del ay the sudden absorpti on of anestheti c
into the systemi c circul ati on, although thi s may not l ower the eventual peak levels achi eved.
7. The durati on of anesthesia i s mi ni mal beyond the ti me of tourni quet release. Al though
bupi vacai ne may produce a sl i ght prol ongati on of anal gesia, the advantage i s short.
Furthermore, the cardi otoxi city of systemi c level s of bupivacai ne makes thi s drug a less
desi rabl e choi ce for a Bier block.
The simpli ci ty of thi s technique i s offset by the signifi cant ri sk of systemi c l ocal anesthetic toxi ci ty
if the tourniquet fai l s or i s rel eased prematurely. Careful testi ng of the tourni quet and sl ow
injecti on of sol uti on into a peripheral (not antecubi tal ) vein wi l l reduce the chance of leakage
under the tourniquet. Systemic blood l evel s are ti me dependent, and careful attention shoul d be
pai d to the sequence of tourniquet rel ease and to patient moni toring during thi s peri od. A
separate iv si te for injecti on of resusci tation drugs i s needed as well as ready avai labi li ty of al l
appropriate resuscitati ve equipment. With careful attention to these detai ls, this techni que is one
of the most effecti ve and rel i abl e avai l abl e to the anesthesi ol ogist.
Distal Upper Extremity Blockade
The nerves to the hand can be blocked at the poi nt where they cross the two major joi nts, the
el bow and the wri st (Fi g. 26-17). At these two l evels, the overl yi ng muscl es are thi nned and the
bony landmarks are more prominent, al lowi ng easi er i denti ficati on of the nerves. Peri pheral
bl ockade i s usual l y not as dense as central bl ockade but may be useful i n anestheti zi ng one
branch that was mi ssed with a central bl ockade or in provi ding l ocali zed anesthesia on the hand.
Because the sensory branches to the forearm from the musculocutaneous nerve and the i nternal
cutaneous nerve have al ready branched so extensively that adequate anesthesi a of the forearm i s
not easi ly obtained, bl ockade at the elbow real l y produces no greater anesthesi a than bl ockade at
the wrist.
P.731
Blockade at the Elbow. Two nerves to the hand cross thi s joi nt on the i nner aspect. The ul nar
travel s posteri orl y i n its wel l -known superfici al groove.
1. The ul nar nerve i s bl ocked by injecti on of 1 to 4 mL of l ocal anestheti c proxi mal to the
groove formed by the medial condyle of the humerus and the ol ecranon wi th the joi nt fl exed
at approxi matel y 30 degrees. Further fl exi on may cause the nerve to rol l medi al l y and
anterior to the condyl e. Paresthesi as can usual l y be readi l y obtai ned, but di rect injecti on on
an eli citati on of a paresthesi a or di rectly i nto the groove under pressure i s not advised
because of the risk of damage to the nerve. If the i njecti on i s made deep to the fascia,
anesthesia shoul d commence wi thin 5 minutes.
2. The medi an nerve crosses the joint in the company of the brachi al artery. A l ine i s drawn
between the two condyles on the inner aspect of the joi nt, and a skin wheal i s rai sed at the
poi nt where thi s l ine crosses the pul sation of the brachi al artery, usuall y 1 cm to the ul nar
si de of the bi ceps tendon. A needle i s i ntroduced perpendicularl y at thi s poi nt, and nerve
responses are sought i mmediately adjacent to the artery. Fi ve mi ll i li ter of sol ution is
suffi ci ent to produce anesthesi a, and, again, i ntraneural injecti on i s careful l y avoided.
3. The radi al nerve is i denti fi ed al ong the same i ntracondyl ar l i ne, approximatel y 2 cm lateral
to the bi ceps tendon. Another ski n wheal i s raised here, and, agai n, a needl e is i nserted to
search for nerve responses i n a fan-shaped pattern. If nerve responses are not obtai ned, a
wal l of anestheti c sol ution can be deposited here but with less chance of rel i abl e
anesthesia.
FIGURE 26-17. Sensory dermatomes of the arm. Sensati on i s provi ded by the termi nal
nerves, as i dentified. Thi s pattern is di fferent from the cl assic dermatomal di stri buti on of the
nerve roots. Di fferent patterns of anesthesi a devel op i f the bl ockade i s performed at the root
level (i nterscal ene bl ockade) versus the termi nal nerve l evel (axi l l ary bl ockade). (Reproduced
Wi l li ams & Wi l ki ns, 2002.)

Blockade at the Wrist. The nerves l i e more superfi cial ly at thi s joint and are cl osely associ ated
with easi ly identi fi ed l andmarks (Fi g. 26-18).
1. The ul nar nerve l i es between the ul nar artery and the fl exor carpi ul nari s. A ski n wheal is
raised at the l evel of the styl oid process on the palmar side of the forearm between these
two l andmarks. A smal l -gauge needl e is i nserted, and 3 mL of sol ution is i njected i nto the
area, with or wi thout paresthesi as.
2. At the same level on the forearm, the medi an nerve li es between the tendons of the palmari s
longus and the fl exor carpi radi ali s. If onl y the pal maris l ongus can be felt, the nerve is just
to the radi al si de of thi s tendon. A ski n wheal i s raised, and a needle i s i nserted until i t
pi erces the deep fasci a. Three mi ll i li ter of soluti on produces anesthesia.
3. The radi al nerve requi res a broader i njecti on because it has already started to rami fy as i t
crosses the wrist. The anatomic snuffbox formed by the tendons of the extensor pol li cus
longus and extensor poll i ci s brevi s tendons i s located, and 3 mL of sol uti on i s injected here.
A subcutaneous wheal is then rai sed from this poi nt, extendi ng over the dorsum of the wri st
3 to 4 cm onto the back of the hand.
Suprascapular Block
The suprascapular nerve i s another terminal branch of the brachial plexus that can be
anesthetized by a separate i njection. Anesthesia of thi s nerve provi des postoperati ve pain rel i ef
fol l owing shoul der arthroscopy or reconstructi ve surgery. The nerve ari ses from the superi or trunk
of the brachi al plexus i n the neck, courses through the suprascapul ar notch, and then passes
P.732
FIGURE 26-18. Terminal nerves at the wrist. The medi an nerve l i es just to the radi al si de of
the fl exor pal maris l ongus. The ul nar and radi al nerves li e just outsi de thei r respecti ve
arteries. The radi al nerve has already begun branchi ng at thi s l evel and must be bl ocked by a
wide subcutaneous ri dge of anestheti c. (Reproduced wi th permi ssion from Mul roy M:
Handbook of Regi onal Anesthesi a. Phil adel phi a, Li ppincott Wil l iams & Wi lkins, 2002.)
behind the l ateral border of the spi ne of the scapul a to the i nfraspi natus fossa. It has two terminal
branches, a sensory arti cul ar branch to the shoulder joi nt and a motor branch to the
supraspi natus muscl e. The techni que for nerve blockade is as foll ows:
1. The pati ent i s pl aced i n the upri ght si tti ng positi on, l eaning forward so that the scapul ae are
accentuated. The spine of the scapul a i s identi fi ed and marked al ong i ts enti re length. The
inferi or ti p of the scapula is then i dentified, and the ori ginal l i ne of the spi ne is bi sected at a
poi nt immedi atel y superior to thi s i nferior ti p.
2. A skin wheal i s rai sed approximately 1 cm superi or and 1 cm lateral from this mi dpoi nt of
the scapul ar spi ne, and a 3.75-cm needl e i s advanced through the ski n unti l contact i s made
with the superior surface of the scapul a. The needle is then wi thdrawn and redi rected
cephal ad and medi al l y toward the mi dl ine unti l the edge of the suprascapul ar notch i s
encountered. At this poi nt, the patient may percei ve a paresthesi a i nto the shoulder joi nt, or
the nerve sti mul ator may produce an i nternal rotation of the arm itself.
3. Once the nerve i s l ocal ized, 10 mL of local anestheti c i s injected. Even in the absence of
nerve local i zati on, thi s vol ume of sol ution injected i nto the notch shoul d produce adequate
anesthesia of the shoulder joi nt.
Tr unk
Anesthesi a of the abdomen and chest i s most si mpl y obtai ned with spi nal and epi dural i njecti ons
of local anestheti cs, as di scussed i n Chapter 25. In some situations, a narrower band of i ntercostal
or paravertebral anesthesi a is preferabl e, or epi dural i njecti on may be hazardous because of the
presence of an i nfection or coagul opathy. In many cl i ni cal si tuati ons, it may al so be desi rabl e to
separate the anesthesi a of the somatic and sympatheti c fi bers that occurs i n combi nati on when
axial blockades are performed. The sympathetic nerves separate from thei r somatic counterparts
early in thei r course, whi ch makes independent somati c and sympathetic bl ockade a practi cal
consi derati on. Sympatheti c blockade is most commonl y performed at the major gangli a,
parti cul arl y the stell ate, cel iac, and l umbar pl exus. These blockades often requi re mul tipl e
injecti ons and are techni cal l y more di ffi cul t than axi al anesthesia, but they do offer advantages in
certai n cl inical si tuati ons.
The somati c nerves of the chest emerge from thei r respecti ve intervertebral forami na and pass
through the narrow, triangular-shaped paravertebral space. In thi s tri angl e, they gi ve off the
sympatheti c branch and al so a smal l dorsal branch, whi ch provi des sensation to the midl i ne of the
back. The mai n trunks then pass i nto the intercostal groove along the ventral caudad surface of
each ri b. An artery and vei n travel al ong wi th each of these nerves in the groove under the
protecti on of the overhangi ng external edge of the ri b. The fasciae of the i nternal and external
intercostal muscl es provi de interi or and external borders of thi s i ntercostal groove. As the nerves
travel beyond the mi daxil l ary li ne, they gi ve off a l ateral sensory branch whi l e the mai n trunk
conti nues on to the anteri or abdomi nal wal l to provi de sensory and motor innervati on for the trunk
and abdomen down to the l evel of the pubis. The intercostal groove becomes much less wel l
defined anteri or to the mi daxil l ary li ne, and the nerve begi ns to move away from i ts protected
positi on. The lowermost i ntercostal nerve (the twel fth) i s much l ess cl osel y appli ed to its
accompanying rib and i s not as easy to i dentify and anesthetize usi ng a cl assic intercostal
bl ockade techni que. The upper l umbar roots form the i li oingui nal nerves, which pass laterall y
within the muscl es of the abdominal wal l at the level of the il i ac crest and eventual l y move
anteriorl y to provi de i nnervation of the groi n regi on as the il i oi ngui nal nerves.
The anatomi c basi s for separate sympatheti c anesthesi a is the earl y separation of sympatheti c
fibers. The whi te rami communi cantes join the sympatheti c gangl ia, whi ch l ie anteriorly on each
si de of the vertebral bodi es. These pregangl i onic fibers

of the sympatheti c system usual ly ari se only from the fi rst thoracic through the second l umbar
segments. The spinal gangl i a formed by these fi bers consti tute the sympathetic trunks, whi ch
P.733
extend upward into the neck and caudad along the lumbar spi ne. They give termi nal sympatheti c
branches to al l the areas of the body. The sympatheti c i nnervati on of the head and the l ower
extremi ti es i s deri ved from fi bers that ori ginate from the spi nal cord, join sympathetic trunks, and
then pass cephalad or caudad al ong the chai n of gangl ia before reaching thei r target organs.
Segmental sympatheti c innervati on of the body from the cervi cal to the sacral roots i s provi ded by
postgangl i onic nerves departi ng from the chai ns (the gray rami communi cantes), whi ch rejoin the
somati c nerves earl y i n their course. In the head (where motor and sensory i nnervati on i s by
cranial nerves), the sympathetic fi bers reach thei r end organs by travel i ng with the arteri al
vascul ar suppl y. The sympatheti c gangli a i n the neck l i e al ong the l ateral border of the rel atively
flat vertebral bodies. In the chest, the vertebral bodi es become more rounded, and the chai n of
gangli a li es more posteri orly on the l ateral si de of the vertebral body near the head of each ri b. In
the abdomen and pel vi s, the sympathetic chai ns begi n to move anteriorly and l ie on the ventral
surface of the vertebral bodi es and thus are more wi del y separated from their respecti ve somati c
nerves.
Intercostal Nerve Blockade
Anesthesi a of the i ntercostal nerves provides both motor and sensory anesthesi a of the abdominal
wal l from the xi phoi d to the pubi s. The si xth to el eventh ri bs are usual l y easi l y i denti fied, and
thei r accompanyi ng nerves are rel i abl y bl ocked by i njecti ons al ong the easil y pal pated sharp
posterior angul ati on of the ri bs, whi ch occurs between 5 and 7 cm from the mi dl ine in the back.
Ribs above the fifth are difficult to pal pate because of the overl yi ng scapul a and paraspi nous
muscles and are therefore most easi l y blocked usi ng the paravertebral technique. Establ i shi ng fi ve
or six levels of intercostal nerve bl ockade i s a useful anesthetic procedure for provi ding anal gesia
and motor rel axati on for upper abdomi nal procedures such as chol ecystectomy and gastric
surgery. Uni lateral blockade of these nerves i s a useful treatment for the pain of rib fracture and
al so serves to reduce postoperati ve analgesi a requi rements in pati ents wi th subcostal i nci sions.
Several segments must be bl ocked i n each of these appl icati ons because of the overl ap of the
intercostal nerves. Thi s techni que i s al so useful i n reduci ng the pai n associ ated wi th the inserti on
of chest tubes or percutaneous bi l i ary drai nage procedures.
1. For the performance of i ntercostal bl ockade, the patient may be in the l ateral , si tti ng, or
prone posi tion. For operati ve anesthesi a, the prone positi on i s most practical. A pillow is
pl aced under the abdomen to provi de sli ght flexi on of the thoraci c spi ne. The arms are
draped over the edge of the stretcher or operati ng tabl e so that the scapul a fal l s away
lateral l y from the mi dli ne. The anesthesiol ogi st stands at the patient' s side. Most
anesthesiol ogi sts prefer to stand on the side that all ows their domi nant hand to hol d the
syri nge at the caudad end of the patient.
2. The spinous processes in the midl i ne from T6 through T12 are marked (Fi g. 26-19). The ribs
are then i denti fi ed al ong the l ine of thei r most extreme posteri or angulation. For the twelfth
ri b, thi s i s usual l y 7 cm from the midl i ne. At the level of the si xth ri b, thi s posteri or
angul ati on i s best appreciated somewhat more medially, usual ly 5 cm from the mi dl ine.
These two ri bs are marked fi rst at thei r inferior borders, and a l ine i s drawn between these
two points. The rest of the ri bs between them are identi fi ed, and a mark i s pl aced on the
inferi or border of each rib al ong the angled parasagi ttal pl ane i denti fi ed by the fi rst l ine
between the si xth and twel fth ribs.
3. After asepti c preparati on, sedati on and anal gesi a are provi ded for the pati ent, and a ski n
wheal is rai sed at each mark.
4. The ri bs are bl ocked starti ng with the lowermost and movi ng upward.
5. Starti ng with the l owest ri b on the si de cl osest to the anesthesi ol ogi st, the i ndex fi nger of
the cephal ad hand is pl aced on the skin above the identi fyi ng mark; this finger shoul d l i e
immedi ately over the mi dpoi nt of the ri b. The skin i s then retracted i n a cephal ad di recti on,
so that the previ ous mark now li es over the ri b i tsel f, somewhat toward the inferior side. The
anesthesiol ogi st' s other hand i nserts a 22-gauge, 3.75-cm needl e directl y onto the rib. Thi s
needle is attached to a 10-mL syringe fi ll ed with l ocal anestheti c. The syri nge and needle are
hel d in such a way that they mai ntai n a constant 10-degree cephal ad angulati on.
6. Once the needle is safely parked on the dorsal surface of the rib, the cephal ad hand
rel eases the tensi on on the ski n and takes control of the needl e and syringe (Fi g. 26-20).
Thi s i s done by pl aci ng the ul nar border of the hand fi rml y agai nst the ski n and grasping the
hub of the needl e fi rml y between the thumb and i ndex fi nger. The middl e fi nger of thi s hand
rests along the shaft of the needl e to provi de gui dance. Once the syri nge i s fi rml y gri pped by
the cephal ad hand, the fi ngers of the

caudad hand are pl aced i n an injecti on positi on, ei ther i n the rings of a three-ri ng syri nge
or on the pl unger of a strai ght syringe.
7. The needl e and syri nge are then rai sed sl i ghtly off the bone and walked in a caudad directi on
unti l they pass bel ow the i nferi or border of the ri b. The entire needl e and syri nge uni t is
kept at a 10-degree cephal ad angl e to the ri b at al l ti mes. As i t passes the i nferi or border,
the needl e is advanced 4 to 6 mm under the rib, wi th the needl e actual l y pointi ng sl i ghtl y
cephal ad into the i ntercostal groove.
8. Once i n the groove, aspi rati on i s performed, and 3 to 5 mL of local anestheti c sol uti on i s
injected.
9. As soon as the injecti on i s compl ete, the needl e i s wi thdrawn from the groove and moved
cephal ad and parked agai n on the safe dorsal surface of the ri b. The fingers of the caudad
hand are then removed from the injecti on posi tion and assume control of the syri nge again.
The cephalad hand now reli nqui shes control and i s moved up to the next ri b to repeat thi s
cycl i c process.
10. The ri bs on the opposi te side are bl ocked i n a si mi l ar manner. Thi s can be done wi th the
anesthesiol ogi st standi ng on the same si de and reachi ng across the back, or by moving to
the opposi te si de of the pati ent.
11. Intercostal nerve bl ockades can be suppl emented by a number of somatic paravertebral
nerve bl ockades or sympatheti c blockade of the cel i ac pl exus. Care should be taken to adjust
the total dose of drug in such combi nations of techniques so that the maxi mal recommended
amounts are not exceeded.
P.734
FIGURE 26-19. Landmarks for intercostal bl ockade. The inferi or borders of the ribs are
identi fi ed at their most promi nent poi nts on the back. The marks then usual l y l i e al ong a li ne
that angl es sl i ghtly medi all y from the twelfth to the si xth ri b. The tri angl e drawn between the
twel fth ri bs and thei r spi nous processes i s used for the cel i ac pl exus bl ockade. (Reproduced
Despi te frequent concern about the i nci dence of pneumothorax wi th intercostal bl ockade, thi s
compl i cati on i s rare i n experienced hands. This depends pri maril y on mai ntai ni ng strict safety
features of the descri bed techni que. Emphasi s shoul d be pl aced on absolute control of the syringe
and needl e at al l ti mes, parti cularly during the i njecti on.
A common compl icati on i s rel ated to the sedation requi red to perform thi s bl ockade i n the prone
positi on. Overdose can lead to ai rway obstructi on and respi ratory depressi on i n the prone posi tion.
Attenti on must be pai d to the pati ent' s mental status because thi s blockade produces the hi ghest
bl ood level s of l ocal anesthetics when compared wi th any other regional anestheti c technique.
When the bl ockade i s performed for postoperati ve pai n rel i ef, the dose shoul d be reduced to
0.25% bupi vacaine or ropi vacai ne to minimize the chance for toxi ci ty.
It i s possibl e to produce partial spi nal or epi dural anesthesi a i f the i njecti on i s made cl ose to the
mi dli ne and the anestheti c tracks al ong a dural sl eeve to the epi dural or subarachnoi d space.
Respi ratory i nsuffici ency can al so be seen if the i ntercostal muscles are bl ocked i n a pati ent who
depends on them for ventil ati on. Pati ents wi th chroni c obstructive di sease with ineffecti ve
di aphragm motion are not good candi dates for thi s techni que.
Paravertebral Blockade
The upper fi ve ri bs are more difficult to pal pate l ateral l y, and blockade of their associ ated
intercostal nerves is best performed wi th a paravertebral i njecti on. This approach i s technicall y
more di ffi cul t and has sl i ghtl y greater potential for compl icati ons because of the proxi mi ty of the
lung and of the i ntervertebral foramina. Anatomicall y, the i njecti on i s made into the triangl e
formed by the i ntervertebral body, the pl eura, and the pl ane of the transverse processes (Fi g. 26-
21). The intervertebral foramina at each l evel li e between the transverse processes and
FIGURE 26-20. Hand and needl e posi ti ons for i ntercostal bl ockade. The depth of the needl e
is controll ed by the hand resti ng on the back. The other hand i njects sol ution when the
needle is under the ri b, but that i s the onl y functi on performed whi le the needl e is near the
pl eura. (Reproduced wi th permission from Mul roy M: Handbook of Regi onal Anesthesi a.
Phi ladelphi a, Lippi ncott Will i ams & Wil ki ns, 2002.)
approxi mately 2 cm anterior to the pl ane formed by the transverse processes i n their associ ated
fasciae. At thi s poi nt, the sympatheti c gangl ia l i e cl ose to the somati c nerves, and coi nci dental
sympatheti c blockade is usual l y attai ned. Thi s is al so related to the i njection of l arger vol umes of
local anestheti c, whi ch is requi red because locati on of the nerve i s l ess reli able with thi s
technique. Neverthel ess, i t i s a useful techni que for segmental anesthesi a, particul arl y of the
upper thoraci c segments. It i s al so useful i f a more proxi mal bl ockade is needed, such as to
rel ieve the pai n of herpes zoster or of a proxi mal ri b fracture. Lumbar paravertebral bl ockade has
been used successful l y for outpatient hernia operations, providi ng si gni fi cant postoperati ve
anal gesi a.

The paravertebral approach vari es somewhat, dependi ng on the spi nal level . In the upper thoracic
spi ne, the transverse process i s l ocated l ateral to the spinous process of the vertebral body above
it. In the lower thoraci c spine, the spinous processes are less steepl y angl ed, so that the el eventh
and twelfth spi nous processes l i e between the associ ated transverse processes. In the l umbar
regi on, the spi nous processes are strai ght, and the transverse processes l i e opposite thei r own
respective spinous process. Thus, paravertebral bl ockade i n the upper thoraci c regi on i s performed
at each l evel by i dentifyi ng the spi nous process of the vertebra above the level to be bl ocked; i n
the lumbar regi on, the spi nous process of the l evel to be bl ocked is used to l ocate the transverse
process.
1. Thi s bl ockade i s al so performed i n the si tti ng or prone posi ti on, wi th a pi l l ow under the
pati ent' s abdomen to produce fl exi on of the thoraci c and l umbar spine. The spi nous
processes i n the regi on to be bl ocked are marked. These can be i dentified by counting
upward from the fourth l umbar process (whi ch usuall y li es just at or above the li ne joi ni ng
the two i l i ac crests) or by counti ng down from the seventh cervi cal process (whi ch i s the
most prominent i n the cervi cal regi on).
2. Transverse l i nes are drawn across the cephal ad border of the spi nous processes and
extended laterall y to overl i e the transverse process (~1 to 4 cm). In the l umbar regi on, the
P.735
FIGURE 26-21. Paravertebral bl ockade. As it exits the i ntervertebral foramen, the thoraci c
somati c nerve enters a smal l triangul ar space formed by the vertebral body, the pl ane of the
transverse process, and the pleura. Medi al di rection of the needl e is obvi ously i mportant in
reduci ng the chance of a pneumothorax.
li nes overl i e the transverse process of the associ ated vertebra. In the thoraci c regi on, they
indicate the transverse process of the vertebral body i mmedi atel y bel ow the associ ated
spi nous process. Fi nall y, a vertical li ne is drawn paral l el to the spine 3 to 4 cm lateral to i t,
joi ni ng the transverse l i nes from the spi nous processes. For a diagnosti c bl ockade, a single
nerve may need to be anesthetized. For pain control , several l evels must be i dentified. The
injecti on of at least three segments (as in i ntercostal bl ockade) i s required to produce
rel iabl e segmental bl ockade because of sensory overl ap.
3. After asepti c ski n preparation, skin wheal s are rai sed at the intersections of the verti cal and
transverse l ines.
4. A 22-gauge needl e is i ntroduced through the ski n wheal i n the sagi ttal plane and directed
sl i ghtly cephal ad to contact the transverse process. A 7.5-cm needl e i s usuall y requi red in
the average pati ent, and the transverse process l i es between 3 and 5 cm from the ski n.
Gentl e cephalad or caudad expl oration may be requi red to i denti fy the bone. The depth of
the transverse process i s careful l y noted on the needl e shaft.
5. The needl e i s now wi thdrawn from the transverse process and walked inferiorl y to pass
bel ow i ts caudad edge. Thi s usual l y requi res more perpendi cul ar di rection rel ati ve to the
ski n. The needle is advanced 2 cm below the transverse process and angled sl ightly medi al
to attempt to contact the vertebral body. Nerve responses are not sought unless a neurolyti c
injecti on i s planned. When the needl e has entered the paravertebral space, 5 to 10 mL of
local anestheti c sol ution is i njected after careful aspi rati on.
The compli cati on of pneumothorax i s more l i kel y i n the thoraci c regi on wi th a paravertebral
technique than with intercostal blockade. The needl e shoul d be di rected medial ly as it passes
bel ow the transverse process and never more than 2 cm beyond the transverse process (see Fi g.
26-21). If cough or chest pain occurs, a chest radi ograph shoul d be performed to rul e out
pneumothorax. Subarachnoi d i njecti on i s also more li kel y in the thoraci c area because of the
extensi on of the dural sleeves to the l evel of the i ntervertebral forami na. Careful aspi ration is
important but may not prevent the unintenti onal i njecti on of l ocal anesthetic i nto a subdural
pocket. Total spi nal anesthesi a can resul t wi th a 5- to 10-mL i njection. Systemic toxi city i s also a
possi bi li ty because of the need for rel ati vel y large vol umes of l ocal anesthetic. Attention must be
pai d to the total mi l l igram dose injected. The vol ume requi red for each l evel obviousl y l i mi ts the
concentrations that can be used and the total number of l evel s that can be bl ocked. If l umbar
paravertebral injecti ons are combined wi th i ntercostal s, the concentrati on and total vol ume for
both bl ockades may have to be reduced.
Intrapleural Anesthesia
Upper abdomi nal anal gesi a can al so be obtai ned by i nserti ng an epidural catheter i nto the
intrapl eural space for i njection or i nfusion of local anestheti c. The anestheti c appears to di ffuse
through the pari etal pl eura onto the i ntercostal nerves and produces anesthesia si mi lar to that
provi ded by injecti on of mul ti pl e i ntercostal nerve blocks. It may also act on the sympatheti c
nerves by di ffusi on to the gangl i a l yi ng al ong the anteri or vertebral borders.
1. As with intercostal bl ock, the techni que can be performed wi th the pati ent i n the prone,
lateral , or sitti ng posi ti on.
2. The seventh or eighth i ntercostal space is i dentified 8 to 10 cm from the mi dl ine and marked
at the upper border of the l ower ri b.
3. A skin wheal i s made at this si te, and a bl unt-ti pped epi dural needl e (e.g., Touhy) i s
inserted with the bevel di rected cephalad and advanced over the inferior rib in a slightly
medial and cephal ad angle through the intercostal muscl es. Once in the i ntercostal layers,
the styl et is removed, and an ai r-fi l l ed 5-mL gl ass syringe i s attached.
4. The needl e i s advanced farther unti l the pari etal pl eura i s punctured, si gnal ed by a negati ve
pressure that moves the pl unger of the syringe forward. The syringe i s removed, and a
standard epi dural catheter i s threaded 5 to 6 cm beyond the ti p. Aspi rati on i s performed to
excl ude perforation of the l ung or a bl ood vessel.
5. Twenty mil l il i ter of 0.5% bupivacaine or ropi vacai ne with epinephrine i s i njected i nto the
pl eural space, and the catheter i s careful ly taped to the skin. Rei njecti on i s requi red every 3
to 6 hours, or a constant infusi on of 0.25% bupivacaine (0.125 mL/kg
-1
/h
-1
) or 0.2%
ropivacai ne can be i ni ti ated.
There have been several enthusiasti c reports of success wi th thi s techni que, but l i mi tati ons have
been descri bed. Pai n rel i ef i s usuall y rel iabl e, and respi ratory depressi on i s not a probl em.
However, the durati on i s short enough that l arge quanti ties of l ocal anestheti c are required to
maintai n anal gesia, and systemi c toxi city has been reported i n 1.3% of pati ents.
15
The i nci dence
of pneumothorax (averagi ng 2%) i s not inconsequenti al, especi al l y wi th first attempts. Puncture of
the lung al so occurs, apparentl y wi th a hi gher i nci dence if a loss-of-resistance technique is used
rather than the passi ve i dentificati on process descri bed earl ier. A major li mitati on i s the unil ateral
anal gesi a, which l imits thi s technique to procedures such as chol ecystectomy and nephrectomy,
ri b fracture, and treatment of herpeti c pai n. Loss of l ocal anestheti c soluti on to thoracostomy
drainage makes thi s technique unrel i abl e for thoracotomy pai n.
Ilioinguinal Blockade
The L1 nerve root (occasi onal l y joi ned by a branch of the T12 root) provi des sensory i nnervati on
to the l owermost porti on of the abdomi nal wal l and the groi n by means of i ts superi or
il i ohypogastri c branch and its i nferior il i oi ngui nal branch. These nerves travel in a path simil ar to
that of the intercostal nerves, but without the conveni ent bony l andmark of a rib to identi fy them.
Nevertheless, they can be anestheti zed rel ati vel y easil y in the groi n because of their relationshi p
to the anterosuperi or

il i ac spine. Anesthesi a of these two nerves is useful i n providi ng l ower abdominal wal l anesthesi a
to suppl ement i ntercostal bl ockade. It i s more commonly used to produce fi eld anesthesi a for
ingui nal herni a repair surgery. Anesthesia of these nerves alone i s not suffi ci ent for herni a repai r;
subcutaneous i nfil trati on i s also necessary.
1. The pati ent l i es i n a supine posi tion, and the anterosuperi or il i ac spi ne i s i dentifi ed. An X
is pl aced on the skin 2.5 cm medial to the spi ne and sli ghtl y cephal ad.
2. After asepti c preparati on, a ski n wheal is raised at the X.
3. A 2.5-cm, 22-gauge needl e is i ntroduced through the X and

di rected perpendicular to the ski n unti l it reaches the fascia of the external obl i que muscle.
A wal l of local anestheti c sol ution is then l ai d down between thi s poi nt and the il i ac spi ne
and al so opposi te the mark on an imagi nary l i ne extendi ng toward the umbil i cus. Injecti ons
are made at and below the level of the external obl i que, wi th some sol uti on i njected at the
level of the i nternal obl i que. A total of 10 to 15 mL of anestheti c i s usuall y requi red.
4. If fi eld anesthesia for i ngui nal herni a repai r i s requi red, further subcutaneous i nfi ltration of
anesthetic i s performed al ong the ski n crease of the groin and al ong the i magi nary li ne
extending to the umbil i cus. Thi s produces a tri angul ar-shaped area of ski n anesthesi a. For
hernia operati ons, further anesthesi a of the spermatic cord i s required. Thi s i s usual ly
performed by l ocal i njecti ons i n the area of the cord and the i nternal ri ng. Al though
epi nephri ne is useful i n the subcutaneous and il i oi ngui nal bl ockade, i t shoul d be avoi ded i n
solutions used to anestheti ze the base of the peni s or the spermati c cord (see Penil e
Bl ockade secti on). Further anesthesi a of the groi n area and bel ow can be obtai ned by
bl ockade of the femoral and l ateral femoral cutaneous nerves, but thi s may result i n
P.736
P.737
unwanted weakness of the leg muscul ature, whi ch may prevent ambul ati on.
Compli cati ons of this procedure are extremel y rare. Hematoma formation and unwanted motor
bl ockade of the femoral nerve are possi bl e, but rare. More commonl y, anesthesia produced by thi s
technique i s i nadequate for herni a repair because the pati ent i s stil l able to percei ve the
di scomfort of peri toneal tracti on. Administrati on of l ocal anesthesi a by the surgeon or systemi c
opi oi ds may be requi red.
P eni l e Bl ockade
If surgery i s confi ned to the peni s (e.g., ci rcumcisi on, urethral procedures), the organ should be
bl ocked wi th simpl e local i nfil trati on. Two skin wheal s are rai sed at the dorsal base of the peni s,
one on each si de just below and medi al to the pubi c spine. A 25-gauge, 3.75-cm needl e i s
introduced on each si de, and 5 mL of anesthetic i s deposi ted superfi ci al l y and deep al ong the
l ower border of the pubi c ramus to anestheti ze the dorsal nerve. An additi onal 5 mL i s i nfi l trated
in the subcutaneous ti ssue around the undersi de of the shaft to produce a compl ete ri ng of
anesthetic. A larger needl e or a second i njecti on si te may be needed to compl ete the ri ng. Twenty
to 25 mL of 0.75% li docai ne or 0.25% bupi vacai ne usual l y suffi ces. Epinephrine i s stri ctl y avoi ded.
Sympat het i c Bl ockade
Stellate Ganglion
Separate bl ockade of the sympathetic fibers of the upper extremity and head can be achi eved by a
si ngl e i njection of a local anestheti c on the stel late gangli on. The gangl ion is the l arge fusi on of
the fi rst thoraci c sympatheti c gangl ion wi th the l ower cervical gangli on on each si de, and i t l ies on
the general ly fl at l ateral border of the vertebral body of C7. Al l the fi bers to the mi ddl e and
superi or cervi cal gangl i a pass through thi s l owermost col lection and thus can be anesthetized wi th
a si ngl e i njecti on. Although techni call y si mpl e, the location of thi s gangli on near the caroti d
artery, the vertebral artery, and the pl eura makes thi s a chal l engi ng bl ockade. It i s useful in
provi ding pain rel i ef for sympatheti c dystrophi es of the upper arm. Stel l ate gangli on bl ockade may
rel ieve the pai n of acute herpes zoster i nfection of the head or neck regi on. It has al so been
advocated as a means of reduci ng post-thoracotomy pai n by bl ocki ng the sympatheti c sensory
fibers to the pl eural cavi ty. The procedure for bl ockade fol l ows:
1. The pati ent i s pl aced i n a supi ne posi ti on wi th a smal l towel or pil l ow under the neck, and
the arms are hel d at the si de.
2. The medi al border of the sternocl eidomastoid muscl e on the involved side i s marked, as is
the level of the cri coi d carti l age. Gentl e pal pati on approxi matel y 2 cm l ateral to the carti l age
often reveals the anteri or tubercl e of the transverse process of the si xth cervical vertebra
(Chassaignac' s tubercl e). A ci rcl e i s marked over thi s tubercle, and an X is pl aced 1.5 to 2
cm caudad to thi s mark at the same distance from the mi dli ne. Thi s X should overl ie the
tubercle of the seventh cervical vertebra and should fal l at the medi al border of the
sternocl ei domastoid muscle body and approxi matel y two fi ngerbreadths above the cl avi cl e
itsel f.
3. A skin wheal i s made at the X after asepti c ski n preparation.
4. Wi th the i ndex and mi ddl e finger of one hand, the sternocl ei domastoi d muscl e and the
carotid sheath are retracted l ateral l y (Fi g. 26-22). A 22- or 25-gauge, 3.75-cm needl e i s
introduced through the X and passed di rectl y posterior unti l i t rests on bone. A paresthesia
of the brachi al pl exus impli es that the needle is too far laterall y and has passed beyond the
transverse process. It may have to be readjusted sl i ghtl y more medi al l y and perhaps more
cephal ad or caudad.
5. Once bone i s contacted, the needl e is withdrawn a few mi l li meters, and careful aspi ration is
performed to rul e out contact with the vertebral artery. A 2-mL test dose is i njected to
eval uate further an unrecognized i ntravascul ar positi on. The pati ent's mental status must be
cl osel y observed.
6. If no change occurs, a total of 10 mL of l ocal anestheti c can be injected i ncrementall y with
frequent aspi ration. One percent l idocai ne or 0.25% bupi vacai ne or their equi val ents are
more than adequate to produce anesthesi a of the sympatheti c nerves.
7. Onset of sympathectomy i s usuall y, but not rel i abl y, i ndi cated by the appearance of a
Horner' s syndrome on the ipsi lateral si de. Ptosi s, miosi s, and anhydrosi s usual l y devel op
within 10 mi nutes, as wel l as vasodi l atati on i n the arm. Nasal congesti on i s another common
si gn usuall y associ ated wi th Horner' s syndrome.
There are several potential compli cati ons of stel l ate gangl i on bl ockade. The pl eura can be
punctured, wi th resulti ng pneumothorax. Intravascul ar i njecti on i s the most seri ous compli cati on
because of the proxi mi ty of the vertebral artery to the site of i njecti on. Careful aspi ration and
incremental injecti ons are essenti al. Only a few mi ll i grams of l ocal anestheti c is requi red to
produce cerebral symptoms when i njected directl y i nto the vertebral ci rcul ati on. Cardiovascular
changes are possibl e wi th the loss of the cardiac accel erator fi bers from the cervi cal sympatheti c
gangli a. Thi s i s particul arl y a probl em if bil ateral bl ockade i s performed, a procedure rarel y
indicated. Hoarseness from recurrent laryngeal nerve paralysi s i s a mi nor but troubl esome si de
effect. Somatic anesthesia of the brachial pl exus nerves can be produced by i njecti on behi nd the
l evel of the tubercl e, and phreni c nerve paral ysi s has al so been reported. Subarachnoid injecti on
is also a possibi l ity if the needl e i s mi splaced. The cl ose associ ati on of so many vi tal structures
has di scouraged the use of neurol ytic agents i n the regi on of the stel l ate gangli on.
FIGURE 26-22. Stel l ate gangl ion blockade. The sternoclei domastoi d muscl e and the caroti d
sheath are retracted l ateral l y with one hand whi l e the needl e i s introduced directl y onto the
lateral border of the seventh vertebral body, just medi al to the transverse process. The
vertebral artery passes posteriorl y at thi s level to enter i ts canal i n the transverse process,
but here i t l i es near the level of intended injecti on. After contacti ng bone, the needl e i s
withdrawn sl i ghtly and careful aspi rati on i s performed before i ncremental injecti on.
(Reproduced wi th permi ssi on from Mulroy M: Handbook of Regional Anesthesi a. Phil adel phi a,
Lippi ncott Wi ll i ams & Wi l ki ns, 2002.)
Celiac Plexus
The thoracic sympathetic gangl i a send branches anteri orl y that merge as greater and l esser
spl anchni c nerves to pass below the diaphragm and around the aorta to coal esce i n a diffuse
peri aorti c supplementary sympatheti c gangli on known as the cel iac pl exus. This extensi ve network
is usual l y l ocated at the l evel of the first lumbar vertebra i n the retroperi toneal space, along the
aorta at the l evel of the origi n of the cel i ac artery. Fi bers from thi s gangli on send postgangli oni c
innervati on to al l the i ntraabdomi nal organs and appear to carry pai n sensation from many of the
intraperi toneal organs such as the pancreas and l iver. Injecti on into thi s retroperitoneal space
al lows anestheti c sol ution to di ffuse around the gangl i a and the spl anchni c nerves to provi de
bl ockade of these fibers. Thi s bl ockade produces suppl ementary i ntraabdomi nal anesthesi a when
used in conjuncti on wi th i ntercostal blockade or general anesthesi a. It i s more commonl y appli ed
as a neurolyti c sympathetic blockade for the rel ief of pain from malignancy of the pancreas, liver,
or other upper abdomi nal organs.
1. As with intercostal bl ockade, the patient i s pl aced i n the prone posi ti on with the thoraci c
spi ne flexed by the use of a pi l l ow under the abdomen.
2. The spinous processes of the twelfth thoraci c and the first lumbar vertebral bodies are
identi fi ed and marked along their enti re extent. The twel fth ri b i s l i kewi se identi fi ed and
marked 7 cm from the midl i ne. A li ne is drawn between the twelfth ribs on each si de, usual ly
crossing the mi dl ine at the level of the spi nous process of the L1 vertebra. Lines are also
drawn from the spinous process of the twel fth thoracic vertebra to the poi nts on these ri bs
on both si des. The net resul t is a shal low triangl e, with the spi nous process of the twel fth
vertebra at its apex (see Fi g. 26-19).
3. Ski n wheal s are raised bi laterall y at the marks along the ri bs after aseptic ski n preparati on.
Deeper i nfi l trati on of l ocal anestheti c wi th a 22-gauge needl e is often helpful i n i mprovi ng
patient tol erance of thi s procedure.
4. On each si de, a 12.5-cm, 22- or 20-gauge needl e is i ntroduced through the ski n wheal s and
advanced anteri orl y and medi al l y and cephal ad al ong the two l i nes of the tri angl e that was
previ ously drawn (Fi g. 26-23). The needl e shoul d be passed at approximatel y a 45-degree
angle anteri orl y so that it wi l l contact the l ateral border of the vertebral body of L1 at a
depth of approximatel y 5 cm from the ski n. (The twelfth spi nous process partial ly overl ies
the L1 vertebral body.)
5. When contact wi th a vertebral body i s made, the needl e i s wi thdrawn several centi meters,
and the angl e of i nserti on i s steepened so that it advances more anteriorl y wi th subsequent
passage, i n the hope that it wi l l walk off the anterior border of the vertebral body. The
peri osteum may be encountered several ti mes during thi s attempt and shoul d always be
pal pated gently because of the associ ated di scomfort. Intravenous sedati on may be requi red
for tol erance of thi s bl ockade, although i t must be kept to a mi ni mum if evaluati on of a
di agnosti c pai n blockade i s desi red.
6. Once the anterior border of the vertebral body i s reached, the needl e is advanced 2 to 3 cm
beyond thi s, and careful aspirati on i s performed. On the l eft side, advancement shoul d be
halted whenever aorti c pul sati on i s appreci ated. If the artery is uni ntenti onal l y

punctured, the needl e shoul d be withdrawn sl i ghtl y and cl eared i mmedi atel y of bl ood. On the
ri ght side, the needl e can often be advanced 1 to 2 cm farther than the needle on the l eft
si de.
7. If radi ographi c confi rmati on i s desi red, it i s obtained at thi s poi nt, before injecti on of the
anesthetic. The bony l andmarks themsel ves are usual ly suffi ci ent to i denti fy the
retroperi toneal space anteri or to the fi rst lumbar vertebral body. If neurol yti c agents are to
be used or i f the anatomy i s di ffi cul t, fl uroscopi c confi rmati on i s desi rable.
8. Careful aspiration is performed, and a test dose i s i njected on each si de to rul e out
P.738
subarachnoi d or intravascul ar i njecti on.
9. A l arge volume of l ocal anestheti c sol ution is requi red. Twenty to 25 mL of 0.75% l idocai ne
or 0.25% bupi vacai ne i s usual l y adequate.
10. The most rel iabl e si gn of successful anesthesia i s the disappearance of pai n in pati ents or
the appearance of hypotensi on i n normal pati ents. Pati ents with pai n must remain supi ne for
several hours and should have appropri ate i v fl ui d suppl ementati on to avoi d orthostati c
hypotensi on. Gradual ambul ati on i s mandatory.
Hypotensi on i s the most common compli cati on of cel i ac pl exus bl ockade. It can be reduced by the
administrati on of 1L of bal anced sal t sol ution before performi ng the blockade. The most seri ous
compl i cati on i s the development of paral ysi s from unrecognized subarachnoi d i njecti on of a
neurol yti c drug. Radi ographi c confirmation of needle location is advi sabl e before i njection of any
neurol yti c drug. Even wi th correct pl acement of neurolyti c drugs, back pai n i s common and
patients may require i v opi oi ds. Thi s pai n can be reduced by di l uti ng the alcohol solution with an
equal vol ume of local anestheti c such that a total vol ume of 50 mL is i njected, consi sti ng of 25 mL
of al cohol and 25 mL of anestheti c. Even with this approach, di aphragmatic irritati on (mani fested
as shoul der pai n) i s not uncommon. The duration of pai n rel i ef i n the patient wi th chronic pai n i s
unpredictabl e but is often 2 to 6 months. The bl ockade can be repeated as often as necessary,
al though a trial diagnosti c bl ockade wi th a l ocal anesthetic agent i s indi cated before each use of
neurol yti c drugs. One mi nor si de effect of celi ac pl exus bl ockade i s the i ncreased peristal sis of the
gut produced by the shi ft i n the bal ance of the parasympathetic and sympathetic i nnervations.
Thi s may produce di arrhea wi thi n the fi rst 12 hours after the bl ockade and may be a source of
rel ief to pati ents on chronic opi oi d therapy for cancer pai n.
FIGURE 26-23. Cel i ac pl exus bl ockade. The surface landmarks are descri bed i n Fi gure 26-
19. The needles are advanced medi all y and superi orl y to contact the l ateral aspect of the
vertebral body. They are then advanced more anteri orly to pass beyond the vertebra to the
prevertebral space, where the greater and lesser spl anchni c nerves and thei r subsequent
cel iac plexus l ie. No attempt i s made to advance the needles to the anteri or aspect of the
vessel s. (Reproduced wi th permi ssi on from Mulroy M: Handbook of Regional Anesthesi a.
Phi ladelphi a, Lippi ncott Wi ll i ams & Wi l ki ns, 2002.)
Lumbar
As with the sympathetic i nnervation of the head and arm, the sympatheti c nerves to the lower
extremi ti es all exi t the cord above L2 and al l pass through a common gateway gangli on i n the
sympatheti c chai n at the L2 level . Thus, as i n the neck, sympathetic bl ockade of the lower
extremi ty can be achi eved by a single i njecti on of one gangl i on. The approach to this gangl i on i s
si mi l ar to paravertebral anesthesia, as di scussed previousl y, except that in the lumbar regi on, the
sympatheti c chai n l ies much more anteri or from the somati c nerves, and thus a cl ean separati on
of sympatheti c bl ockade from somati c bl ockade can be attai ned more easi l y.
As i n the upper extremi ty, lumbar sympathectomy can be used i n the treatment of sympatheti c
dystrophies. It is al so occasi onall y used i n pati ents wi th severe vascul ar di sease i n the lower
extremi ti es to gi ve some i ndi cati on of whether the patient would profi t from permanent chemi cal
or surgical sympathectomy.
1. The pati ent posi tion is si mi lar to that for cel i ac pl exus bl ockade. The patient l i es prone with
a pi l low under the l umbar spi ne.
2. The spinous processes of L2 and L3 are identifi ed and marked over their enti re course. A
hori zontal l i ne i s drawn through the mi dpoi nt of the L2 spi nous process and extended 5 cm
to ei ther si de of the mi dl i ne. An X is placed at this point, whi ch should overl ie the space
between the transverse process of the second and thi rd vertebrae or the caudad edge of the
second transverse process.
3. A skin wheal i s rai sed after aseptic ski n preparati on at each X.
4. A 10-cm needl e i s i ntroduced on each side through the X, angled 30 to 45 degrees
cephal ad, and advanced unti l i t contacts the transverse process (Fi g. 26-24).
5. The depth of the needle inserti on i s marked, and the needle is then withdrawn sl i ghtly,
angled caudad, and wal ked i nferi orl y off the transverse process (usual l y i n a di recti on
perpendi cul ar to the skin). A sl i ght medi al angul ati on i s used i n the hope of contacti ng the
vertebral

body bel ow the transverse process. The needl e is advanced 5 cm bel ow the depth of the
transverse process. If i t encounters a vertebral body, it i s angled sl i ghtly more anteriorl y to
wal k off that body at the desi red depth.
6. Once the needle is i n positi on, careful aspirati on i s performed, and a test dose i s i njected on
both si des. Ten mil l il i ter of l ocal anesthetic sol ution injected on each si de shoul d produce
sympatheti c blockade. Agai n, 1% li docai ne, 0.25% bupivacaine, or an equi valent
concentration is more than suffi cient to produce sympatheti c nerve bl ockade. If a neurol yti c
drug such as phenol i s used, confi rmation of needl e posi ti on by radi ography shoul d be
obtai ned. A sli ghtl y more caudad si te of injecti on may be more effecti ve for neurolyti c
bl ockade; i njection of smal l er quanti ties at several level s may be more appropriate for
neurol yti c drugs.
7. Care i s taken not to i nject anestheti c sol ution as the needle i s wi thdrawn, because thi s may
produce a somatic nerve bl ockade as the needl e passes the course of the L2 nerve root.
8. Vasodi l atati on and increase i n skin temperature should be noted wi thin the l eg i n 5 to 10
mi nutes. Thi s can be quanti tated objecti vely i f a skin temperature probe i s placed on the
foot before the start of the blockade.
P.739
Compli cati ons wi th thi s technique are unusual , but, agai n, intravascul ar or subarachnoi d injecti on
can be a potenti al probl em. The most troubl esome and frequent compli cati on is si multaneous
bl ockade of the L2 somatic nerve root. Thi s produces a band of anesthesi a across the l ateral and
anterior thi gh, whi ch may confuse the eval uati on of a di agnostic sympatheti c blockade.
Hypogastric Plexus
At the termi nal end of the prevertebral sympatheti c chai n is the superi or hypogastri c pl exus,
whi ch extends from the lower one-third of the fifth lumbar vertebral body to the upper thi rd of the
fi rst sacral vertebral body. Fi bers passi ng through thi s gangl ion provi de vi sceral sensati on to the
pel vi c organs. Mal i gnanci es in the pel vi s often produce chronic pai n syndromes that involve
transmi ssi on of nocicepti on through this gangl i on pl exus, and si gnifi cant rel i ef can be obtai ned by
the performance of neurolyti c bl ocks i n thi s area.
16

1. The pati ent i s placed i n the prone posi tion wi th a pi l l ow under the pel vi s to reduce the
lumbar l ordosi s.
2. The L4-5 intervertebral space i s i denti fi ed and marked, and a l i ne drawn at the mi dli ne of
this space. An X is then placed on the ski n 5 to 7 cm lateral to thi s interspace on both
si des.
3. Aseptic ski n preparati on i s performed, and a skin wheal rai sed at the X marks at each side.
4. Fi fteen-centi meter, 22-gauge needl es are then i ntroduced through the ski n wheals and
di rected medi all y. Both needl es are advanced at approximatel y a 45-degree angl e wi th a 30-
degree caudad defl ecti on to approach the anterolateral body of the L5-S1 space. If the L5
vertebral body i s encountered, the needl e is redirected more anteri orly. The use of
fluoroscopy and contrast dye documents the correct pl acement of the needl es just anteri or
to the L5-S1 intervertebral space.
5. After careful aspirati on to excl ude intravascul ar pl acement, anesthesi a can be obtai ned wi th
8 mL of 0.25% bupivacaine for a di agnosti c block. For neurol yti c procedures, an equal
volume of 10% phenol can be used on each side.
FIGURE 26-24. Lumbar sympathetic blockade. The needle i s fi rst pl aced on the transverse
process of L2 and then advanced bel ow it to pass 5 cm deeper. The needle can be angled
sl i ghtly medi al l y to contact the body of the vertebra; the sympathetic chai n l ies along the
anterior margi n of these bodi es. (Reproduced wi th permission from Mul roy M: Handbook of
The major ri sk of thi s block i s i ntravascular pl acement of the drug. The si de effects and
compl i cati ons of neurol ytic agents appl y here if they are used.
Lower Ext r emi t y
The nerves to the lower extremity are most easi l y bl ocked by the spi nal , caudal , or epi dural
techniques descri bed i n Chapter 25. There are occasi ons when anesthesi a by these routes i s
contrai ndi cated because of systemi c sepsis or coagul opathy, or when selective anesthesi a of one
leg or foot i s needed. Peri pheral nerve bl ockade i s possi bl e because the motor and sensory fi bers
to the l ower extremi ti es are somewhat si mil ar to those of the upper extremi ties i n that they form
a seri es of i ntertwi ned branching roots and divisi ons that are enclosed in a fasci al sheath before
they emerge as the termi nal nerves to the extremi ty. They can also be successful l y bl ocked by a
si ngl e i njection in one pl ane, although the anatomic landmarks i denti fyi ng this fasci al sheath are
not as clearl y defined as those i n the upper extremity. Because of this, the majori ty of lower
extremi ty bl ockades are performed more di stall y, where the nerves have al ready separated i nto
termi nal branches. Thus, i n addi ti on to the fasci al compartment approach (psoas bl ockade), there
are peri pheral approaches descri bed at the hi p, knee, and ankl e.
The nerves to the legs emerge from the roots of L2 through the thi rd sacral spi nal segments (Fi g.
26-25). The upper nerve roots from L2 to L4 form the lumbar plexus, whi ch then rami fi es
eventuall y to form the l ateral femoral cutaneous, femoral , and obturator nerves. These pri maril y
provi de sensori motor i nnervation of the upper l eg, although a branch of the femoral nerve
commonly extends al ong the medi al si de of the knee as far down as the bi g toe. A branch of thi s
lumbar pl exus, the l umbosacral trunk of L4 and L5, joi ns the sacral fibers to form the major trunks
of the large nerve of the posteri or thi gh and l ower l eg, the sciatic. The sci ati c nerve i s made up of
two mai n trunks, the ti bial and the common peroneal, whi ch di vi de just above the knee. As in the
brachial pl exus, the upper nerve roots emerge from thei r forami na i nto a compartment li ned by
the fasci ae of muscles anteri or and posteri or to it. In this case, the

quadratus lumborum i s posteri or, whi l e the posteri or fasci a of the psoas muscl e provi des the
anterior border of the compartment before the nerves move into the body of the muscl e. The
sacral roots have a simi lar envel ope except that the posteri or border i s the bone of the il i um.
P.740
The l umbar pl exus branches form their three termi nal nerves earl y. Each of these passes
anteriorl y and l ateral ly to ci rcl e around the pelvis and emerge anteriorl y in the groi n. The femoral
nerve becomes associ ated with the femoral artery in the area of the groin and passes under the
ingui nal li gament just l ateral to the artery. The l ateral femoral cutaneous nerve mi grates laterall y
earl y and passes under the i ngui nal l igament near the anterosuperior il i ac spi ne. The thi rd branch
of the lumbar plexus, the obturator, remains somewhat medial and posterior in the pel vi s and
emerges under the superi or ramus of the pubi s through the obturator foramen to suppl y motor
and sensory fi bers to the medi al thi gh and medi al border of the knee.
The branches of the sacral pl exus also travel l aterall y wi thin the pelvis before exiti ng posteriorly
through the sci ati c notch as the sci ati c nerve. This l argest nerve of the body i s actuall y the
conjunction of two trunks. The l ateral trunk forms from the roots of L4 through S2 and eventual l y
emerges as the common peroneal nerve. Other branches of L4 through S3 form the medial trunk,
eventuall y becomi ng the ti bi al nerve. These combi ned nerves exit through the sci ati c notch and
pass anteriorly to the pi riformi s muscl e between the ischi al tuberosi ty and the greater trochanter
of the femur. They curve caudad and descend the posteri or thi gh i mmedi atel y behind the femur.
After thei r bifurcation hi gh i n the popl i teal fossa, the peroneal nerve provides the motor and
sensory fi bers to the anteri or cal f and dorsum of the foot. The tibi al nerve remai ns posterior and
provi des sensati on to the cal f and sol e of the foot. There are three major branches that cross the
knee: the femoral , ti bial, and peroneal . By the time these nerves reach the ankl e, there are five
branches that cross thi s joi nt to provi de i nnervati on for the ski n and muscl es of the foot.
Psoas Compartment Blockade
The fasci al compartment of the l umbar pl exus i s more di ffi cul t to i denti fy than that of the brachi al
pl exus in the upper extremi ty and l i es much deeper beneath the ski n than i ts equi val ent i n the
neck (see Fi g. 26-25). Nevertheless, psoas compartment bl ockade is useful i f si ngle-injecti on
anesthesi a of the l eg i s desi red.
17

1. The pati ent i s placed i n the l ateral positi on. The spi nous processes of the l umbar vertebrae
and the posteri or superi or i li ac spi ne are identi fi ed, and a l i ne drawn paral l el to the spine
from the top of thi s i li ac spi ne (Fi g. 26-26). Another l i ne i s drawn perpendicular to thi s one
intersecting the L4 spi ne. This l i ne i s then trisected, and an X i s pl aced on the skin at the
juncti on of the l ateral thi rd and medi al two-thirds of the l ine.
2. After asepti c preparati on, a ski n wheal is raised at the X. A 10-cm needl e i s advanced
perpendi cul ar to the skin i n al l pl anes and passed through the muscles of the back. The
transverse process of the vertebral body is sought, whi ch may l ie at a depth of between 5
and 8 cm. Once the bone is contacted, the needle i s redi rected caudal l y and advanced 2 cm
further. Regardl ess of the depth of the bone from the ski n, the nerve roots shoul d l i e 2 cm
further. Although i n some patients the wel l -demarcated fasci al pl anes can identi fy the entry
into the perineural sheath, anesthesia i s more reli able if nerve responses are obtained. If
they are not obtai ned at a 2.5-cm depth beyond the bone, probing wi th the needle in a fan-
l i ke manner shoul d be performed i n a cephal ad-caudad pl ane (whi ch i s perpendi cul ar to the
known paths of the emergi ng nerves).
3. When a nerve response i s obtai ned, the needle i s fi xed i n posi ti on and careful aspi rati on and
FIGURE 26-25. Psoas compartment anatomy. The roots of the lumbar plexus emerge from
thei r forami na i nto a fasci al pl ane between the quadratus lumborum muscle posteriorly and
the psoas muscle anteriorl y. The ori gi n of the lumbosacral pl exus i s broader than the
correspondi ng brachi al pl exus i n the neck, and the l ower sacral roots cannot be easi ly
reached by a si ngl e i njecti on. (Reproduced wi th permission from Mul roy M: Handbook of
administrati on of a test dose are used to rule out i ntravascul ar or subarachnoid pl acement.
Thi rty-five to 45 mL of local anestheti c sol uti on i s usual ly required to fil l the sheath. Fi fteen
to 20 mi nutes may be required for spread of the anestheti c to al l the roots of the
lumbosacral plexus. It may take longer to produce anesthesi a of the caudad branches (the
l ower sacral fi bers that form the tibi al nerve), or they may not be anestheti zed at al l .
4. A catheter may be i nserted here, wi th the directi on of the bevel ideal ly l ateral and away
from the neuraxi al canal. Infusi ons provi de postoperati ve analgesi a for knee and hip
repl acement surgeri es.
Compli cati ons of this technique include hematoma in the muscl e sheath and retroperitoneal space
or the ki dney. Neuropathy of the nerves is possibl e. Uni ntended spread to the epidural or even
subarachnoi d space has al so been reported. Inadequate anesthesi a of some of the branches may
occur more frequently than these rare compli cati ons.
Anesthesia at the Level of the Hip
Many anesthesi ologists feel more confi dent when admi nisteri ng regi onal anesthesia i n the hi p
regi on when nerve responses are sought for each of the major nerves. Thi s technique i s
cumbersome and usually requires the pati ent to assume at least two separate positi ons for the
injecti ons. The anesthesi a requi res a l arger volume of anestheti c drug. Each of the four nerves
may be bl ocked sel ecti vel y on an individual basis. Anesthesi a of the l ateral femoral cutaneous
nerve is occasional ly used to provi de sensory anesthesi a for obtaining a ski n graft from the l ateral
thi gh. It can al so be bl ocked as a diagnosti c tool to i dentify cases of meralgi a parestheti ca. A
sci atic nerve blockade al one provides adequate anesthesi a for the sol e of the foot and l ower l eg.
Procedures on the knee requi re anesthesia of the femoral and the obturator nerves, al though
postoperative anal gesia of the knee can usual l y be provided by femoral nerve bl ock al one. Femoral
nerve bl ock provi des si gni fi cant postoperati ve analgesi a for the fi rst 18 hours after total knee
arthroplasty, and the use of a continuous techni que can faci l itate rehabil i tation.
18

Sciatic Nerve Blockade, Classic Posterior Approach
FIGURE 26-26. Psoas block. The nerves of the l umbar pl exus can be approached posteri orl y
by i nserti on of a needl e at a point lying l ateral to the L4 spi nous process, two thirds of the
way between a l ine drawn along the spinous processes themsel ves, and a parall el li ne
intersecting the posteri or superi or i li ac spi ne. (Repri nted wi th permi ssi on from Capdevi l l a X,
Macai re P, Dadure C, et al : Anesth Anal g 94:1606, 2003.)
1. The pati ent l i es wi th the si de to be bl ocked uppermost and rol ls sl i ghtl y anteri or, flexi ng the
knee so that the

ankl e of the i nvol ved side rests on top of the knee of the opposite si de (Fi g. 26-27). Thi s
positi on rotates the femur so that the trochanter i s more easil y pal pated and the muscl es
overlying the sciatic nerve become stretched.
2. The superi or aspect of the greater trochanter of the hi p i s marked wi th a circl e. A si mil ar
ci rcl e i s pl aced on the posterosuperi or i l i ac spi ne, and a l ine i s drawn between these two
poi nts.
3. A perpendicul ar l i ne i s drawn from the midpoi nt of thi s ori ginal li ne and extended 5 cm in
the caudad di rection. An X is marked at this poi nt. A thi rd l i ne drawn between the greater
trochanter and the sacral hiatus shoul d i ntersect thi s X. In the tal l er patient, the ori ginal
perpendi cul ar may need to be extended caudad to intersect wi th the third l ine, and the nerve
may l ie cl oser to the intersection of the second and third l i nes than to the ori ginal X.
4. A skin wheal i s rai sed at the X after asepti c ski n preparation.
5. A 10-cm needl e i s i ntroduced perpendi cul ar to the skin i n al l planes, and nerve responses of
the lower l eg and foot are sought. If they are not obtai ned at the ful l depth of the needl e,
the needl e is withdrawn to the skin and rei ntroduced i n a fanwise fashi on i n a path
perpendi cul ar to the imagi ned course of the nerve i n the hi p. Thi s path can usuall y be
visual i zed by fol lowi ng the muscular groove on the back of the thi gh up and into the
imagi ned positi on of the sciatic notch. The bony edges of the sciatic notch itself may be
encountered. These shoul d be noted, and the search conti nued. The nerve should li e at
approxi mately thi s depth as i t emerges from i nsi de the pel vi s. If l ocal izati on cannot be
obtai ned in the fi rst 10 minutes, the landmarks shoul d be reassessed.
6. When a nerve response i n the foot i s obtained, the needl e i s hel d immobi le, and 25 mL of
local anestheti c is i njected. A l ow concentrati on of local anestheti c may be needed i f several
nerves are to be bl ocked, whi ch requires a large total volume of anesthetic i n several
locations.
P.741
FIGURE 26-27. Sci ati c nerve bl ockade, cl assi c posteri or approach. With the pati ent i n the
lateral posi ti on and the hi p and knee fl exed, the muscl es overlying the sciatic nerve are
Sciatic Nerve Blockade, Supine Approach (Lithotomy). If a pati ent i s uncomfortable in the
lateral positi on or cannot be turned to the si de because of a fracture or pai n, the nerve can be
bl ocked wi th the patient i n the supi ne positi on. An assistant is requi red to elevate the l eg i nto a
li thotomy-type positi on so that the posterior aspect can be reached.
1. Wi th the patient supine, the hi p is flexed by an assi stant so that the upper leg i s at a 90-
degree angl e to the torso.
2. The greater trochanter is i denti fied as wel l as the ischi al tuberosi ty, and a li ne is drawn
between these two. An X is marked on the mi dpoi nt of this l i ne.
3. A skin wheal i s rai sed at the X after asepti c ski n preparati on. A 10-cm needl e i s
introduced, and nerve responses are sought i n a di rection al ong the length of thi s li ne
(whi ch i s perpendicul ar to the course of the nerve).
4. When a nerve response in the foot is obtained, 25 mL of l ocal anestheti c is i njected.
Lateral Femoral Cutaneous Nerve Blockade. The other three nerves of the leg can be bl ocked
at the l evel of the hip wi th the pati ent i n the supine posi tion.
1. In the supi ne positi on, the anterosuperi or i l i ac spine i s identi fi ed and marked. An X is
pl aced on the ski n 2.5 cm below and 2.5 cm medi al to the spine.
2. A skin wheal i s rai sed at the X after asepti c preparation.
3. A 3.75-cm, 22-gauge needl e is i ntroduced through the wheal and directed l ateral l y until a
pop is felt as it pierces the fasci a lata. Three to 5 mL of l ocal anestheti c soluti on i s
injected as the needl e i s withdrawn sl owl y. The needl e i s then reinserted sl i ghtly medi al l y,
and the procedure i s repeated unti l a wal l of anesthesi a has been spread over a 5-cm area
above and bel ow the fasci a lata extending medi all y from the level of the anterosuperi or
spi ne. A total of 15 to 20 mL of local anestheti c may be required. No nerve responses are
sought.
Femoral Nerve Blockade. Thi s bl ockade can be performed bl i ndl y, or nerve responses can be
sought for a three-in-one bl ockade (see Lumbar Plexus [Three-in-One] Bl ockade section). The
procedure for bl i nd bl ockade fol l ows:
1. In the supi ne posi ti on, a l i ne is drawn from the anterosuperi or il i ac spi ne to the pubi c
tubercle. The femoral artery i s identi fi ed as it passes bel ow thi s l ine, and an X is marked
on the ski n l ateral to the artery 2.5 cm bel ow the l ine.
2. After asepti c preparati on, a ski n wheal is raised at the mark.
3. A 5-cm, 22-gauge needl e is i ntroduced through the X and passed perpendi cul ar to the ski n
unti l it l i es next to the artery and sl i ghtly deep to i t (Fi g. 26-28).
4. Fi ve mil l i li ter of l ocal anestheti c is i njected sl owl y as the needl e is withdrawn. The needl e i s
stretched to al l ow easier i dentificati on. The nerve l i es beneath a poi nt 5 cm caudad al ong the
perpendi cul ar l ine that bisects the l i ne joi ning the posterosuperior il i ac spi ne and the greater
trochanter of the femur. Thi s is al so usual l y the i ntersecti on of that perpendi cular li ne wi th
another l ine joining the greater trochanter and the sacral hi atus. (Reproduced with
Wi l li ams & Wi l ki ns, 2002.)
then reinserted sl i ghtly more laterall y, and the process is repeated twice to create a wal l
of anesthesi a l ateral to and sli ghtl y deep to the femoral artery.
5. Anesthesi a of the thi gh should ensue wi thi n 5 to 10 mi nutes.
Obturator Nerve Blockade. Thi s nerve i s more di ffi cul t to l ocate because of i ts depth.
1. In the supi ne posi ti on, the pubi c tubercl e i s i dentifi ed and an X is pl aced 1.5 cm below and
1.5 cm l ateral to thi s structure. Thi s shoul d li e medial to the femoral artery, and a li ne
drawn between the three Xs used for these three nerve bl ockades shoul d be parall el to the
li ne between the superi or spi ne and the pubi c tubercl e.

2. After asepti c ski n preparation, a skin wheal i s rai sed at the X, and a 7.5-cm, 22-gauge
needle is i ntroduced through the X perpendi cul ar to the ski n.
3. The needl e i s advanced unti l it contacts bone, whi ch shoul d be the inferior ramus of the
pubi s. The needl e i s wi thdrawn sli ghtl y and redi rected laterall y and sli ghtl y caudad to enter
FIGURE 26-28. Bl ockade of the anteri or l umbosacral branches in the groi n. The l ateral
femoral cutaneous nerve emerges approximately 2.5 cm medial to the anterosuperi or i li ac
spi ne and i s best bl ocked 2.5 cm caudad to this poi nt. The femoral nerve emerges al ongsi de
and sl i ghtl y posteri or to the femoral artery and i s agai n easil y approached approxi matel y 2.5
cm below the ingui nal l igament. On that same l i ne, the obturator nerve emerges from the
obturator canal but i s deeper and l ess rel iabl y l ocated. (Reproduced wi th permi ssi on from
Mul roy M: Handbook of Regional Anesthesia. Phil adelphia, Li ppi ncott Wil l iams & Wi lkins,
2002.)
P.742
the obturator foramen. It i s advanced another 2 to 3 cm, and 5 mL of anestheti c i s injected
as the needl e is withdrawn through the presumed depth of the obturator foramen.
4. The needl e i s then reinserted sl i ghtl y more laterall y, and the process i s repeated agai n unti l
20 mL of anesthetic sol uti on has been injected to form another wal l al ong the presumed
path of the obturator nerve (see Fi g. 26-28).
5. Alternati vel y, motor response to a nerve sti mulator (adduction of the thi gh) can confi rm
nerve local i zati on.
Lumbar Plexus (Three-in-One) Blockade. The concept of a si ngle-injecti on bl ockade for the
lumbar pl exus, uti li zi ng the fasci al pl ane that the femoral nerve travel s in as it crosses the pel vi s,
is popul ar. The premise of thi s bl ock i s that injecti on of a l arge quanti ty of l ocal anesthetic
solution i n thi s plane wil l spread upward i nto the pelvis and anesthetize the obturator and l ateral
femoral cutaneous nerves at the point where they stil l travel in conjuncti on wi th the femoral
nerve. Unfortunately, the obturator i s frequentl y mi ssed wi th thi s technique.
19
Because it is
essential to have the needl e exactl y i n the pl ane of the nerve, eli citi ng nerve responses i s cri ti cal
for thi s approach.
1. Preparati on for femoral nerve bl ockade i s made as descri bed previ ousl y.
2. The needl e i s inserted in a cephalad manner rather than i n a perpendi cul ar angl e
recommended previ ousl y (Fi g. 26-29). It i s advanced al ongside the artery angl ed at about
45 degrees so that it passes under the i ngui nal li gament. A nerve response is sought,
recognizing that the nerve l ies sli ghtl y posterior to and occasional ly partial ly under the
femoral artery. When the nerve response i s obtai ned, the needl e i s fixed and the fi ngers of
an assistant are used to compress the femoral artery and the neural sheath bel ow the
ingui nal li gament whi le the operator i njects 40 mL of anestheti c sol ution. The i njection is
performed incremental ly after careful aspi rati on.
3. A conti nuous peri neural catheter can be i nserted wi th thi s approach, keeping the bevel of
the introducing needl e di rected cephal ad to al l ow the catheter to advance centrally in the
fascial pl ane. Advancement of more than 5 cm of catheter may resul t in coi l ing or other
mi sdi rection.
20

4. An al ternati ve to di rect local izati on i s identi fi cation of the fasci al pl ane by the penetrati on of
the two fascial sheaths by the pop sensati on of the needl e passing through them (the
fascia i l iaca bl ock).
21
A needl e i s introduced 1 cm caudad to the juncti on of the l ateral and
mi ddle thi rd of a l ine marking the i ngui nal li gament. The needl e wi l l fi rst pierce the fasci a
lata, then the fasci a il i aca, and wil l l ie i n the nerve compartment. Local anesthetic can be
injected di rectl y, or the needle angl ed 30 degrees cephal ad and a catheter threaded. Thi s
technique requires li ttl e pati ent cooperation, and i s ideal i n chi ldren, or for repeati ng a
parti all y successful bl ock (when further sti mulation of the femoral nerve may not be
successful ).
Compli cati ons of these techniques are rare. Hematomas can occur i n any of the areas of i njection
and are annoyi ng but rarely seri ous. The probl em of systemi c toxici ty is si gni fi cant because of the
large vol umes of anestheti c sol ution required. As menti oned previ ousl y, careful attention must be
pai d to the total mil l i gram dose involved when mul ti pl e injecti ons are used. Neuropathy is a
possi bi li ty. Intraneural i njection must be avoided by watching for si gns of any di scomfort at the
ti me of

actual i njecti on. If the techni que is used for anal gesi a foll owi ng outpati ent surgery, quadri ceps
weakness may l imi t ambul ati on, and crutches may be needed to enabl e pati ent di scharge home.
Popliteal Fossa Blockade
The nerves of the l ower leg can al so be anestheti zed by i njections at the l evel of the knee. The
success of this techni que depends on l ocati ng the sci ati c nerve near its bi furcation into the ti bi al
and peroneal branches hi gh i n the popli teal fossa (Fi g. 26-30). Suppl emental anesthesia of the
femoral nerve i s needed to bl ock i ts terminal saphenous branch, whi ch serves the medi al anterior
calf and the dorsum of the foot. Inserti on of a conti nuous peri neural catheter can provi de
prol onged anal gesi a for foot procedures.
22

FIGURE 26-29. Continuous femoral catheter. The i nguinal approach to the femoral nerve can
al so be used for the i nserti on of a conti nuous catheter. The needl e is i nserted just lateral to
the artery and a motor response is sought i n the quadri ceps muscl e, produci ng patel l ar
el evati on. On i denti fi cati on of the nerve, a conti nuous catheter i s threaded cephalad from
this point. A 45-degree angul ati on of the needle faci li tates easy passage of the catheter and
encourages spread of the local anestheti c proxi mal ly. (Reproduced wi th permission from
Mul roy M: Handbook of Regional Anesthesia. Phil adelphia, Lippi ncott Wi l li ams & Wi l ki ns,
2002.)
P.743
Classical Approach.
1. The pati ent i s placed i n a prone posi ti on. The tri angul ar borders of the popli teal fossa are
outl i ned by drawi ng the borders of the bi ceps femori s and the semitendi nosus muscl es. The
base of the tri angl e i s the skin crease behind the knee. The patient can hel p i dentify the
muscles by sl i ghtl y fl exi ng the l ower leg.
2. After the triangl e i s drawn, a perpendi cul ar l i ne i s drawn from the mi dpoint of the base to
the apex of the tri angl e. Si x centimeters from the base, an X is drawn 1 cm lateral to thi s
bi secti ng l i ne.
3. After asepti c ski n preparation, a skin wheal i s rai sed at the X.
4. A 7.5- or 10-cm needl e i s i ntroduced through the X and directed 45 degrees cephal ad
al ong the middl e of the triangl e (Fi g. 26-31). A fanwi se search i s conducted perpendi cular to
this l i ne until the nerve i s contacted. If the femur is contacted by the needl e, the depth i s
noted. The nerve shoul d l i e mi dway between the skin and the femur.
5. Once a nerve response i s obtai ned, the needle i s fi xed i n posi ti on and 30 to 40 mL of l ocal
anesthetic soluti on i s i njected.
FIGURE 26-30. Popl i teal fossa bl ockade. The two major trunks of the sci ati c bi furcate i n the
popl iteal fossa 7 to 10 cm above the knee. A tri angle i s drawn usi ng the heads of the bi ceps
femori s and the semi tendi nosus muscl es and the ski n crease of the knee; a l ong needl e i s
inserted 1 cm l ateral to a point 5 cm cephal ad on the l i ne from the ski n crease that bi sects
this tri angl e. (Reproduced wi th permi ssi on from Mul roy M: Handbook of Regi onal Anesthesi a.
Phi ladelphi a, Lippi ncott Wi ll i ams & Wi l ki ns, 2002.)
6. A peri neural catheter can be i nserted here, and advanced 5 cm beyond the needle.
7. The femoral branches can be i njected i n the same posi ti on by rai si ng a subcutaneous wheal
of 5 to 10 mL of l ocal anesthetic al ong the medi al ti bial head just bel ow the knee.
Lateral Approach. An al ternative approach to the bl ock of the popli teal fossa i s from the l ateral
si de whil e the patient is l yi ng supi ne.
1. On the l ateral side of the knee, the groove between the bi ceps femori s tendon and the
vastus l ateral is muscle i s i dentified and marked. An X is placed 7 cm cephal ad to the
lateral femoral epi condyl e.
2. A 22-gauge, 10-cm needl e i s i nserted at thi s mark at a horizontal plane. The shaft of the
femur i s usual ly contacted withi n about 5 cm. The needl e is then redi rected 30 degrees
posteriorly to search for the sciati c nerve or i ts divisi ons at approxi matel y the same depth of
the femur. A response to nerve stimul ati on i n the foot (toe movement i s parti cul arl y hel pful )
identi fi es the nerve, usual l y the common peroneal nerve that li es lateral l y. A second nerve
response of the ti bi al nerve may be sought. Ten to 15 mL of anesthesi a i njected around each
nerve provi des adequate anesthesi a.
Ankle Blockade
Al l the nerves of the foot can be bl ocked at the l evel of the ankle. Although this approach i s ideal
in produci ng the least amount of immobi li ty of the l ower extremi ty, i t is techni cal l y more di ffi cul t
because at least five nerves must be anesthetized (Fi g. 26-32). Several of these nerves can be
bl ocked by si mpl e i nfi l trati on of a wal l of anesthesi a, but i ncreased rel iabi li ty can be produced
by seeking paresthesi as of the major branches. If paresthesias are not sought, thi s bl ockade may
FIGURE 26-31. Popl i teal fossa bl ockade, needl e directi on. The needl e is i nserted at the point
descri bed in Fi gure 26-32 and angl ed 45 degrees cephalad. The nerves usual ly are contacted
halfway between the ski n and the femur. This approach i s sui tabl e for si ngl e i njection or
catheter i nserti on. (Reproduced with permission from Mul roy M: Handbook of Regi onal
actual l y be

less ti me-consuming than other techni ques, even though fi ve separate i njecti ons are requi red. The
procedure for bl ockade foll ows:
1. Posterior ti bi al nerve. The posterior ti bi al nerve i s the major nerve to the sol e of the foot. It
can be approached wi th the pati ent either i n the prone posi ti on or with the hi p and knee
fl exed so that the foot rests on the bed. The medi al mal l eol us i s identi fi ed, al ong wi th the
pul sation of the posteri or tibi al artery behind i t. A needl e i s introduced through the ski n just
behind the posterior ti bi al artery and di rected 45 degrees anteri orl y, seeki ng a paresthesi a
in the sol e of the foot. Five mi ll i l iter of a l ocal anestheti c produce anesthesi a if a paresthesi a
is i dentified. If not, a fan-shaped i njection of 10 mL can be performed i n the triangle formed
by the artery, the Achi ll es tendon, and the ti bi a itsel f.
2. Sural nerve. Wi th the foot i n the same positi on, the other posteri or nerve of the ankl e can
be blocked by i njecti on on the l ateral si de. The subcutaneous i njecti on of a ri dge of
P.744
FIGURE 26-32. Ankle bl ockade. Injecti ons are made at fi ve separate nerve l ocati ons. The
superfi cial peroneal nerve, sural nerve, and saphenous nerve are usual l y bl ocked si mpl y by
subcutaneous i nfil trati on because they may have al ready generated many superfici al
branches as they cross the ankl e joint. Paresthesi as can be sought i n the posteri or ti bial or
the deep peroneal nerve, but the bony l andmarks usual ly suffi ce to provi de adequate
local izati on for the deeper i njecti ons. (Reproduced wi th permi ssi on from Mulroy M: Handbook
of Regi onal Anesthesi a. Phi l adel phi a, Li ppincott Wil l iams & Wi lkins, 2002.)
anesthesia behind the l ateral mall eolus, fi ll i ng the groove between i t and the cal caneus,
produces anesthesi a of the sural nerve. Thi s wil l requi re another 5 mL of local anestheti c.
3. Saphenous nerve. The last three branches of the ankl e l i e anteri orly. The patient is ei ther
turned supine, or the leg can now be extended so that the anesthesiologi st' s attention is
turned to the anteri or surface. The saphenous nerve i s anestheti zed by infi ltrating 5 mL of
local anestheti c around the saphenous vein at the l evel where thi s vein passes anteri or to
the medi al mal l eol us. A wal l of anesthesi a between the ski n and the bone i tsel f suffi ces to
bl ock the nerve.
4. Deep peroneal nerve. Thi s i s the major nerve to the dorsum of the foot and l i es i n the deep
pl ane of the anterior ti bi al artery. Pulsati on of the artery is sought at the l evel of the ski n
crease on the anterior mi dli ne surface of the ankle. If i t can be felt, 5 mL of l ocal anestheti c
is i njected just l ateral to thi s. If the artery i s not pal pable, the tendon of the extensor
hall uci s longus can be i denti fi ed by aski ng the pati ent to extend the bi g toe. Injecti on can be
made into the deep pl anes bel ow the fasci a using either one of these l andmarks.
5. Superfici al peroneal branches. Fi nal l y, a subcutaneous ri dge of anestheti c sol ution is l ai d
al ong the ski n crease between the anterior ti bi al artery and the l ateral mal leolus. Thi s
subcutaneous ridge overl ies the previ ous subfasci al injecti on for the deep peroneal nerve.
Another 5 to 10 mL of l ocal anesthetic may be required to cover this area.
Anesthesi a of the foot shoul d ensue wi thi n 15 mi nutes after performance of these fi ve i njections.
Compli cati ons of this bl ockade are rare, al though neuropathy can be produced. Care shoul d be
taken not to pi n any of the deep nerves agai nst the bone at the ti me of injecti on, and i ntraneural
injecti on shoul d be avoi ded as usual .
References
1. Liu SS, Salinas FV: Continuous plexus and peripheral nerve blocks for postoperative
analgesia. Anesth Analg 96:263, 2003
2. Pavl i n DJ, Rapp SE, Pol i ssar NL et al : Factors affecting di scharge ti me in adul t outpatients.
3. Sel ander D, Brattsand R, Lundborg G et al : Local anesthetics: Importance of mode of
appl icati on, concentrati on, and adrenal i ne for the appearance of nerve l esi ons. Acta
4. Hadzi c A, Vl oka J, Hadzi c N, Thys DM, Santos AC: Nerve sti mulators used for peri pheral
nerve blocks vary i n thei r electri cal characteri sti cs. Anesthesi ology 98:969, 2003
5. Brown DL, Ransom DM, Hal l JA et al : Regi onal anesthesi a and local anestheti c-induced
systemi c toxi city: Seizure frequency and accompanyi ng cardi ovascul ar changes. Anesth Anal g
81:321, 1995
6. Lee LA, Posner KL, Domino KB, Caplan RA, Cheney FW: Injuries associated with
regional anesthesia in the 1980s and 1990s: A closed claims analysis. Anesthesiology
101:143, 2004
7. Auroy Y, Benhamou D, Bargues L et al : Major complications of regional anesthesia
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8. Lanz E, Theiss D, Jankovic D: The extent of blockade following various techniques
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9. Wi nni e AP: Interscalene brachi al pl exus block. Anesth Anal g 49:455, 1970
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intraarti cul ar infusi on of ropi vacai ne. Anesth Anal g 93:601, 2001
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Parasagittal anatomy i mportant to the coracoi d techni que. Anesth Anal g 87:870, 1998
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a new approach at the mi dhumeral l evel . Anesth Analg 84:1058, 1997
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17. Capdevi l a X, Macai re P, Dadure C et al : Continuous psoas compartment bl ock for
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18. Singelyn FJ, Deyaert M, Joris D et al : Effects of intravenous patient-controlled
analgesia with morphine, continuous epidural analgesia, and continuous three-in-one
block on post-operative pain and knee rehabilitation after unilateral total knee
arthroplasty. Anesth Analg 87:88, 1998
19. Parki nson SK, Muel l er JB, Little WL, Bail ey SL: Extent of bl ockade wi th various approaches
to the l umbar pl exus. Anesth Anal g 68:243, 1989
20. Ganapathy S, Wasserman RA, Watson JT et al : Modi fi ed conti nuous femoral three-in-one
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21. Capdevi l a X, Bi boul et P, Bouregba M et al : Comparison of the three-in-one and fascia
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> Tabl e of Contents > Secti on V - Management of Anesthesi a > Chapter 27 - Anesthesi a for Neurosurgery
Chapter 27
Anesthesia for Neurosurgery
Audre A. Bendo
Ira S. Kass
John Hartung
James E. Cottrell
KEY POINTS

P.747
The i ntracrani al compartment has a fixed volume. Increases i n the volume of
the brai n, the bl ood, or the cerebral spi nal fl ui d can l ead to an increase i n
intracranial pressure; this may compromise bl ood fl ow or cause the brai n to
herniate.
Hypoxi a and ischemia l ead to neuronal death. With severe i nsul ts the neurons
di e of necrosi s, which leads to infl ammation and extensive damage to other
neurons in the area; after l ess severe insul ts, neurons may be damaged so they
cannot functi on properly and di e of a regul ated cel l death process cal l ed
apoptosis, whi ch does not i njure adjacent neurons.
Both intravenous and vol ati l e anestheti c agents reduce brain metabol ism. It i s
the balance of this effect with blood fl ow, because of flow metaboli sm coupl ing,
that determi nes the extent of the i ncrease or decrease i n cerebral bl ood fl ow
with a particul ar anesthetic agent.
Cerebral precondi ti oni ng and augmentati on of endogenous processes of repair,
incl udi ng both neurogenesi s and diaschi si s, are promisi ng approaches to
cerebral protecti on.
Unti l and unless the del eterious effects of mi l d hypothermi a can be reduced, or
the brai n can be cool ed wi thout reduci ng systemi c temperature bel ow 35C,
cl i ni cal evi dence does not support i nduction of intra-operative mi l d hypothermi a
for neurosurgi cal procedures.
Current evidence cauti ons against the use of prophylacti c etomi date pri or to
temporary vessel occl usi on, magnesium loadi ng in i schemi c stroke patients,
intra-operative ni trous oxi de and ketamine, i ntra-operative moderate
hypothermia i n subarachnoid hemorrhage (SAH) pati ents, postoperati ve
ni modi pi ne and ti ri l azad, and postoperati ve hypothermia i n head trauma
NEUROPHYSIOLOGY AND NEUROANESTHESIA
To understand how anestheti cs act on the nervous system and how these acti ons may affect the
practi ce of neuroanesthesia, one first needs to understand the basi c pri nci ples of neurobi ol ogy.
The fol lowi ng descri pti on of cel l ul ar neurophysiology provi des background i nformati on onl y;
greater detai l may be sought el sewhere.
1

Membr ane P ot ent i al s
Neurons have an electri cal potenti al across thei r cel l membrane owing to di fferent i ntra- and
extracel lul ar i on concentrati ons. These concentrati on differences l ead to an opposi ng vol tage
call ed the equil i bri um potenti al. Sodi um (Na) and potassium (K) are the main i ons responsibl e for
membrane potenti al s i n neurons. The equil i bri um potenti al for K (E
K
) i s approxi matel y -90 mV and
for Na (E
Na
) +45 mV. An i on' s contributi on to the membrane potential of a neuron i s determi ned by
patients.
El ectrophysi ol ogic and cerebral oxygenati on/metabol ism moni tors are used
peri operatively to assess cerebral functi on and pharmacol ogic i nterventions and
to detect cerebral ischemia.
Image-gui ded neurosurgi cal procedures are used for diagnosis, three-
di mensional l ocal i zati on, and resecti on of intracrani al l esi ons.
The admi ni strati on of anesthesi a to neurosurgical pati ents requi res an
understandi ng of the basi c pri nci ples of neurophysi ol ogy and the effects of
anesthetic agents on i ntracrani al dynamics.
Neuroanestheti c management of pati ents wi th supratentorial di sease maxi mi zes
therapeutic modali ties that reduce intracrani al pressure.
Because of the rel ati vely confi ned space withi n the posteri or fossa, the
chal l enge of i nfratentori al surgery i s to prevent further neurologic damage from
surgi cal posi tion and expl orati on.
The anestheti c goal s for i ntracrani al aneurysm surgery are to avoid aneurysm
rupture, mai ntai n cerebral perfusi on pressure and transmural aneurysm
pressure, and provi de a sl ack brain.
Wi th more extensi ve arteri ovenous mal formations, hypothermi a and hi gh-dose
barbiturates have been recommended for brai n protecti on. Induced hypotensi on
may al so be requi red to reduce l esi on si ze and bl ood fl ow.
Severe i ntracrani al hypertensi on can precipi tate refl ex arterial hypertension and
bradycardia (Cushing' s triad). A reducti on i n systemi c bl ood pressure i n these
patients can further aggravate cerebral i schemi a by reduci ng cerebral perfusi on
pressure.
its conductance, whi ch i s proporti onal to the membrane' s permeabi l i ty for that i on. Because the
conductance to potassi um (g
K
) is much hi gher than the sodium conductance (g
Na
) i n an unexci ted
neuron, the resti ng membrane potenti al (approximatel y -60 mV) i s nearer to the potassi um
equil i bri um potenti al (-90 mV) than the sodium equi li bri um potenti al (+45 mV).
The conductance of i ons across the cell membrane i s through channel s, which are proteins that
span the membrane; gates open and cl ose these channel s. Duri ng rest, most of the sodium
channel s have thei r gates cl osed, whereas more potassi um channel s have gates in the open
positi on. That i s why there i s a greater conductance to K in resting neurons.
Neurons transmi t signal s over l ong di stances by propagati ng acti on potenti al s, which are rapi d
depol arizati ons of the membrane, al ong thei r axons. The acti on potenti al i s caused by a rapi d
increase i n the sodi um conductance (because of the openi ng of the sodi um activati on gate) and a
sl ower i ncrease i n the potassi um conductance. These conductance changes are tri ggered by a
depol arizati on of the cel l membrane, and therefore the channel s that open i n response to the
depol arizati on are descri bed as vol tage-sensi ti ve channel s. When the neuron depol ari zes past a
threshold vol tage level , an action potential i s generated. The peak vol tage of the action potential
is approxi matel y +20 mV; thi s l evel i s attai ned because, at the peak, the sodi um conductance i s
much greater than the potassi um conductance. The vol tage duri ng the acti on potenti al returns
rapidl y to resting l evel s (repol ari zes) because the sodi um conductance shuts i tself off by closi ng a
second gate (i nacti vati on gate) i n the channel , and the potassi um conductance increases as a
resul t of the opening of potassi um channel s.
Synapt i c Tr ansmi ssi on
Neurons communi cate usi ng chemical synapses. The chemi cal , cal l ed a transmi tter, is rel eased
from the presynapti c neuron, di ffuses across the synapti c cleft, and combi nes wi th a receptor
mol ecul e on the postsynapti c neuron. The rel ease of the neurotransmi tter is i ni tiated by an acti on
potential traveli ng down the axon of the presynapti c neuron, causi ng the depol arizati on of the
presynaptic terminal . This depol arizati on l eads to the opening of voltage-dependent cal cium
channel s and the entry of calci um from the extracel l ul ar fl uid into the terminal. Vesi cles
contai ning the neurotransmi tter then fuse wi th the termi nal membrane, releasi ng the
neurotransmitter i nto the synapti c cleft. The combinati on of the neurotransmitter wi th i ts receptor
located on the postsynaptic cel l al ters i on channel s associ ated wi th the receptor. These channel s
are descri bed as l i gand-gated channel s. The openi ng of these ion channel s leads to a change i n
the membrane potenti al of the postsynapti c neuron. If the transmi tter i s exci tatory, this
postsynapti c neuron i s depol ari zed and therefore i s more l i kely to generate an action potenti al . If
the transmi tter is i nhi bitory, the neuron i s hyperpolarized and i s less li kel y to generate an action
potential .
In addi tion to openi ng i on channel s, neurotransmitters work through intracel l ul ar second
messengers. One exampl e of a second messenger i s cycl i c cAMP, whi ch acti vates protei n kinases
to phosphoryl ate protei ns and changes their acti vi ty. Ion channel s may be phosphoryl ated, whi ch
may change thei r conductance. A group of protei ns that bi nd guanosine tri phosphate, call ed G
protei ns, are acti vated when a transmi tter bi nds to a speci fi c receptor molecul e. In some cases
these G protei ns acti vate i on channels di rectly, but i n other cases they can ei ther sti mulate (G
s
)
or i nhi bi t (G
i
) adenyl ate cyclase, the enzyme that converts adenosi ne triphosphate (ATP) i nto
cycl i c AMP. G protei ns can al so acti vate the phosphati dyl inosi tol second-messenger system; in thi s
case, a transmi tter bi nds to a receptor, which causes another G protei n (G
p
) to activate
phosphol i pase C. Thi s membrane-bound enzyme breaks down a membrane phosphol i pi d i nto
di acylgl ycerol and i nosi tol tri sphosphate, both of whi ch are second messengers. Di acylgl ycerol
acti vates protei n kinase C, which wi ll then phosphoryl ate other protei ns, whereas i nositol
trisphosphate increases cytosol i c cal ci um by rel easing i t from intracel l ul ar stores (endopl asmi c
reticul um).
There are many neurotransmi tters i n the brai n. In thi s chapter two common neurotransmi tters and
thei r receptors are exami ned.
-Ami nobutyric aci d (GABA) i s a major inhi bi tory ami no aci d transmitter that is acti ve throughout
the brai n and reduces the exci tabili ty of neurons by hyperpol arizing them. There are two major
GABA receptors. Acti vati on of the GABA
A
receptor opens chlori de channel s; this acti vi ty i s
enhanced by benzodi azepi nes and barbi turates. The GABA
B
receptor acts vi a a second messenger
to open potassi um channel s, but does not affect chl ori de channel s.
2
The response to GABA
B

receptor activati on has a sl ower onset and a more prol onged activati on than the response to the
GABA
A
receptor. Both receptors may be present on the same neuron, providi ng a mechani sm for
rapi d and prol onged i nhi bi ti on.
Gl utamate is the major excitatory transmi tter i n the brain. Its activati on depol ari zes neurons,
maki ng i t more l i kel y that they wil l fi re acti on potenti al s. There are three mai n i notropic

gl utamate receptors, whi ch have been named for thei r preferenti al pharmacol ogi c agoni sts. Most
of the AMPA and kai nate receptors al l ow sodi um and potassi um but not cal cium through their
channel s.
3
These channel s are responsi ble for the normal exci tatory responses seen with
gl utamate. The thi rd glutamate receptor, the N-methyl -D-aspartate receptor (NMDA), i s activated
when neurons are depolarized; the channel s associ ated wi th thi s receptor are not opened by
gl utamate at normal resti ng membrane potenti als. These channel s all ow passage of cal ci um as
wel l as sodi um and potassi um. NMDA receptor activati on is i mportant i n changing a neuron' s
exci tabi l ity over a peri od of hours and days (l ong-term potenti ati on); this has been correl ated
with learni ng i n animal s.
3
Glutamate receptors have al so been associ ated with neuronal i njury
after ischemi a and anoxi a. In addi ti on to i notropic effects, gl utamate acti vates metabotropic
receptors, whi ch act vi a a second messenger. Inosi tol tri sphosphate, a second messenger,
rel eases cal ci um from intracel l ul ar stores; thi s can affect the exci tabi l ity of the neuron.
The i nformati on here i s a si mpl e descri pti on of how synapses operate to convey i nformati on from
one neuron to another. This process i s fi nel y control l ed; there are neurotransmi tters that act on
presynaptic terminal s to regulate the amount of transmitter the termi nal rel eases. There are
compounds cal led neuromodul ators that, when appl i ed to a neuron al one, have no observable
effect on the excitability of that neuron but al ter the effect of other exci tatory or inhi bi tory i nputs
to that neuron.
Br ai n Met abol i sm
The mai n substance used for energy producti on i n the brai n i s gl ucose.
4
When oxygen l evel s are
suffi ci ent, glucose i s metaboli zed to pyruvate i n the gl ycolyti c pathway (Fi g. 27-1). Thi s
bi ochemi cal process generates ATP from adenosi ne di phosphate and i norgani c phosphate and
produces the reduced form of ni cotinami de adeninedinucl eotide (NADH) from nicoti nami de adeni ne
di nucl eoti de (NAD). Pyruvate from thi s reacti on then enters the ci tri c aci d cycl e, whi ch, wi th
regard to energy producti on, pri marily generates NADH from NAD. The mi tochondria use oxygen to
coupl e the conversi on of NADH back to NAD wi th the production of ATP from ADP and i norgani c
phosphate. Thi s process, call ed oxi dati ve phosphorylation, forms three ATP mol ecul es for each
NADH converted. The process of aerobi c metabol i sm yi el ds 38 ATP molecul es for each gl ucose
mol ecul e metabol ized.
P.748
Thi s pathway requi res oxygen; i f oxygen is not present, the mi tochondria can neither make ATP
nor regenerate NAD from NADH. The metabol i sm of gl ucose requi res NAD as a cofactor and is
bl ocked i n i ts absence. Thus, i n the absence of oxygen, gl ycol ysi s proceeds by a modi fi ed pathway
termed anaerobi c glycolysi s; thi s modi fi cation involves the conversi on of pyruvate to l actate,
regenerati ng NAD. There i s a net hydrogen ion production, whi ch l owers the intracel lular pH. A
major probl em with anaerobi c glycol ysis, i n addi tion to l oweri ng pH, i s that onl y two mol ecules of
ATP are formed for each mol ecul e of glucose metabol ized. Thi s l evel of ATP production is
insuffi cient to meet the brai n's energy needs.
When the oxygen suppl y to a neuron i s reduced, mechani sms that reduce and/or sl ow the fal l i n
ATP level s i ncl ude: (1) the util i zati on of phosphocreatine stores (a hi gh-energy phosphate that can
donate i ts energy to maintai n ATP l evels), (2) the producti on of ATP at l ow l evel s by anaerobi c
gl ycolysi s, and (3) a rapid cessati on of spontaneous el ectrophysi ologic activity.
Pumpi ng ions across the cel l membrane i s the l argest energy requirement i n the brai n (Tabl e 27-
1). The sodi um, potassi um, and cal cium concentrations of a neuron are mai ntained agai nst large
el ectrochemical differences wi th respect to the outsi de of the cell . When a neuron i s not excited
(fi ring acti on potenti al s), there i s a sl ow l eak of potassi um out of the cel l s and of sodi um i nto the
cel ls. Neuronal activity markedl y increases the flow of potassium, sodium, and cal cium; thi s
increases the rate of i on pumping requi red to mai ntai n the neuron' s i on concentrati on. Because
i on pumpi ng uses ATP as an energy source, the ATP requi rement of acti ve neurons i s greater than
that for resti ng neurons. If energy producti on does not meet the demand of energy use i n the
brain, the neurons fi rst become unexci tabl e and then are i rreversi bl y damaged.
5, 6

FIGURE 27-1. Energy metabol i sm i n the brai n. Dotted l ines indi cate reacti ons that occur
duri ng i schemia. The dotted l i ne across the oxi dative phosphoryl ati on reaction indicates that
this reaction i s blocked duri ng i schemi a.
TABLE 27-1 Cellular Processes That Require Energy
Intracel lular signal i ng
Metabol i sm of DNA, RNA, protei ns, l i pi ds, carbohydrates, and other mol ecules
Transporti ng of mol ecules wi thi n cel ls and across the cel l membrane
Pumpi ng ions across membranes to mai ntai n ion gradi ents
Synaptic transmi ssi on
Neurons requi re energy to mai ntai n their structure and i nternal functi on. The cel l ' s membranes,
internal organell es, and cytopl asm are made of carbohydrates, l i pi ds, and protei ns, whi ch requi re
energy for thei r synthesi s. Ion channel s, enzymes, and structural components are i mportant
protei n mol ecul es that are conti nuousl y formed, modi fi ed, and broken down i n the cel l . If ATP i s
not avai labl e, protei n synthesi s cannot conti nue and the neuron wi l l die. Carbohydrates and l i pids
are al so conti nuousl y synthesi zed and degraded i n normal l y functioni ng neurons; their metabol i sm
al so requi res energy. Most cel l ul ar synthesi s takes pl ace i n the cel l body; thus, energy is requi red
for the transport of components down the axon to the nerve termi nal. The i mportance of thi s
transport i s i ll ustrated by the death of the distal end of an axon when it i s severed from i ts cel l
body. Thus, energy i s requi red to mai ntai n the integri ty of neurons even i n the absence of
el ectrophysiol ogi c activity.

The overal l metaboli c rate for the brai n of a young adul t man (mean age, 21 years) is 3.5 mL
O
2
/min/100 g brain tissue or 5.5 mg glucose/min/100 g.
4
Thi s rate is virtuall y the same in el derl y
men (mean age, 71 years). Chi l dren (mean age, 6 years) have a markedly hi gher metabol ic rate
of 5.2 mL O
2
/min/100 g brain tissue. Al though the reasons for thi s hi gh metabol i c rate are
unknown, it may reflect extra energy requi rements for the growth and devel opment of the nervous
system.
4

Cer ebr al Bl ood Fl ow
The brai n receives approxi mately 15% of cardiac output, yet makes up onl y 2% of total body
weight.
4
The di sproporti onatel y l arge bl ood fl ow i s a resul t of the hi gh metabol i c rate of the brai n.
Gl obal bl ood fl ow and metabol i c rate remai n fairly stabl e. Regi onal bl ood fl ow and metabol i c rate
of the brai n can change dramati cal l y; when metabol ic rate goes up i n a regi on of the brai n, the
bl ood flow to that regi on al so increases. The mechani sm of thi s coupl i ng of bl ood fl ow and
metaboli sm i s not known; however, an i ncrease in ei ther potassium or hydrogen i on
concentrations i n the extracel l ul ar fluid surroundi ng arteriol es may l ead to dil atation and
increased fl ow. Other agents that may mediate the coupl i ng are cal ci um, adenosi ne, ni tri c oxide,
and the ei cosanoi ds (e.g., prostagl andi ns).
5
None of these mechani sms need be exclusive, and
more than one or all of them may contri bute to thi s exqui si te coupl i ng of fl ow and metabol ism.
Increasi ng carbon di oxi de level causes vasodil atation and i ncreased blood fl ow (Fi g. 27-2).
Increasi ng the carbon dioxi de tensi on from 40 to 80 mmHg doubl es the fl ow; reduci ng the carbon
di oxi de from 40 to 20 mmHg halves the fl ow.
7, 8
These changes are transi ent, and bl ood fl ow
returns to normal in 6 to 8 hours, even if the altered carbon dioxi de l evels are maintai ned. These
effects may be rel ated to the hydrogen i on concentrati on. High carbon di oxi de l evel s increase the
extracel lul ar hydrogen i on concentrati on and blood fl ow, whereas low carbon di oxi de level s
decrease the extracell ul ar hydrogen i on concentrati on and reduce bl ood fl ow. The bi carbonate
concentration in the extracel lular fl ui d of the brain adjusts, bri ngi ng the pH back to normal , even
Neuronal plasti city (structural and bi ochemi cal changes)
P.749
though the carbon di oxi de l evels remain altered.
9
Thi s has important cl i ni cal i mpl icati ons i n
pati ents hyperventi l ated for prol onged peri ods. If normocarbi a i s rapi dl y reestabl i shed, brai n
i ntersti ti al fl ui d pH wi l l decrease and cerebral bl ood fl ow (CBF) will i ncrease dramaticall y, perhaps
increasi ng i ntracranial pressure (ICP).
If a patient is hypoventilated, carbon dioxi de i ncreases, pH decreases, and bl ood fl ow i ncreases
throughout the brain. The arteri ol es coul d become maximal l y di l ated throughout the brai n,
i mpedi ng the abi l i ty to di rect fl ow to areas of hi gh metabol ic demand. Thus, thi s l uxury fl ow
caused by hi gh carbon di oxi de l evel s throughout the brai n coul d steal bl ood flow from areas that
requi re extra oxygen and produce metabol i tes. This i s particul arl y important duri ng focal i schemia
wi th the bl ockage of an i ntracerebral artery. The vessels suppl yi ng col lateral fl ow to the area of
the bl ocked artery woul d al ready be maxi mal l y di l ated because of the metabol i c demands of the
ischemi c ti ssue, and hi gh Pa
CO2
woul d cause bl ood fl ow to be shunted away to areas of l ess
demand. The blood fl ow to the brain can be manipulated to advantage duri ng focal i schemi a.
Reduci ng carbon dioxi de wi th hyperventil ati on or reducing metabol ism wi th agents such as
thi opental woul d reduce bl ood fl ow to most areas of the brai n, and the vessels i n the i schemic
area woul d be maxi mal l y di l ated because of l ow pH. These manipul ati ons, whi ch are someti mes
call ed inverse steal , could have the effect of maxi mizing blood flow to compromi sed areas.
10
The
cl i ni cal rel evance of fl ow redi stri bution because of hypocarbi a has been questi oned.
11

The CBF autoregulates with respect to pressure changes. In normotensive individuals, mean
arterial pressure (MAP) can vary from 50 to 150 mmHg and CBF wi l l be maintai ned constant
because of an adjustment of the cerebral vascular resistance (see Fi g. 27-2). Thi s phenomenon i s
a myogeni c response of the arteri ol es because of thei r abi l ity to constri ct in response to an
increased di stendi ng pressure. Thi s response takes a few mi nutes to devel op; therefore, after a
rapi d i ncrease i n MAP, there i s a short peri od (about 1 to 3 minutes) of i ncreased bl ood fl ow.
12
If
mean bl ood pressure fal l s bel ow 50 mmHg, CBF i s reduced; at a pressure of 40 mmHg, mi l d
symptoms of cerebral ischemi a occur.
12
Pati ents who are hypertensi ve demonstrate a shi ft of
autoregulation to a hi gher bl ood pressure. Thei r l ower l i mi t of autoregul ati on coul d be wel l above
50 mmHg; thei r upper l imi t of autoregul ation is al so i ncreased. Thi s shi ft, a resul t of hypertrophy
FIGURE 27-2. The effect of perfusion pressure (PP), arteri al carbon di oxi de pressure
(PaCO
2
), and arteri al oxygen pressure (PaO
2
) on cerebral bl ood fl ow. Each parameter on the
absci ssa i s vari ed independentl y whi le the other parameters are held at thei r normal l evels.
(Repri nted with permi ssi on from Mi chenfelder JD: Anesthesi a and the Brai n, pp 6, 94113.
New York, Churchi ll Li vi ngstone, 1988.)
of the vessel wal l, takes 1 or 2 months to become establ i shed.
13
Autoregul ati on can be abol i shed
by trauma, hypoxi a, and certai n anestheti c and adjuvant anesthetic drugs. When bl ood pressure
exceeds the autoregul ated range, i t can cause a disrupti on of the bl ood-brai n barri er and cerebral
edema.
The cerebral vasculature i s al so regul ated by neurogeni c factors that seem to have thei r greatest
infl uence on the larger cerebral vessels. They control fl ow to large areas of the brai n and pl ay l ess
of a role i n the regulation of local CBF.
12
The i nnervati on includes chol i nergi c, adrenergi c, and
serotonergi c systems. Sympatheti c activati on l eads to i ncreased MAP and shifts the autoregulatory
curve to the ri ght, i ncreasi ng the pressure at which the breakthrough of autoregulation occurs.
13

Cer ebr ospi nal Fl ui d
The neurons i n the brai n are exqui sitel y sensiti ve to changes in their envi ronment. Smal l
al terati ons in extracell ul ar ion l evel s can profoundly al ter neuronal acti vi ty. Substances that
ci rculate in the bl ood, such as catechol ami nes, i f not sequestered from di rect contact wi th the
brain, might al so disrupt brai n function. Thus the compositi on of the fl uid surroundi ng the

brai n i s ti ghtl y regul ated and di sti nct from extracel l ul ar fl uid in the rest of the body (Tabl e 27-
2).
14
There are two barri ers, the blood-brain barrier and the bl ood-cerebrospi nal fl ui d barri er, that
maintai n the difference between blood and cerebrospi nal fl ui d (CSF) composi tion.
P.750
TABLE 27-2 Composition of cerebrospinal fluid and serum in man
CSF SERUM
Sodi um (mEq/l ) 141 140
Potassium (mEq/l) 2.9 4.6
Calcium (mEq/l) 2.5 5.0
Magnesi um (mEq/l ) 2.4 1.7
Chl ori de (mEq/l ) 124 101
Bicarbonate (mEq/l) 21 23
Gl ucose (mg/100 mL) 61 92
Protei n (mg/100 mL) 28 7,000
pH 7.31 7.41
Osmolal ity (mOsm/kg H
2
O)
289 289
Adapted wi th permi ssi on from Artru AA: Cerebrospi nal fl ui d. In Cottrel l JE, Smith DS
Brai n capil l ary endothel i al cell s (the bl ood-brain barri er) have ti ght junctions that prevent
extracel lul ar passage of substances between the endotheli al cel ls. They al so have a l ow l evel of
pi nocytoti c activi ty, whi ch reduces the transport of l arge mol ecul es across the cel l s. Processes of
astrocyte gl i al cell s are i nterposed between the neurons of the brai n and the capi l l ari es. The
functi onal i mportance of the astrocytes to the bl ood-brain barri er is currently unknown; however,
they are l ocated wherever the blood-brain barri er is present and appear to be necessary for the
development and perhaps the mai ntenance of the barri er. The bl ood-brai n barri er i mpedes the
flow of ions such as potassi um, cal ci um, magnesi um, and sodi um; pol ar mol ecules such as
gl ucose, amino aci ds, and manni tol ; and macromolecul es such as protei ns.
14
Li pi d-sol ubl e
compounds, water, and gases such as carbon dioxi de, oxygen, and vol ati l e anestheti cs pass
rapi dl y through the bl ood-brain barrier. Many substances that do not cross the blood-brain barrier
are requi red for brai n functi on; these substances are transported across the capi ll ary endotheli al
cel l by carrier-mediated processes. These processes consi st of ei ther active transport, whi ch
requi res the expendi ture of energy, or passive transport, which does not. Passi ve transport, also
referred to as faci l i tated di ffusi on, can move mol ecul es i nto the brai n only i f thei r concentration in
the blood is hi gher than thei r concentration i n the brai n. Gl ucose is an example of a mol ecul e that
enters the brai n by passi ve transport. All of these transport processes have a l i mi ted capaci ty. The
bl ood-brain barrier can become disrupted by acute hypertension, osmoti c shock, disease, tumor,
trauma, i rradi ati on, and ischemia.
Cerebrospi nal fl ui d i s pri mari l y formed i n the choroi d pl exus of the cerebral ventricl es. The
capi l l ari es of the choroi d pl exus have fenestrati ons and i ntercel lular gaps that all ow free
movement of mol ecul es across the endotheli al cel l s; however, they are surrounded by choroi d
pl exus epithel i al cell s, whi ch have ti ght juncti ons and form the basi s of the blood-CSF barri er. It i s
these cel ls that secrete the CSF. The CSF vol ume i n the brai n i s between 100 and 150 mL; i t i s
formed and reabsorbed at a rate of 0.3 to 0.4 mL/mi n. Thi s al l ows a compl ete replacement of the
CSF vol ume three or four ti mes a day. The bl ood-CSF barri er i s si mi l ar to the blood-brain barrier
in that i t al l ows the free movement of water, gases, and l i pid-solubl e compounds but requires
carri er-mediated active or passi ve transport processes for glucose, amino aci ds, and i ons. Protei ns
are largel y excluded from the CSF. The CSF i s pri maril y formed by the transport of sodi um,
chlori de, and bicarbonate with the osmotic movement of water. Two cl i ni cal ly used substances that
reduce CSF formation are furosemi de, whi ch inhi bits the combi ned transport of sodi um and
chl ori de, and acetazol ami de, whi ch reduces bi carbonate transport by i nhi bi ti ng carbonic
anhydrase.
15
The CSF fl ows from the lateral ventri cl es to the thi rd and fourth ventricl es and then
to the ci sterna magna. It then flows around the brai n and spinal cord i n the cerebral and spi nal
subarachnoi d space. The fl uid i n the subarachnoi d space provi des cushi oni ng for the brai n,
reduci ng the effect of head trauma. The CSF i s absorbed i nto the venous system of the brain by
the vi ll i i n the arachnoid membrane. These arachnoid vi ll i al l ow one-way fl ow of CSF from the
subarachnoi d space into the venous si nuses when CSF pressure is greater than the pressure i n
these si nuses. Owing to the hi gh rate of CSF formati on and i ts absorpti on i nto the venous system,
(eds): Anesthesi a and Neurosurgery, p 95. St Loui s, CV Mosby, 1994.
protei ns and other matter rel eased i nto the brai n extracel lular fl uid are removed. If the foramina
connecti ng the ventri cles or the arachnoid vil l i are bl ocked, pressure buil ds and hydrocephalus
develops.
I nt r acr ani al P r essur e
The brai n is encl osed i n the crani um, which has a fi xed vol ume; therefore, i f any of the
components l ocated i n the crani al vault increase i n volume, the ICP wi ll i ncrease (Tabl e 27-
3). An increase i n volume of one of these components can i ncrease ICP and result i n two major
del eteri ous effects on the organism. The first i s to reduce bl ood fl ow to the brai n. The cerebral
perfusi on pressure (CPP) i s determi ned by the MAP mi nus the ICP. If ICP increases to a greater
extent than MAP, CPP i s reduced. If ICP ri ses suffi ci entl y, the brain can become i schemic. The
second i mportant effect of i ncreased ICP is i ts abi li ty to induce brai n herni ati on. Thi s herni ati on
coul d be across the meni nges, down the spinal canal, or through an opening i n the skul l .
Herni ati on can rapi dl y l ead to neurol ogic deteri orati on and death.
The ICP i n humans i s normal ly l ess than 10 mmHg. Under normal ci rcumstances, a small i ncrease
in i ntracrani al vol ume wi l l not greatl y i ncrease ICP because of the elastance of the components
located in the cranium (Fi g. 27-3). After a certai n poi nt, however, the capaci ty of the system to
adjust to increased vol ume i s exceeded and even a smal l i ncrease i n volume wil l i ncrease ICP.
16

Increases i n ICP can be caused by the fol l owi ng: (1) increased CSF vol ume because of bl ockage of
the ci rculation or absorpti on of the CSF, as descri bed earli er; (2) i ncreased blood volume from
vasodil atati on or hematoma; and (3) i ncreased brain tissue volume caused by a tumor or edema.
TABLE 27-3 The Three Major Components That Occupy Space in the Skull
The brai n, whi ch i ncl udes neurons and gli a
The cerebrospi nal fl ui d and extracel l ul ar fl uid
The bl ood perfusi ng the brai n
Brai n edema i s typi cal ly classi fi ed as cytotoxi c or vasogenic. The former i s because of neuronal
damage, whi ch l eads to increased sodi um and water i n the brai n cel l s, and therefore an i ncrease
in i ntracel l ul ar vol ume. Vasogeni c edema is caused by a breakdown of the bl ood-brai n barri er and
the movement

of protei n from the blood i nto the brain' s extracel l ul ar space. Water moves osmoti cal ly wi th the
protei n, increasi ng the extracel l ul ar fl uid vol ume i n the brain.
P athophysi ol ogy
The brai n is the organ most sensi ti ve to i schemia; therefore, when the bl ood suppl y to the brai n i s
l i mi ted, i schemi c damage to neurons can occur.
17
To understand the rati onale for treatments used
to protect the brai n agai nst anoxic and ischemi c damage, one needs an appreci ation of the
pathophysi ol ogic mechanisms that may lead to this damage. The central event preci pi tating
damage i s reduced energy production because of bl ockage of oxi dati ve phosphorylation. Thi s
causes ATP producti on per mol ecul e of gl ucose to be reduced by 95%. At thi s rate of production,
ATP level s fall , l eading to the loss of energy-dependent homeostati c mechani sms. (Compl ete
i schemi a woul d bl ock al l ATP producti on.) The acti vi ty of ATP-dependent i on pumps i s reduced and
the intracel l ul ar l evel s of sodium and cal cium i ncrease, whi l e i ntracel l ul ar potassium l evel s
decrease (Fi g. 27-4). These i on changes cause the neurons to depolari ze and rel ease exci tatory
amino aci ds such as glutamate. Hi gh level s of gl utamate further depol ari ze the neurons and al l ow
more cal cium to enter through the NMDA receptor channel. The high intracel l ul ar cal cium level i s
thought to trigger a number of events that coul d lead to the anoxic or ischemic damage. These
incl ude increasi ng the activity of proteases and phosphol i pases.
17
The l atter woul d i ncrease the
l evel s of free fatty aci ds and free radicals. Free radicals are known to damage protei ns and l i pi ds,
whereas free fatty aci ds i nterfere with membrane functi on. In addi ti on, there i s a bui l dup of
lactate and hydrogen i ons. Al l of these processes, coupl ed wi th the reduced abi l ity to synthesi ze
protei ns and l i pi ds because of the reduced ATP l evel s, may l ead to irreversibl e damage wi th
FIGURE 27-3. The effect of increasi ng volume on i ntracranial pressure. At fi rst, as vol ume i s
i ncreased, pressure does not i ncrease, owi ng to the el astance of intracrani al structures. Thi s
el astance i s exceeded and then a small increase i n volume can cause a large increase i n
intracranial pressure. (Modi fi ed from Mil l er JD, Gari bi J, Pi ckard JD: The effects of i nduced
changes of cerebrospi nal fl ui d vol ume during conti nuous moni tori ng of ventricul ar pressure.
Arch Neurol 28:265, 1973.)
P.751
ischemi a. In addi ti on, phosphol ipase activation leads to the producti on of excess arachi donic acid,
whi ch, on reoxygenation, can form eicosanoi ds, including thromboxane, prostagl andi ns, and
leukotrienes. Thromboxane can cause intense vasoconstri cti on and reduced bl ood fl ow i n the
posti schemi c peri od, whi l e l eukotri enes can i ncrease edema. Thus, procedures that may protect
against ischemia shoul d i nterfere wi th these damagi ng mechanisms (Tabl e 27-4). Speci fi c agents
that might accompl i sh these objecti ves are detai led i n the secti on on brai n protecti on l ater i n the
chapter.
Ischemi a can be either gl obal or focal i n nature; an example of the former woul d be cardi ac
arrest, of the l atter, a l ocali zed stroke. The mechani sms l eadi ng to neuronal damage are probably
si mi l ar for both, but there are i mportant distincti ons between the two. In focal ischemi a there are
FIGURE 27-4. The effect of hypoxia or i schemi a on ion and metabol ite l evel s in neurons. For
cl ari ty, i on channel s are shown on the top membrane and ion pumps on the bottom
membrane; their actual l ocati on can be on any membrane surface. Circles i ndi cate energy-
dri ven pumps, and a crossed-through ci rcl e indi cates that thi s pump i s bl ocked or has
reduced acti vi ty duri ng i schemi a. V indi cates a vol tage-dependent channel .
TABLE 27-4 Procedures That May Protect Against Ischemic Damage
Mai ntai ni ng bl ood fl ow
Mai ntai ning ATP l evel s by reduci ng the metabol i c rate
Bl ocki ng sodi um or cal ci um i nfl ux
Scavengi ng free radicals
Bl ocki ng the rel ease of or receptors for exci tatory ami no aci ds
Inhi biti ng protei ns that activate or contri bute to damage (e.g., proteases,
phosphol i pases, and some ki nases)
Acti vati ng protei ns that induce repai r or rescue from apoptosi s and necrosi s (e.g., some
kinases)
three regi ons. The first recei ves no bl ood flow and responds the same as gl obal l y ischemic tissue;
the second, call ed the penumbra, receives coll ateral flow and is parti al l y i schemi c; the third i s
normal ly perfused. If the i nsul t i s maintai ned for a prol onged peri od, the neurons i n the penumbra
wil l di e. More neurons i n the penumbra wi ll survi ve i f coll ateral bl ood fl ow is i ncreased.
Mechani sms such as i nverse steal (descri bed i n the Cerebral Bl ood Fl ow section) wi l l enhance
col l ateral bl ood fl ow, and hence neuron survival , i n focal but not gl obal ischemia.
Epi leptic acti vi ty i s sudden, excessive, and synchronous di scharges of l arge numbers of neurons.
Asi de from those patients with establ i shed epil epsy, thi s massi ve i ncrease i n acti vi ty i s seen

in pati ents wi th i onic and el ectrol yte imbal ances, di sorders of brai n metabol i sm, i nfection, brai n
tumor, brain trauma, or el evated body temperature.
18
The electroencephalogram (EEG) shows
spi kes, whi ch are rapi d changes i n vol tage corresponding to excess activity in many neurons.
During the epi lepti form activity, sodi um and cal cium i ons enter the cel l s and potassi um l eaves.
Thus the cel l s use more energy (ATP) for i on pumping. Hi gh extracel l ul ar potassi um may be
responsi bl e for the large and progressi ve depol ari zati on of the neurons that i s commonly found.
The mechanisms that l ead to permanent neuronal damage with epil epsy may be si mil ar to those
that damage cel l s during i schemia. Intracel l ul ar cal cium level s ri se, which may precipi tate the
damage. It i s cl ear that duri ng epil epti form acti vi ty the energy demand, and hence the cerebral
metabol i c rate (CMR) and bl ood fl ow, i ncreases greatl y. Thus, i n condi ti ons i n whi ch blood fl ow to
the brai n may be compromi sed, i t i s i mperative to avoid excess brai n activity. Anticonvulsant
medicati ons i ncrease neuronal inhi biti on or reduce excitatory processes in the brai n. Epi l epti c
acti vi ty may be accompanied by systemic l acti c acidosis, reduced arteri al oxygenati on, and
increased carbon di oxide; therefore, i t is i mportant to maintai n ventil ati on, oxygenati on, and
bl ood pressure. Prol onged or recurri ng epil epti c acti vi ty can lead to profound brai n damage.
Brai n trauma can di rectl y lead to permanent physi cal neuronal damage. Pri mary damage can al so
be caused by brain herniati on or severi ng of blood vessel s i n the brain, resulti ng i n direct
ischemi a. Reversal of the pri mary damage i s not possi bl e; however, much of the brai n injury in
trauma pati ents is secondary and occurs fol lowi ng the i ni ti al insult.
19
Calcium influx resul ting from
the trauma has been impl icated as a tri gger for the damage. It i s i mportant to prevent the
secondary ischemia that frequently foll ows brai n trauma and i s possibl y a resul t of the rel ease of
vasoconstri cti ve substances duri ng reperfusion. In addi ti on, hemorrhage may i ncrease intracranial
bl ood vol ume and ICP, reduci ng CPP. The i ntracrani al bl ood can be damagi ng by di rectl y promoti ng
free-radical formation usi ng the i ron i n hemogl obi n. Secondary damage may be reduced wi th
proper moni toring and treatment. Treatment incl udes reduci ng ICP, mai ntai ni ng bl ood fl ow,
reduci ng vasospasm, removi ng bl ood from the subarachnoi d space, and perhaps usi ng
pharmacol ogic agents that i nterfere with the cascade of events that l ead to neuron damage.
Brai n tumors are expandi ng, space-occupyi ng l esi ons that may si gnifi cantly increase ICP and l ead
to reduced CPP or brai n herni ati on. Frequentl y, the bl ood vessel s suppl yi ng the tumor have a
leaky blood-brain barrier, which may contri bute to vasogeni c brain edema and el evated ICP.
Thus, for several pathophysi ologi c events in the brai n, ATP depl etion; i oni c imbal ance
(parti cularly hi gh intracel lul ar cal cium level s); free-radical formation; and kinase, protease,
and phosphol i pase acti vation have been impl icated as tri ggers of neuronal damage. A common
mechani sm of neuronal cell death for vari ous pathophysi ologic events may exi st. There are two
major processes that l ead to neuronal death. The fi rst, necrosi s, i s characteri zed by a
di si ntegrati on of the cel l and an acti vati on of mi crogl i a and the i mmune response.
20, 21
The i mmune
response and infl ammati on acti vates and recrui ts neutrophi ls and macrophages that produce free
radi cal s and damage adjacent neurons. This expands the lesion in volume and time allowing for
conti nued and expanded neuronal damage.
21
The second process, apoptosis or programmed cel l
death, i nvol ves an acti ve process, whi ch does not damage adjacent neurons.
20
Apoptosi s uses a
metaboli c process that is normal ly used to ki ll off unneeded neurons. This process i s responsibl e
for the death of many neurons duri ng development and can be reacti vated when neurons are
damaged subsequent to i schemi a.
22
A severe i nsult, such as would be encountered i n the core of
an i schemic area, l eads predominantl y to necrosi s, whi l e l ess-compromised areas undergo a
greater degree of apoptosi s. The mi tochondri a, whi ch produce ATP for the cel l when oxygen is
P.752
avai labl e, are thought to be central to the i ni tiation of apoptosis (Fi g. 27-5). The rel ease of a
mi tochondri al protei n, cytochrome c, can ini ti ate thi s process by l eadi ng to the acti vation of
caspases that then cause the programmed cel l death. The pathway of apoptosis i s tightl y
regul ated; some molecul es, such as bcl -2, i nhi bi t this process whi l e other simi lar molecul es, such
as bad and bax, sti mulate apoptosis.
23
Neurons can undergo apoptosi s i n the absence of i schemi a.
Neurons have receptors for trophic factors such as nerve growth factor, neurotrophi ns, and brai n-
deri ved growth factor. These factors activate receptors that phosphoryl ate tyrosi ne resi dues on
certai n protei ns, thereby i nhi bi ti ng apoptosi s. If these growth factors are not present, the
receptors are not acti vated and the proteins are not phosphoryl ated; then the neurons wil l
undergo apoptosis. Indeed the loss of growth factors subsequent to neuronal degenerati on after
ischemi a can exacerbate the del ayed neuronal loss.
NEUROANESTHESIA
Ef f ect s of Anest het i cs and Ot her Adj unct i ve Dr ugs on Br ai n
P hysi ol ogy
Volatile Anesthetics
Hal othane, enflurane, sevofl urane, desfl urane, and i sofl urane have di rect vasodi latory effects
that i ncrease CBF (Tabl e 27-5). Hal othane wi th nitrous oxi de (1.5 mi ni mal alveol ar
concentrations [MAC]) has been shown to i ncrease bl ood fl ow al most 65%, whereas enfl urane and
FIGURE 27-5. The effect of hypoxia or i schemi a on cel l ul ar changes l eadi ng to apoptosi s.
The mi tochondri a are central to the acti vati on of apoptosi s, when hypoxi c or i schemic
triggers activate mi tochondri al release of cytochrome c this l eads to the activati on of a
caspase, which activates other caspases, endonucleases, and other proapoptoti c protei ns.
Thi s causes a cel l sui ci de i n whi ch there is l i ttl e damage to surrounding cell s. Trophi c factors
can acti vate ki nases that activate proteins that arrest apoptosis and can l ead to cel l survival .
Thi s is a complex pathway wi th control poi nts that can ei ther block or initi ate cell death.
isoflurane have a l esser effect at equal anestheti c potency.
24
Enflurane increased bl ood fl ow
approxi mately 35%; isofl urane caused an even smal ler i ncrease. The i ncrease i n CBF returns to
baseli ne level s approxi matel y 3 hours after the i ni ti al exposure to 1.3 MAC of anestheti c.
Sevoflurane and desflurane appear si mi lar to i sofl urane with respect to CBF;
25, 26
however,
desfl urane i ncreases CBF to a greater and sevofl urane to a lesser extent than isoflurane.
27, 28

Desfl urane has been reported to i mpai r autoregulation.
29
The i mportance of i ncreased CBF i s i ts
influence on ICP. Increasing blood fl ow woul d tend to i ncrease the amount of bl ood i n the brai n,
whi ch coul d l ead to increases i n ICP under condi ti ons of abnormal intracrani al el astance. In ani mal
studi es, sevofl urane demonstrated a smal l er increase of ICP than i sofl urane, whi le desfl urane
showed a l arger i ncrease; these differences di sappeared wi th hyperventi l ati on.
30
In any case if
hi gh ICP i s a potenti al probl em i t i s better to use an i ntravenous agent such as propofol since it
does not have any di rect vasodi l atory effect.
31
The vol ati le anestheti cs reduce the CMR; i sofl urane
reduces the metabol i c rate to a greater extent than hal othane. Sevofl urane reduces CMR to a
si mi l ar extent as isofl urane.
32
It i s thought that i sofl urane' s metabol ic effect, which reduces CBF,
competes with its di rect vasodil atory action to l imi t the net i ncrease in CBF wi th thi s agent.
Enflurane has been shown to i nduce seizure-type discharges; this effect i s potenti ated by
hypocapni a. Sei zures i nduced with 1.5 MAC enflurane, hypocapnia, and an audi tory sti mulus
i ncreased CMR and bl ood fl ow by 50%.
33
The mai n advantage of desfl urane over i sofl urane i s a
faster onset and recovery from anesthesi a. Studi es have indi cated that i t can cause greater ICP
increases than i sofl urane i n pati ents with al tered i ntracrani al el astance.
34
Therefore, i t is not
recommended for pati ents wi th space-occupyi ng lesions. Desfl urane has al so been shown to cause
sympatheti c hyperacti vity in heal thy vol unteers.
35
Sevofl urane has the potenti al for toxi city, si nce
it can be converted to toxi c agents; however, the concentrati on of these agents is normal ly below
the toxi c threshol d. Sevofl urane has been shown to be a useful alternati ve to halothane for
pedi atri c i nducti on, however there are

reports of epil epti form di scharges in pati ents given sevoflurane at i nducti on doses (1.5 to 2
MAC).
36
Sevofl urane demonstrated cerebral protecti on during i ncompl ete i schemi a in rats when
compared to fentanyl with ni trous oxide.
37
These consi derations make sevofl urane and i sofl urane
the volatil e anestheti cs of choi ce for neuroanesthesia. However, both of these agents are
vasodil ators and have the potenti al to i ncrease ICP under certain circumstances.
24

P.753
TABLE 27-5 Effects of Anesthetics on CBF/CMRO
2

CBF
CMRO
2
DIRECT CEREBRAL
VASODILATION
Halothane
Yes
Enflurane Yes
Isoflurane Yes
Desfl urane Yes
Sevoflurane Yes
N
2
O al one
Ni trous oxi de can increase CBF and ICP.
24, 38
Barbi turates and hypocapni a i n combi nati on may
prevent these i ncreases. There are i ndi cations that, even when gi ven i ndependentl y, barbi turates,
benzodiazepi nes, and morphi ne are effective in bl unti ng ni trous oxide' s effect on CBF and ICP. In
contrast, a vol ati l e anestheti c may add to the increases i n CBF obtai ned with ni trous oxide.
Although the data on ni trous oxide' s effect on brai n metabol i sm are far from unequi vocal , the
evidence seems to indi cate that there can be a substanti al increase i n CMR i f nitrous oxi de i s
administered al one.
38
Al though nitrous oxi de i s commonl y used i n neuroanesthesia, i ts use should
be careful ly consi dered given i ts potenti al effects on CBF, CMR, and ICP.
39

Intravenous Anesthetics
Barbi turates decrease the CMR and CBF.
24
A major problem wi th barbi turates is that they can
substantial ly reduce MAP, which, if not control l ed, can reduce CPP. At hi gh doses (10 to 55
mg/kg), thi opental can produce an i soel ectri c EEG and decrease the CMR by 50%.
40
Thi s di rect
metaboli c effect of thi opental leads to constriction of the cerebral vasculature and thereby reduces
CBF. Barbiturates are al so effective i n reducing el evated ICP and control l ing epil eptiform acti vi ty.
Methohexital i s an exception wi th regard to epil epti form acti vi ty; it can acti vate some sei zure foci
in pati ents wi th temporal l obe epil epsy.
41

Etomi date, li ke the barbiturates, reduces CMR and CBF.
24
In addition to the indirect effect of
reduced cerebral metabol i sm on bl ood fl ow, etomidate is al so a di rect vasoconstri ctor even

before metabol ism i s suppressed.
24
Its advantage over the barbi turates is that it does not produce
cl i ni cal ly significant cardiovascular depressi on. Prolonged use of etomi date may suppress the
adrenocorti cal response to stress.
42

Propofol i s a rapidl y acti ng intravenous anestheti c that, li ke etomi date and the barbi turates,
reduces the CMR and CBF.
24
It reduces the CMR to a si mi l ar extent as sevofl urane,
43
but si nce i t
does not i ncrease cerebral bl ood fl ow it is able to reduce ICP. However, because i t al so reduces
MAP, its effect on CPP must be carefull y moni tored.
44
Recent studi es have shown a lower jugul ar
bulb oxygen saturation during hyperventilation for patients undergoi ng propofol anesthesi a when
N
2
O with volati l e anestheti cs
N
2
O with intravenous
anesthetics
0 0
Thi opental
No
Etomi date No
Propofol No
Mi dazolam No
Ketamine No
Fentanyl /0 /0 No
P.754
compared to pati ents anestheti zed wi th sevofl urane; thus care must be taken when
hyperventi lating pati ents anetheti zed with propofol .
45
Propofol demonstrated longer l asting
venti l atory depressi on when compared with barbiturates.
46

Benzodi azepines have been shown to reduce CMR and CBF;
24
however, thi s effect i s not as
pronounced as that wi th the barbi turates. As wi th the barbi turates, the bl ood fl ow reducti on by
benzodi azepi nes i s thought to be secondary to a reducti on i n CMR. Benzodi azepi nes may reduce
ICP owing to their effect on CBF. Flumazenil is a benzodi azepi ne antagonist that has been shown
to reverse the CMR-, CBF-, and ICP-loweri ng effects of the benzodi azepi ne mi dazol am.
47
Thus,
flumazenil shoul d be used cauti ousl y, if at al l , i n patients with hi gh ICP or abnormal i ntracrani al
el astance.
The opioi d anestheti cs, morphi ne and fentanyl , cause ei ther a minor reducti on or no effect on CBF
and CMR when compared with condi tions i n the unsti mulated brain.
24
There is controversy
concerning the effects of sufentani l : some studi es demonstrate a reducti on i n CBF and
metabolism,
48, 49
whereas others report an i ncrease i n bl ood fl ow and ICP.
50
The duration of the
increased bl ood fl ow and ICP effects of sufentani l i n these earl ier cited studi es was short and
coul d be overcome by hypocapni a. In ani mal studi es, alfentani l decreased CBF and metabol ism
after 35 mi nutes and had no significant effect on ICP.
51
In pati ents wi th brai n tumors, al fentani l
i ncreased CSF pressure.
52
Its effect on CSF pressure was l ess than that found with sufentanil but
greater than that found wi th fentanyl. Alfentanil had the greatest effect on MAP and CPP.
50

Remi fentani l , a rapi dl y metabol i zed opi oi d, had si mil ar effects to fentanyl on CBF; both agents
maintained CO
2
reacti vi ty.
53
Remi fentanil' s main advantage is that i t all ows a more rapi d
neurol ogic assessment of the patient. Asi de from the difference in recovery ti me, there appear to
be only mi nor differences between the di fferent opi oi d anestheti cs.
54
Opi oid anestheti cs do not
substanti al l y suppress metabol i sm as does propofol; however, there was no di fference i n cogni tive
functi on foll owi ng coronary artery bypass surgery compari ng these two classes of anestheti cs.
55

Dexmedetomidi ne i s an -2 sel ecti ve agonist that has anal gesic and sedative effects. It is useful
si nce the patient i s sedated but cooperati ve.
56
Dexmedetomi di ne has been shown to reduce
arousal and decrease cerebral bl ood fl ow.
57

Ketamine, a dissoci ati ve anestheti c, acti vates certai n areas i n the brai n and can increase CBF and
CMR.
58, 59
It is therefore not commonl y used in neuroanesthesi a.

Barbi turates, propofol , and benzodi azepi nes are i ntravenous agents recommended for
neuroanesthesia; opi oids, parti cul arly fentanyl and remifentanil , have al so proved useful.
BRAIN PROTECTION
Morbidi ty and mortal i ty rates for elective neurosurgery are so l ow that detecti ng a decrease i n
mortal i ty i s virtuall y out of the questi on and daunti ng sampl e si zes woul d be requi red to detect
less than a 30% i mprovement i n major morbi di ty. Accordi ngl y, i nferences about cerebral
protecti on are li mi ted to those that we can draw from the l aboratory, from cli ni cal trial s of
therapies that are insti tuted subsequent to i schemi c injurypri mari l y i n stroke and head-trauma
patientsand from the small number of cl i ni cal tri al s that test for prophylacti c neuroprotection in
neuro- and cardiac surgery.
Cer ebr al P r econdi t i oni ng
Usi ng the reti na as a model for the CNS, Barbe and co-authors found that subjecting rats to heat
shock (15 minutes at 41C) protected neurons from hi gh-intensi ty l i ght damage i f the rats were
al lowed to recover for 18 hours subsequent to heat exposure.
60
Thi s phenomenon was soon
repl icated i n a model of cerebral i schemi a
61
and i nducti on of endogenous protei ns of repai r, and
the genes that code for them are now wel l documented.
62
Among the most i ntriguing recent
genomic discoveri es is Stenzel -Poore and col leagues' fi ndi ng that i schemi c precondi ti oni ng i n a
homeothermi c mammal el i ci ts an evoluti onari l y conserved endogenous response to decreased
bl ood flow and oxygen li mi tati on such as seen during hibernati on.
63

P.755
Perhaps precondi ti oni ng wil l bri ng us cl oser to a vi sion arti cul ated by James Cottrel l more than a
decade ago: Much research has been di rected toward enabl i ng homeothermi c mammal s to gai n
the benefi ts of hypothermi a without payi ng the costs, as do hi bernators. If that research
succeeds, we may eventual ly be able to provi de brai n protecti on duri ng protracted peri ods of
ischemi c' CBF and even i nduce ci rculatory arrest i n neurosurgi cal pati ents wi thout goi ng on
bypass.
62

Cli nicall y acceptable means of accompli shi ng cerebral precondi ti oni ng are bei ng sought.
Experimental results suggest the possibi l ity of preop hyperbari c oxygen, normobari c 100% oxygen
exposure, el ectroconvul sive shock, and the potassi um channel opener di azoxide among other
candi dates.
62
The first human tri al of a cerebral precondi ti oni ng agent
64
empl oys a substance that
i s endogenousl y produced i n the brai n after hypoxi c or i schemi c insul tserythropoi eti n (EPO).
Although EPO i s wel l characteri zed i n its systemic rol e as a cytoki ne growth hormone that
increases the producti on of erythrocytes by preventi ng their apoptoti c sel f-destructi on duri ng
differentiation, EPO' s role in the brai n has onl y recentl y been elucidated. EPO i s produced in the
adult mammal i an brai n pri mari l y by astrocytes i n the ischemic penumbra. EPO receptors (EPOr)
are upregul ated by neurons i n the ischemi c penumbra, and the EPO ->> EPOr i nteracti on i n these
and other cerebral and cerebrovascul ar cel l types has been reported to sti mul ate protei ns of
repair, di mi ni sh neuronal excitotoxi ci ty, reduce i nfl ammation, inhi bi t neuronal apoptosi s, and
stimul ate both neurogenesi s and angi ogenesi s subsequent to experi mental i schemic, hypoxic, and
toxi c injury.
62

Limiti ng thei r study to ischemi c stroke pati ents whose treatment coul d begin wi thin 8 hours of the
onset of symptoms, Ehrenrei ch and co-authors found that i ntravenous injecti on of recombi nant
EPO once dai ly for 3 days led to 60- to 100-fol d i ncreases of EPO i n the CNS, reduced serum
concentrations of the gli al marker of cerebral i njury S100, reduced i nfarct size, and i mproved
recovery.
64
If these resul ts hold up i n a multi center, randomized, control l ed tri al , there i s reason
to hope that EPO woul d be even more effecti ve as a prophyl acti c protectantbecause we mi ght be
abl e to harness EPO' s precondi ti oni ng effects by i ni ti ati ng admi ni stration 24 to 48 hours pri or to
surgery, del iver EPO during surgery (often i ntraventri cularly, whi ch is parti cularly effecti ve), and
maintai n admi ni strati on i n the neuro ICU.
Unfortunatel y, EPO has the attri bute of i ncreasi ng hematocri ta potenti al l y del eterious effect i n
the context of i schemi c injury. Fortunatel y, nonhematopoi etic analogues of EPO, such as
asi al oEPO, have been devel oped and are showi ng equival ent potency as neuroprotectants i n the
laboratory.
Neur ogenesi s and Di aschi si s
The old adage that neurogenesi s is onl y for the young has been shown to be wrong.
65

Acti vated neural stem cel ls contri bute to stroke-induced neurogenesis and neurobl ast
mi grati on toward the i nfarct boundary in adul t rats
66
and therapy of stroke in rats wi th a ni tri c
oxi de donor and human bone marrow stromal cel l s enhances angi ogenesi s and neurogenesis
subsequent to 2 hours of mi ddl e cerebral artery occl usi on. Thi s ki nd of evi dence lends
encouragement to the hypothesis that adul t neurogenesi s i s functi onal and that neural precursors
resident i n the brai n initi ate a compensatory response to stroke that resul ts i n the producti on of
new neurons. Moreover, admini stration of growth factors can enhance thi s compensatory
response [and] we may eventually be able to mani pul ate these precursors to improve recovery of
function in individuals afflicted by thi s devastati ng i njury.
67

At the other end of the l adder of repai r, Stroke produces an area of focal damage and di stant
areas of reduced bl ood fl ow and metabol i sm, termed di aschisi s di aschi si s may be part of a
process of structural reorgani zation after i njury.
68
In other words, perhaps the brai n is such a
ti ghtl y i ntegrated ci rcuit that dysfuncti onal subci rcuits add noise to the system and need to be
removed to faci l itate rewi ri ng. Accordi ngl y, we shoul d be cautious, i f not outright skepti cal , of
proposed therapi es that nonsel ecti vel y i mpede programmed cel l death or apoptosisthat i s, the
prevail i ng assumpti on seems to be that al l neuron death i s bad, but thi s may be wrong.
Mi l d Hypot her mi a and P ost oper at i ve Fever
Laboratory results have demonstrated since 1956 that the benefi ci al attri butes of mi ld
hypothermia are li kel y to outwei gh i ts real but manageable untoward effects when
neurosurgi cal procedures are hi gh ri sk and/or protracted. Berntman et al found that one degree of
hypothermia (to 36C) maintai ns ATP at normoxi c l evel s during an hypoxi c i nsul t that depl etes
ATP by hal f at normothermi a (37C), and three degrees of hypothermia (to 34C) more than
doubl ed preservati on of phosphocreati ne.
69
These resul ts suggest the possi bi li ty that the i ni ti al
decline of CMR during hypothermi a is greater than has been previ ousl y assumed.
70, 71

Unfortunatel y, the most current and defi ni tive cl i ni cal tri al of mi l d hypothermi a has concl usively
shown a fai lure to i mprove outcome after surgery for repai r of a ruptured cerebral aneurysm. The
Intraoperative Hypothermia for Intracrani al Aneurysm Surgery Tri al (IHAST) was compl eted i n
2003. Wi th 499 pati ents randomized to undergo aneurysm cl i pping at 33C compared to 501
control s at 36.5C, the study had ampl e power to detect a 10% i ncrease i n the frequency of good
outcomes. Mil d hypothermi a was not benefi cial .
Prel iminary resul ts for Intention-to-Treat anal ysis i ndi cate that 66% of pati ents in the
hypothermi c group had a good outcome at 90 days versus 63% of pati ents in the normothermic
group. Because people do not easi l y cool down as schedul ed, onl y 373 of the 499 pati ents
assi gned to the hypothermic group actuall y reached a core temperature bel ow 33.5C, whi le 467
of the 501 normothermi c pati ents maintai ned core temperature above 36C.
72
In a pl anned
secondary anal ysis of these pati ents who were wi thi n 0.5C of thei r target temperature during
aneurysm cli ppi ng, 62% of the hypothermi c pati ents had a good outcome versus 63% of the
normothermi c pati ents. It i s of i nterest to note that the warmer pati ents i n the enti re hypothermi c
group (>33.5C, N = 126) had more good outcomes (77%) than the cooler pati ents (<33.5C, N =
373) i n the hypothermi c group (62%) (p<0.003, two-way Fi sher exact).
73
The onl y stati sti cal l y
si gni fi cant intergroup di fference i n adverse outcomes was a hi gher incidence of bacteremi a in the
hypothermi c group.
Why has so much l aboratory evidence for a therapeuti c benefi t of mi l d hypothermi a not been born
out i n aneurysm patients? It shoul d be remembered that al most all of that evi dence i s from, or i s
anal ogous to, models of i schemi c stroke, as di sti nct from hemorrhagi c stroke, and the few
hemorrhagi c stroke models that do exi st have appl i ed hypothermia before, duri ng, or wi thi n a few
hours of the intracrani al bl eedas di sti nct from several days postrupture. If there i s any benefi t
of intraoperative mild hypothermia for hemorrhagic stroke pati ents, it may not be detectabl e
because i t i s dwarfed by damage that precedes surgery (the i ni tial bl eed) and damage that occurs
in the postsurgical ICU (vasospasm, etc.). The i ni tial bleed may also activate functional diaschi si s
and postinjury repai r mechani sms to whi ch i ntra-operative mi l d hypothermi a is not therapeuticall y
addi ti ve.
The mul ti -insti tuti onal study of postoperati ve mil d hypothermi a i n head-injury patients came to an
even more di scouragi ng conclusionthe study was termi nated by i ts

Safety Moni tori ng Board after enrol l ment of 392 pati ents.
74
A decrease i n the number of
hypothermi c pati ents wi th ICP >30 mmHg (59% vs. 41%) did not produce a difference in mortali ty
(28% vs. 27% i n the normothermi c group) and normothermi c pati ents experi enced fewer bouts of
criti cal bradycardi a and hypotensi on, and fewer medi cal compli cati ons.
These fi ndi ngs accord wel l wi th resul ts from a cli nical study of the effect of prol onged mi l d
hypothermia on el ectrol yte balance. Pol derman and co-authors found that serum magnesi um,
phosphate, and potassium fel l to criti cal level s despite the fact that moderate and, i n some
cases, substanti al doses of electrolyte suppl ementation were gi ven.
75
More generally, some of the
most competent l aboratory studi es i ndi cate that hypothermi a administered subsequent to an
ischemi c event onl y del ays neuronal death, and other i n vi vo work suggests that i f there i s a
window of opportuni ty for i nducing protecti ve post-ischemic hypothermia, it i s very narrow.
62

Indeed, the narrowness of that window may account for reports of neuroprotective effects from
mi ld hypothermia after cardi ac arrest. In both major studi es,
76, 77
most pati ents were mi l dl y
P.756
hypothermic on admission, and i t is reasonable to speculate that thei r brai ns began to cool as
soon as they l ost CBF. Pati ents assi gned to the hypothermi c groups were cool ed further for 12 to
24 hours, whi l e those assi gned to the normothermi c groups were passively warmed to
normothermi a or above over a 6- to 8-hour period, such that the hypothermi c groups began to
cool i mmedi atel y and were kept cool for a substanti al peri od of time whil e pati ents i n the
normothermi c groups began to cool i mmedi atel y but di d not remai n hypothermi c for a substanti al
peri od of ti me. Put di fferentl y, both groups of pati ents became hypothermi c wi thin the wi ndow of
opportuni ty, but the opportunity for a protective effect may have been lost too soon thereafter in
the normothermi c pati ents.
Evi dence that this considerati on mi ght be criti cal ly i mportant comes from the definiti ve head-
injury study: Among the patients who had normothermi a on admi ssi on, the outcomes were si mi lar
in the two treatment groups.[But] among the patients who had hypothermia on admission and
were treated with hypothermia, 61 percent had poor outcomes, as compared with 78 percent of
those wi th hypothermi a on admi ssi on who were in the normothermia group (P = 0.09)[and]
among pati ents 45 years of age or younger who had hypothermi a on admissi on, 52 percent of
those assi gned to the hypothermia group had poor outcomes, as compared wi th 76 percent i n the
normothermi a group (P = 0.02).
74

Unti l and unless the del eterious effects of mi l d hypothermia can be reduced, or the brai n can be
cool ed wi thout reducing systemic temperature below 35C, cli nical evidence does not support
inducti on of perioperative hypothermi a for neurosurgi cal procedures that do not entai l ci rculatory
bypass.
Nevertheless, fever i n the neurosurgi cal or cardi ac intensi ve care unit associ ates strongl y with
poor outcome.
62
In vi tro results i ndi cate that just as hypothermi a preserves ATP, reduces CA
2+

infl ux, and i mproves el ectrophysiologi c recovery from hypoxi a, so does hyperthermi a depl ete ATP,
increase CA
2+
i nfl ux, and i mpai r recovery.
78, 79
A potenti all y promi si ng devel opment i n ICU
temperature control is the concept of low normothermi akeeping nonventil ated pati ents servo-
control led at 36C i n order to provi de substanti al assurance agai nst bouts of fever.
80

Anest het i c and Adj uvant Dr ugs
Cl i ni cal l y veri fi ed pharmacol ogi cal brai n protecti on i s even more elusi ve than the benefits of mi l d
hypothermia. Del ayed neuronal necrosis, apoptosis, di aschisi s, and neurogenesis can cause
protecti on, whi ch appears to be evi dent wi thi n 1 to 100 hours of experi mental i nfarct, to vani sh
after 3 to 6 months. Accordingl y, decades of l aboratory research on the short-term
cerebroprotecti ve effects of general anesthetics, both i nhal ati onal and intravenous, i s cal l ed into
question by studies that have found no l ong-term differences.
81, 82
Unti l and unl ess l ong-term
laboratory studies suggest a di fference i n the neuroprotecti ve efficacy of general anesthetics that
are wi dely used for neurosurgery, cl inical deci si ons about whi ch anesthetic i s most appropriate
shoul d be based on consi derati ons other than potenti al to provi de superi or cerebral protecti on per
se. Nevertheless, as with hypothermi a, the search conti nues for the optimal anesthetic i n
subgroups of pati ents.
Barbiturates
As with mi l d hypothermi a, reducti on of CMR i s a catch-al l term that may or may not i ndi cate
cerebral protecti on. Although an i ntel lectual backl ash has chal l enged the operating hypothesi s that
loweri ng CMR has a substanti al protecti ve effect,
83
all known means of lowering CMR entail
si multaneous negati ve effects, wi th the conti nuum of drugs, techni ques, and toxins that reduce
CMR rangi ng, on bal ance, from protecti ve to damagi ng. Nakashi ma and co-authors found that for
si mi l ar reducti ons of CMR obtained wi th hypothermi a, pentobarbital , or i sofl urane, hypothermi a
resul ted i n substanti al l y l onger ti mes to depol arizati on of cerebral cortex subsequent to cardiac
arrest.
84
Concomitantly, Verhaegen and co-authors found that hypothermi a reduces CMR during
ischemi a proportionatel y more than does pentobarbi tal or i sofl urane.
85

Accordi ngl y, we fi nd mi l d hypothermia near the protecti ve end of the conti nuum, fol l owed at some
di stance by anestheti cs (reversi bl e neurotoxi ns), then movi ng to the damaging end, we fi nd
nonreversibl e neurotoxins foll owed at some di stance by blunt traumaal l of which lower cerebral
metaboli sm. The poi nt here is that the benefi t of reducing CMR remains constant whi l e the cost of
doi ng so vari es from mi nor to l ethal. From thi s perspecti ve i t seems rash to chal l enge the efficacy
of reduci ng CMR i n and of i tsel f.
Some of the proxi mate mechani sms by whi ch barbi turates l ower CMR include reducti on of cal cium
infl ux, sodi um channel bl ockade, i nhibi tion of free-radical formation, potentiation of GABAergi c
acti vi ty, and i nhi bi ti on of glucose transfer across the bl ood-brai n barri er. Al l of these mechani sms
are consi stent with Goodman and co-authors' report that pentobarbi tal coma markedl y reduces
lactate, glutamate, and aspartate in the extracell ul ar space of head-injured pati ents wi th severel y
i ncreased ICP.
86
An in vi tro i nvestigati on suggests that thi opental al so del ays the l oss of
transmembrane electri cal gradi ents caused by appl i cation of NMDA and AMPA. Thi s stands i n
marked contrast to the effect of propofol, whi ch can aggravate gl utamate exci totoxi city and
increase neuronal damage.
87

Sodium Channel BlockadeLidocaine
Sodi um i nfl ux i s the fi rst step i n the i schemic cascade. Truncati ng ini ti al steps of the cascade, as
di sti nct from bl ocki ng glutamate receptors and scavengi ng free radicals, reduces damage done by
downstream events and l owers the probabil i ty of i nterferi ng wi th endogenous mechani sms of
repai r. In addi ti on to bl ocki ng sodi um i nfl ux, l idocai ne may also reduce postnecroti c injury. Recent
in vi vo data suggest that l i docai ne truncates ischemi c damage i n the penumbra by bl ocki ng the
apoptoti c cell death pathways that i nvol ve cytochrome C rel ease and caspase-3 activation.
88

These appear to be some of the mechani sms by whi ch experi mental , prophyl acti c, low-dose
li docaine has demonstrated neuroprotecti ve properti es both in vi tro
89, 90
and in vivo.
91, 92

Looki ng for neuroprotection in cardi ac val ve pati ents, Mi tchel l and co-authors found that l i docai ne
i nfusi on begun

at i nducti on of anesthesi a and conti nued for 48 hours wi th a target pl asma concentration between
6 and 12 mol /L i ncreased scores i n 6 of 11 neuropsychol ogi cal tests and i n pati ents' memory
inventory.
93
Si mi lar resul ts were obtai ned by Wang and co-authors in coronary artery bypass
patients,
94
but a thi rd trial of l idocai ne i n cardiac pati ents fai l ed to fi nd a protecti ve effect and
found an adverse effect i n di abeti c pati ents.
95
Neverthel ess, i ni tial data presentati on i ndi cates a
substanti al posi ti ve effect i n nondi abeti c li docaine pati ents compared to nondi abeti c control s. An
addi ti onal consi derati on i s that these patients were mai ntained at 30 to 32C duri ng surgery
whi ch cardi ac col leagues tend to thi nk of as not hypothermi cbut which may provide a l evel of
neuroprotecti on to whi ch l i docaine i s not addi ti ve.
Calcium Channel BlockadeMagnesium
Magnesi um bl ocks both l i gand and vol tage dependant cal ci um entry, has shown considerabl e
neuroprotecti on i n animal experi ments, and appears to neurologi cal ly protect preterm i nfants i f
administered to their mothers immedi atel y before birth. The fact that magnesium is also
powerfully protective in vitro
96
suggests that it may cri ti cal l y reduce calci um i nfl ux i n addi ti on to
i mprovi ng CBF subsequent to cerebrovascul ar dil ati on. Recent l aboratory work i ndi cates that
magnesium defi ciency exacerbates traumatic brain injury while magnesium loading shortly
subsequent to trauma reduces i njury. If the same hol ds for stroke patients, efficacy is most l ikely
to be real ized by the FAST-MAG (Fi eld Admi ni strati on of Stroke TreatmentMagnesi um) trial . A
prel iminary report on the first 20 FAST-MAG pati ents indicates that paramedics can admi ni ster a 4
g loading dose of magnesium sulfate en route to the hospi tal wi thout substanti al compl i cations.
97

In di sti ncti on, the long-awai ted RCT of not-fast MgSO4 (withi n 12 hours of stroke) has shown
rather concl usi vely (2,386 patients) that magnesium l oadi ng is not neuroprotecti ve and may
increase mortal ity i n stroke pati ents.
98

For reasons detai l ed earl ier regardi ng i ntra-operative hypothermi a in stroke pati ents, cardiac
patients are probabl y a better model for testi ng the general neuroprotecti ve effi cacy of MgSO4.
Unfortunatel y, however, a meta-anal ysi s i ndicates that the only benefi t of prophyl actic magnesi um
P.757
in cardiac surgery patients i s a reducti on in postsurgical atri al fi bri l lation.
Additional Clinical TrialsRemacemide and High-dose Mannitol
Remacemi de reduces gl utamate rel ease, and so excitotoxi ci ty, by blocki ng NMDA channel s.
Evi dence for a prophyl acti c benefi cial effect of this NMDA blocker was gleaned by combi ning scores
from ni ne neuropsychologi cal tests in coronary artery bypass pati ents. Those data al l ow the
inference (p<0.03) that i n exchange for a hi gher ri sk of di zziness duri ng 9 days of drug
administrati on, patients i n the treatment group retai ned more of thei r abi l ity to l earn.
99

Comatose patients wi th severe di ffuse brai n swell i ng and recent cl i ni cal si gns of i mpendi ng brai n
death
100
have a justi fi abl y l ower threshol d for bei ng subjected to experi mental treatments. Cruz
and col l eagues reported dramati c success wi th admi ni strati on of hi gh-dose mannitol versus
conventi onal -dose mannitol in such patients randomi zed in the emergency room to recei ve ei ther
1.4 g/kg or 0.7 g/kg manni tol . Ul tra-early improvement of bi lateral abnormal pupi l l ary wi deni ng
was si gnifi cantly more frequent in the hi gh-dose mannitol group than in the conventional -dose
group as was the number of pati ents wi th Good or Moderate (GOS) 6-month cl inical outcomes (10
in the high-dose group versus 2 in the conventional -dose group, p<0.02). These stark resul ts beg
to be tested i n a multi nati onal randomi zed controll ed tri al.
101

What t o Avoi d
As with postoperati ve mi l d hypothermi a in head-injury patients (see earli er), evidence against
some anesthetic and adjuvant drugs is stronger than the evi dence i n thei r favor.
Calcium Channel BlockersPostoperative
Several cl i ni cal tri als and two meta-anal yses suggest that cal ci um channel bl ockers ni modi pine,
ni cardi pi ne, and AT877 reduce the frequency of vasospasm subsequent to subarachnoi d
hemorrhage and/or i mprove outcome.
102
The most favorabl e fi ndi ng of the recent meta-anal yses
suggests that ni modi pi ne i mproves outcome, on average, by preventi ng one poor outcome i n 1 out
of every 13 pati ents treated.
100
Whether the reducti on i n bl ood pressure that accompanies these
Ca
2+
blockers i mproves outcome rel ati ve to hypertensive, hypervolemic, hemodil uti on remains
controversi al. Nei ther meta-anal ysi s was abl e to detect a stati sti cal l y si gni fi cant reduction in
mortal i ty. Two subsequentl y publi shed cl inical tri al s, one that administered ni modi pine wi thi n 24
hours of acute stroke
103
and one that admini stered ni modipi ne within 6 hours of stroke,
104
fai l ed
to detect a benefi ci al effect.
The most di sturbi ng reports yet publ i shed about ni modi pi ne, di sturbi ng for medi cal research i n
general , are two systematic revi ews that reveal a lack of evidence to justify Phase 3 cl inical trial s.
Contrary to conventional assumpti on, publ i shed l aboratory experi ments found as many negati ve as
positi ve results, and ani mal experiments and cli ni cal studi es ran si mul taneousl y. Maki ng matters
worse, several methodol ogi cal l y sound cl i ni cal studi es of cal cium antagoni sts in i schemi c stroke
patients remained unpubl i shed. In each of those unpubl ished studi es, resul ts were si gni fi cantl y
worse for pati ents in the treatment groups.
105

Etomidate
EEG burst suppression wi th etomi date pri or to temporary vessel occlusi on gai ned prominence
el even years ago on the basi s of a cl i ni cal tri al for whi ch there was no control group, no
al ternative drug tested, and no hi stori cal standard for compari son. Despite the absence of
supporti ve cl ini cal evi dence, and the presence of troubli ng l aboratory results,
106
etomi date
remai ns the standard regi men for cerebral protection at several i nsti tuti ons. We now have cl i ni cal
evidence that the standard propylene gl ycol formulation of etomi date i nduces more cerebral ti ssue
hypoxi a, ti ssue aci dosi s, and neurol ogi cal defi cits than an EEG-equival ent dose of desflurane.
107

Nitrous Oxide and Ketamine
In 1938 C.D. Courvil l e publ i shed The pathogenesi s of necrosis of the cerebral gray matter
fol l owing ni trous oxi de anesthesi aan articl e that presents photographs of vacuol ated cortical
neurons from pati ents who di ed subsequent to administrati on of ni trous oxide (N
2
O).
108
Sixty
years later, Jevtovi c-Todorovi c and co-authors publ ished compel l ing evi dence that N
2
O causes
vacuol ati on of both the endoplasmi c reti culum and mi tochondria of neurons in the posterior
ci ngul ate and retrospl eni al cortices of rats.
109
Are we on our way to where we mi ght have been i f
Courvil l e's work had recei ved more sustai ned attenti on?
110

Ni trous oxi de' s mechanism of action is NMDA receptor antagonism, and l ike other NMDA

antagonists, N
2
O has been shown to reduce damage from excessive gl utamate rel ease.
Unfortunatel y, however, because NMDA al so exci tes i nhibi tory neurons, NMDA blockade causes
inhi biti on of GABA release, and thus general di si nhibi tion. Thi s i s probabl y a component of the
mechani sm by whi ch N
2
O, l i ke other NMDA antagoni sts (e.g., ketamine, phencycl i dine,
dextrorphan, MK-801), can cause neuronal damage.
111

The question of N
2
O' s effect on the neuroprotecti ve efficacy of pri mary anestheti cs has been
addressed by several i nvesti gati ons. Fol lowi ng Arnfred and Secher' s demonstration that thi opental
more than doubles survival ti me i n mi ce subjected to hypoxi a whi l e N
2
O reduces survival ,
112, 113
it
was found that co-administrati on of N
2
O virtuall y el i mi nates the protecti ve effect of thiopental i n
the same model.
114
Two years l ater, Baughman and co-authors found that N
2
O cut the protecti ve
effect of isoflurane in half.
115
More recentl y, Jevtovic-Tedrovic and co-authors found that N
2
O
converts a nontoxi c dose of ketami ne i nto a substanti al l y toxic dose in rats,
116
and addi ng N
2
O to
isoflurane or i sofl urane wi th midazol am substanti al l y exacerbates those agents' pro-apoptoti c
effect duri ng the brai n growth spurt in devel opi ng rats.
117

Evi dence that the earli er-menti oned cl i ni cal and l aboratory fi ndi ngs resulted i n part from a di rect
neurotoxi c effect of N
2
O i s bol stered by our fi ndi ngs i n the hippocampal sli ce model , where nitrous
oxi de markedl y reduced el ectrophysiol ogi cal recovery from severe hypoxi a without affecti ng
fundamental bi ochemi cal parameters l i ke ATP concentration, Ca influx, K efflux, and Na influx.
118

Direct neurotoxi ci ty aside, N
2
O has been repeatedly shown to increase CMR, CBF, and ICP when
used al one, but these effects are variabl e when N
2
O is used as an adjunct anestheti c, wi th or
wi thout hypocapni a, and wi th or wi thout EEG burst suppressi on. Recent evidence indicates that
N
2
O di sturbs CBF/CMRO
2
coupl i ng i n humans recei vi ng sevofl urane.
43
In pati ents wi th fol i c aci d
defici ency, a si ngl e exposure to N
2
O can cause spinal cord degenerati on.
119
Less di rect, but al so
less rare, exposure to N
2
O causes a substantial increase i n plasma homocystei ne, whi ch can
increase coagul ati on, decrease fl ow-mediated vasodi lation, and i ncrease postoperati ve myocardi al
ischemi aal l of which compl i cate recovery in the neuro ICU. Prol onged hyperhomocysteinemi a is
al so an i ndependent ri sk factor for cerebrovascular disease.
Perhaps the most pressi ng questi on regardi ng the use of N
2
O i n neurosurgi cal pati ents has been
framed by Enlund, Edmark, and Revenas: It i s no consol ation for the patient who suffers from an
irreversibl e neurologi cal sequela after ni trous oxi de exposure that he happens to be the fi rst one
at your cl i ni c for the l ast fi ve years. For those l i ke us who admini ster drugs, or for the regulatory
authoriti es, such an i nci dent might nevertheless be acceptabl e provi ded that a great number of
patients recei ve indi spensable benefi ts, whi ch outwei gh a severe si de effect. Are there such pros
[benefits] from ni trous oxide?
120

SteroidsTirilazad
Cli nical appl icati on of the 21-amino steroi d ti ri l azad looked promi sing.
121
Unfortunately, more
substantive resul ts from a North American tri al in subarachnoi d hemorrhage patients fai l ed to
reach stati sti cal si gni fi cance,
122
and a fol l ow-up study of hi gh-dose ti ri l azad i n women depended
on an i diosyncrati c groupi ng of data to reach stati sti cal si gni fi cance.
123
A detai l ed commentary on
that analysi s concl uded that any eventual l y proven therapeuti c effi cacy i s likely to be modest,
124

and a systemati c revi ew of tiri lazad use i n 1,757 stroke pati ents concluded that Ti ril azad
mesylate i ncreases death and disabi l i ty by about one fi fth when gi ven to pati ents wi th acute
ischemi c stroke.
125
A recent reanal ysi s of i ni ti all y promi sing results has reveal ed a fail ure to
adjust for i mbalances i n basel i ne characteri sti cs.
P.758
Caut i on and Hope
Current evidence cauti ons against the use of prophylacti c etomi date pri or to temporary vessel
occl usi on, magnesi um l oadi ng i n ischemic stroke pati ents, i ntra-operative ni trous oxi de and
ketami ne, intra-operative moderate hypothermia i n subarachnoid hemorrhage (SAH) pati ents,
postoperati ve ni modi pi ne and ti rilazad, and postoperati ve hypothermia i n head-trauma pati ents.
On the posi ti ve si de, cerebral precondi tioni ng and augmentati on of endogenous processes of repai r
may del i ver standard-of-care brai n protecti on to neurosurgi cal pati ents wi thi n a decade.
MONITORING
El ect r oencephal ogr am
The EEG can be used to moni tor cerebral functi on duri ng general anesthesia. The pri mary use
of intraoperative EEG moni toring i s the detection of cerebral ischemia duri ng caroti d
endarterectomy, cerebral aneurysm, and arteri ovenous malformati on management and
cardi opul monary bypass procedures. EEG monitori ng i s also used for intraoperative or
peri operative assessment of pharmacologic i nterventions, such as barbi turate-i nduced burst
suppressi on, duri ng del i berate hypotension, and for the assessment of coma or brai n death.
Another i mportant i ntra-operative appl i cation of EEG is i n the diagnosis and management of
intractabl e epi lepsy.
The EEG waves recorded on the surface of the scal p are spontaneous electri cal potenti al s
generated by the pyrami dal cel l s of the granular cortex. The EEG signal consi sts of graded
summations of i nhi bitory and excitatory postsynapti c potenti al s that create di pol e fi el ds i n the
dendri tes of the pyramidal cel l s. When a number of di pol es devel op at once, the summation
creates electri cal potenti al s l arge enough to produce detectabl e voltage on the scalp.
The EEG waveforms are i nterpreted by pattern recogni ti on and quanti fi cati on. Speci fi c compl exes
are descri bed i n terms of morphol ogy, spati al and temporal di stributi on, and reactivity of the
waveforms. Quanti fi cation involves measuri ng frequency and ampl i tude. Frequency i s measured in
hertz (Hz) and i s defi ned as the number of ti mes per second the wave crosses the zero voltage
li ne. Ampl itude, whi ch i s measured in microvol ts (V), is the el ectrical hei ght of the wave. The
frequency bands are di vi ded i nto del ta (03 Hz), theta (47 Hz), al pha (813 Hz), and beta (>13
Hz) rhythms (Tabl e 27-6).
The traditi onal EEG i s a plot of voltage agai nst ti me. Sixteen channel s are usual l y recorded,
al lowi ng anal ysi s of activity of different regi ons of the brai n. EEG waveform changes associ ated
TABLE 27-6 EEG Frequency Ranges
Delta rhythm
(03 Hz)
Deep sl eep, deep anesthesi a, or pathologic states (e.g., brai n
tumors, hypoxia, metabol i c encephalopathy)
Theta rhythm
(47 Hz)
Sleep and anesthesia i n adults, hyperventil ati on i n awake chi ldren
and young adul ts
Alpha rhythm
(813 Hz)
Resting, awake adul t with eyes cl osed; predominantl y seen i n
occi pi tal l eads
Beta rhythm
(>13 Hz)
Mental acti vi ty, li ght anesthesi a
with anestheti c drugs, PaO
2
, PaCO
2
, and temperature are descri bed in Tabl e 27-7.

TABLE 27-7 EEG Changes Associated with Anesthetic Drugs, PaO
2
, PaCO
2
, and
Temperature
INCREASED FREQUENCY
Barbi turates (l ow dose)
Benzodi azepines (l ow dose)
Etomi date (l ow dose)
Propofol (low dose)
Ketamine
N
2
O (3070%)
Inhalation agents (<1 MAC)
Hypoxi a (i ni ti al l y)
Hypercarbi a (mi l d)
Sei zures
DECREASED FREQUENCY/INCREASED AMPLITUDE
Barbi turates (moderate dose)
Etomi date (moderate dose)
Propofol (moderate dose)
Opi oi ds
Inhalation agents (>1 MAC)
Hypoxi a (mi l d)
Hypocarbi a (moderate to extreme)
Hypothermia
DECREASED FREQUENCY/DECREASED AMPLITUDE
Barbi turates (hi gh dose)
Hypoxi a (mi l d)
Hypercarbi a (severe)
Hypothermia (<35C)
ELECTRICAL SILENCE
Barbi turates (coma dose)
Etomi date (hi gh dose)
Propofol (hi gh dose)
Desfl urane (2 MAC)
Isoflurane (2 MAC)
Sevoflurane (2 MAC)
Hypoxi a (severe)
Hypothermia (<1520C)
Brai n death
The EEG response to anestheti c agents can vary from corti cal excitati on through depressi on to
isoel ectrici ty. Usual ly,

anesthetic i nducti on produces a decrease i n al pha and an i ncrease in beta acti vi ty. As the depth of
anesthesia i ncreases, EEG frequency decreases unti l theta and del ta acti vi ty predomi nate. By
further increasi ng the dose of anesthesia, the EEG changes to a burst suppressi on pattern, which
coincides wi th near-maxi mal depressi on of cerebral metabol i c activity. Compl ete el ectri cal si lence
or i soelectri ci ty fol l ows an addi ti onal increase i n anesthesi a. Anesthesi a-induced burst suppressi on
i s used to provi de cerebral protection by metabol i c suppressi on. EEG monitori ng veri fi es burst
suppressi on and el ectri cal si l ence and i s val uable when determi ni ng the dose of drug requi red to
i nduce and mai ntai n barbi turate coma.
Efforts to use the EEG as a monitor of depth of anesthesi a have been probl ematic because of the
vari ety of agents used to mai ntai n anesthesi a and because some anestheti c agents do not fol l ow
the general pattern descri bed above.
33
Several di fferent cerebral -moni tori ng techni ques based on
EEG-deri ved algori thms, el ectromyograms, audi tory evoked responses, or combi nations of these
have been i ntroduced to more precisel y determi ne depth of anesthesi a duri ng surgery.
126, 127, 128

These vari ous techniques are currentl y under i nvestigati on with promi sing resul ts.
129, 130
A recentl y
publ ished mul ticenter, randomi zed control l ed tri al reveal ed that Bi spectral index (BIS) moni toring
reduced the ri sk of awareness i n at-ri sk adul t surgi cal pati ents (cardi ac surgery, cesarean section,
and trauma surgery) undergoi ng rel axant general anesthesi a.
130

Intraoperative EEG moni tori ng al l ows early detecti on of cerebral hypoxi a and i schemi a. Inadequate
PaO
2
or i nsuffi ci ent CBF is refl ected withi n seconds i n the EEG.
131
Hypoxi a may i ni tial ly produce
EEG acti vati on, whi ch i s foll owed by sl owi ng and eventual ly electri cal sil ence.
Other physi ol ogi c parameters that affect EEG waveforms are PaCO
2
, temperature, and sensory
stimul ati on. Hypocarbi a causes EEG sl owi ng. Mi l d hypercarbi a causes increased frequency, and
severe hypercarbi a produces a decrease i n frequency and ampl i tude. When body temperature fall s
bel ow 35C, hypothermi a causes a progressive slowi ng of acti vi ty. Complete electri cal sil ence
occurs at 15 to 20C. Sensory sti mulation is associ ated with EEG activation.
When monitori ng an EEG during anesthesi a, the changes resulti ng from hypoxi a or i schemi a must
be di sti ngui shed from the drug and physi ol ogic effects that al so may i nfluence the EEG. Because of
this, the EEG must al ways be interpreted wi thi n the cl i ni cal context in which it i s observed.
A speci fi c intra-operative appl i cation of the EEG, cal l ed el ectrocorticography (ECoG), i s the
local izati on of epil epti c foci during surgery for i ntractabl e epil epsy. For these procedures,
recordi ng el ectrodes are appl i ed on or in the brai n. The craniotomy can be performed under l ocal
anesthesia with conscious sedati on (typicall y using propofol and fentanyl ) or under a l i ght general
anesthetic usi ng ni trous oxi de, narcoti c and l ow dose i sofl urane (maxi mum 0.25% end-ti dal
concentration). The anestheti c administered must avoi d pharmacol ogi c corti cal depressi on, whi ch
woul d prevent provocati ve sei zure acti vi ty. Provocati ve techni ques and agents, such as
hyperventi lation, low-dose barbi turates (methohexital 10 to 50 mg, thi opental 25 to 50 mg),
propofol 10 to 20 mg, or etomi date 2 to 4 mg, have been used to acti vate the foci . Under general
anesthesia, al fentani l 20 to 50 g/kg and fentanyl 10 g/kg al so have been used to successfull y
produce ECoG acti vati on.
Computerized EEG Processing
The devel opment of the computer-processed EEG has faci li tated intraoperati ve EEG moni toring.
The most wi del y used and best val i dated techni que i s power-spectrum analysi s, which uses a
computer to perform a Fouri er transformation. A gi ven epoch of EEG (usual ly 2 to 8 seconds) is
converted from a pl ot of vol tage agai nst ti me to a plot of power (ampl i tude squared) agai nst
frequency. Wi th thi s techni que, data are di spl ayed in one of three formats: the compressed
spectral array, the density spectral array, and the band spectral array or power bands. For
example, to generate the compressed spectral array format, the Fouri er transformation converts
the irregular EEG waves to equival ent sine waves of known frequency and power (Fi g. 27-6).
131

Thi s displ ay shows ti me and power as one axi s (verti cal ) and frequenci es on the hori zontal axi s.
P.759
The Fouri er spectral data from successive segments are stacked one on top of the other, creati ng
a pseudo three-di mensional di spl ay; that i s, the pl ot i s shi fted verti cal ly wi th ti me and
compressed. A major advantage of power-spectrum anal ysi s is that i t retai ns al most all the
information in the ori gi nal EEG. Power-spectrum analysi s has documented val ue as a moni tor of
cerebral i schemi a and possi ble val ue in the determinati on of anestheti c depth.
126
The mai n
di sadvantages of thi s anal ysi s technique are l ack of detecti on of spi ke acti vi ty, i nclusion of arti fact
within frequency bands, and l imi ted revi ew of raw EEG data to determine rel i abi l ity of the ongoi ng
input.
Several technical matters must be consi dered to effectivel y impl ement i ntraoperati ve EEG
moni tori ng. Awake controls shoul d be obtai ned before i nducti on of general anesthesia. Moni toring
should be conti nuous throughout anesthesi a and

FIGURE 27-6. Schemati c di agram of techni que used to generate compressed spectral array.
Below the diagram i s an exampl e of compressed spectra of the al pha rhythm from a normal
subject. (Repri nted wi th permi ssi on from Stockard JJ, Bi ckford RG: The neurophysi ol ogy of
anesthesia. In Gordon E (ed): A Basis and Practi ce of Neuroanesthesi a, 2nd ed, pp 349.
Amsterdam, El sevi er, 1981.)
P.760
conti nue unti l the pati ent i s awake. Bi lateral data must be obtai ned, especial ly during
cerebrovascul ar procedures. For exampl e, duri ng a caroti d endarterectomy, bi l ateral changes may
indicate anestheti c or systemic effects, whereas i psil ateral changes on the operati ng si de are most
li kel y consistent wi th surgical trauma or ischemi a. Marked changes in anestheti c depth, systemi c
bl ood pressure, PaCO
2
, and brai n temperature must be avoi ded i n order to di sti ngui sh between
anesthetic and physi ol ogic effects on the EEG and those resul ting from hypoxia or ischemia.
Evoked P ot ent i al s
Evoked potenti als are used intraoperati vely to moni tor the integri ty of speci fi c sensory and motor
pathways. Sensory evoked potenti als (SEPs) eval uate the functi onal integrity of ascendi ng sensory
pathways, whereas motor evoked potenti al s (MEPs) test the functi onal i ntegrity of descendi ng
motor pathways.
There are major di fferences between evoked potenti als and the EEG. The EEG is a recording of
spontaneous, random el ectri cal activity that has a nonspeci fi c functi on and generates a relatively
large si gnal , for example, 50 V or more. Evoked potential s are comparati vel y smal l -ampli tude
responses (0.1 to 20 V) to a speci fi c sti mulus that are pathway-specific.
Sensory Evoked Potentials
The appli cati on of a sensory sti mul usa cl ick, a fl ash, a shockresul ts i n an afferent nerve
i mpul se that can be detected by appropriately placed surface electrodes as transi ent potenti al
di fferences. The ampli tude of these evoked potenti al s is very smal l and obscured by normal
background bioel ectri c acti vity from the EEG, electrocardiogram (ECG), muscl e activity, and other
extraneous electri cal acti vi ty. Signal averagi ng i s requi red to extract the evoked responses from
thi s background noi se. The background noi se i s random and i s eli mi nated by the averaging
process.
Three SEP modali ties are employed cl i ni cal ly: somatosensory (SSEP), auditory (BAEP), and vi sual
(VEP). The waves of the evoked potenti al are thought to represent potenti al s from speci fi c neural
generators. The i ndi vi dual peaks in the waveform are descri bed i n terms of polarity (negati ve,
positi ve), post-stimul us l atency (msec), and peak-to-peak ampli tude (V or nV). They are al so
descri bed by the di stance separating the neural generators and recording el ectrodes (near-fiel d,
far-fi el d).
Anesthetic Considerations for Sensory Evoked Potential Recording. Compromise or i njury of
a neurol ogi c pathway i s mani fested as an i ncrease i n the latency and/or a decrease i n the
ampli tude of evoked potenti al waveforms. For SSEPs, a 50% reduction in ampl itude from basel ine
in response to a speci fi c surgical maneuver i s consi dered to be a si gnifi cant change warranting
acti on to avert potenti al damage. For BAEPs, an increase i n latency of more than 1 mi ll i second i s
consi dered cli nicall y si gnifi cant. Accordi ngly, anestheti c, physi ol ogic, and envi ronmental factors
capabl e of produci ng thi s pattern of al terati on must be control led when recordi ng evoked
potential s. All anesthetics that have been studi ed i nfl uence evoked potenti al s to some extent.
Tabl e 27-8 summari zes the

known effects of i ntravenous and i nhal ed agents. The sensiti vi ty of evoked potenti al s to drug
effects vari es wi th the sensory modali ty bei ng moni tored. Evoked potenti als of cortical origi n (i .e.,
the corti cal component of the somatosensory evoked potenti al s [SSEP] and vi sual evoked
potential s [VEP]) are more vul nerabl e to anestheti c i nfl uences than brai nstem potenti al s (e.g.,
brainstem auditory evoked potenti al s [BAEP] and the subcorti cal components of SSEP). In general ,
to obtain sati sfactory intraoperati ve SEP recordi ngs, i t is i mportant to mai ntai n constant
anesthetic drug l evels. Speci fi cal ly, bol us administrati on of intravenous agents and step changes
in i nspired i nhal ati on agent concentrati on must be avoi ded, especi al l y at ti mes when neurol ogi c
injury might occur. When recordi ng corti cal evoked potenti al s (SSEPs or VEPs), one shoul d empl oy
intravenous techni ques. Hi gh concentrati ons of vol ati l e agents essential ly eli mi nate corti cal
evoked potenti al s. However, end-ti dal concentrati ons of 0.5 MAC of a volatil e agent are
compati bl e wi th sati sfactory recordi ngs in pati ents who are neurol ogicall y normal . The newer
P.761
i nhal ed agents, desfl urane and sevoflurane, may permi t the use of hi gher i nhal ed concentrati ons
duri ng electrophysi ol ogical moni tori ng.
TABLE 27-8 Effects of Intravenous and Inhaled Agents on Sensory Evoked Potentials
INTRAVENOUS AGENTS
BAEPS CSSEPS VEPS
LAT AMP LAT AMP LAT AMP
Thi opental
46 mg/kg 0 0 0/
20 mg/kg 0
75 mg/kg
Pentobarbi tal
918 mg/kg 0/ 0
Propofol
26 mg/kg 0 0 /0 0
Etomi date
0.050.3 mg/kg/mi n 0 0 0
Ketamine 0 0 /0
Diazepam
0.1 mg/kg 0 0 /0 /0 0
Mi dazolam 0 0 /0 /0
Droperidol
0.1 mg/kg
Li docai ne
In general , vol ati le agents cause a dose-dependent i ncrease in latency and a decrease in
ampl i tude of the corti cal SSEP or VEP.
132
As exempl i fi ed in a study by Peterson et al (Fi g. 27-7),
1.5 mg/kg; 3 mg/kg/h 0/ 0
Morphi ne 0/
Fentanyl 0 0 0/ /0
Sufentani l 0 0 /0
Alfentanil 0 0 0/
Remifentanil
Cloni di ne 0 0 0 0
Dexmedetomidi ne
INHALATION AGENTS
Desfl urane 0
Enflurane 0
a

Halothane 0
Isoflurane 0
a

Sevoflurane 0
b
a
Ni trous oxi de 0 /0 0
BAEPs = brai nstem audi tory evoked potenti al s; cSSEPs = corti cal somatosensory evoked
potential s; VEPs = visual evoked potenti als; = increased; = decreased; 0 = no
change; = no data; Lat = l atency; Amp = ampl i tude;
= response aboli shed.

a
1.5 MAC wi l l occasi onal l y abol i sh the response.
b
At 1.7 to 2.5 MAC, 100% in ampl itude (fusion to a singl e corti cal hi gh-ampli tude wave
with abol iti on of al l l ater wave components).
reducti ons i n SSEP ampl i tude greater than 50% were observed wi th 1 MAC halothane, 0.5 MAC
enfl urane, and 0.5 MAC i sofl urane, al l admi nistered wi th 60% ni trous oxi de i n oxygen.
133
The
authors concl uded that hal othane di srupted the SSEP the l east, and enflurane di srupted it the
most. At doses of 1.5 MAC sevofl urane and desfl urane, i ncreases in corti cal l atency and decreases
in ampli tude occur. Desflurane up to 1 MAC wi thout nitrous oxi de i s compatibl e wi th corti cal
medi an nerve SSEP moni tori ng duri ng scol i osi s surgery. At 1.5 MAC wi thout ni trous oxide, the
ampli tude of cortical SSEPs i s preserved at 60% of baseline with desflurane. Visual evoked
potential s tend to be more sensiti ve than cortical SSEPs to the effects of anestheti cs.

Ni trous
oxi de al one has been shown to produce signi fi cant decreases i n ampli tude wi th mi ni mal latency
changes i n the corti cal SSEP, but it decreases ampl i tude and i ncreases latency i n the VEP. When
ni trous oxide i s admi ni stered in combinati on wi th a volatil e anestheti c, i t produces a profound
depressant effect on SSEPs and VEPs.

Brai nstem responses are consi derabl y more resi stant to anestheti c infl uences than are corti cal
responses. For exampl e, cl ini cal ly used concentrati ons of the inhal ed agents tend to i ncrease the
latenci es of earl y or subcorti cal peaks of the BAEP with minimal amplitude effects. Most anestheti c
regi mens are compati bl e wi th recordi ng of brai nstem responses. However, as with the other
evoked potential modali ties, l arge step changes (greater than 0.5 MAC) in i nspi red i nhal ati on
agent concentrati on shoul d be avoi ded duri ng cri ti cal peri ods.
Studies on the effects of i ntravenous agents demonstrate that induction doses of thiopental,
etomi date, and fentanyl preserve SSEP recordi ngs. Increasi ng doses of thiopental resul t in dose-
P.762
FIGURE 27-7. The responses of corti cal somatosensory evoked potenti al s to vari ous MACs of
halothane, enfl urane, and isoflurane. A marked alteration of evoked potenti al s occurs at 1
MAC and hi gher l evel s of i nhal ed agents, and a modest i mprovement of the response occurs
when N
2
O i s wi thdrawn. (Repri nted wi th permission from Peterson DO, Drummond JC, Todd
MM: Effects of hal othane, enfl urane, i sofl urane, and ni trous oxi de in mul ti l evel
somatosensory evoked potenti al s. Anesthesiol ogy 65:35, 1986.)
dependent i ncreases i n latency and decreases in ampl i tude in cortical SSEPs and progressi ve
increases i n l atency in BAEPs. Very hi gh doses of thiopental , exceedi ng that which produce an
isoel ectric EEG, al ter SSEPs and BAEPs predi ctabl y, but waveforms are preserved. VEPs are more
sensi ti ve than the other sensory modal i ti es to the effects of barbi turates with only the earl y
potential s persisting at l ow doses and increasing in l atency at hi gher doses. Either bolus
administrati on or intravenous i nfusion of etomi date causes increases i n l atency and i ncreases i n
ampli tude of cortical SSEPs and sl ight decreases in ampl itude of cervi cal potenti al s. Etomi date
produces mi ni mal changes in the earl y or subcorti cal peaks of the BAEP, but causes a dose-
dependent attenuation and prol ongati on of the mi ddl e latency cortical peaks. Etomi date al one
does not change VEP ampli tudes (P100 or N70), but i ncreases latency (P60, N70, and P100).
During fentanyl ni trous oxide anesthesia, etomidate causes decreases i n ampli tude and increases
i n l atency of VEPs. The benzodi azepi nes produce minimal SSEP and VEP changes and no changes i n
BAEPs. Propofol increases the l atency and decreases the ampl i tude of corti cal SSEPs. Propofol (2
mg/kg i v fol l owed by an i nfusi on) increases the BAEP l atency of I, III, and V waves wi thout
changi ng the ampl i tudes. Propofol compl etel y suppresses mi ddl e l atency auditory potenti al s.
The opioi ds produce mi ni mal changes i n SEP waveforms. For exampl e, fentanyl causes mi ni mal
l atency prol ongati on and ampl i tude depressi on of the SSEP waveforms. Compared with the
combi nation of fentanyl and ni trous oxi de, the remifentanil /isoflurane technique preserved corti cal
ampli tude better and wi th less vari abil i ty i n l atency and ampl i tude. Hi gh-dose opi oi d
administrati on al so has been shown to be compati bl e wi th reproducibl e recordi ngs of SSEPs.
Opi oi ds al so produce mi ni mal to no effect on BAEP recordi ngs. Furthermore, l ow-dose conti nuous
infusi ons of opi oids tend to depress SEPs l ess than intermi ttent bol us i njecti ons.
Because opi oi ds preserve SEP recordi ngs even i n rel ati vel y high doses, they are recommended for
use as i nfusi ons duri ng intra-operative moni toring. As wi th al l intravenous agents used, bol us
administrati on should be avoi ded duri ng criti cal ti mes when neurologic i njury might occur.
Cloni di ne and dexmedetomidi ne are -2 receptor agoni sts that are used to decrease anestheti c
requi rements. Cl onidi ne admini stered al one or added to 1 MAC i sofl urane does not change corti cal
SSEP l atency or ampl itude. Dexmedetomi di ne affects SSEP ampl i tude mini mal l y and has been
shown to blunt isofl urane's effect on SSEP ampl i tude. Both agents can be used as an anestheti c
adjuvant wi thout compromi si ng SSEP moni tori ng.
Physi ol ogi c factors such as temperature, systemic bl ood pressure, PaO
2
, and PaCO
2
can al ter SEPs
and must be controll ed during i ntra-operative recordi ngs.
132
Both hypothermia and hyperthermi a
al ter al l SEPs. In addi tion, fl ui ds used to i rri gate the brain or spi nal cord can cause marked
changes i n recordi ngs despite normal core temperature measurement. Therefore, body
temperatureirri gati ng fl ui ds shoul d be used. Systemi c hypotension below l evel s of cerebral
autoregul ati on produces progressi ve decreases i n ampl itude of corti cal SSEPs unti l the waveform
is l ost. Duri ng scol i osi s surgery, SSEP changes have been observed that resol ved wi th i ncreases in
systemi c bl ood pressure, suggesti ng that spi nal cord mani pul ati on duri ng safe level s of
hypotensi on may cause si gnifi cant ischemia. Changes in PaO
2
and PaCO
2
al so al ter SEPs, probabl y
refl ecti ng changes i n bl ood fl ow or oxygen del i very to neural structures.

Motor Evoked Potentials
A motor evoked potenti al (MEP) can be produced by di rect (epi dural ) or i ndi rect (transosseous)
stimul ati on of the brain or spi nal cord. Fol l owi ng transcrani al sti mul ati on, the si gnal descends
through both the dorsol ateral and ventral spinal cord. It i s pri maril y l ocal ized in the pyrami dal
tracts, and can be recorded from spi nal cord (epidural space), peripheral nerve, and muscl e usi ng
conventi onal electromyographi c and evoked potential averaging techni ques. Sti mul ati on of the
motor cortex el i ci ts contral ateral peri pheral nerve si gnal s, electromyographi c signal s, or li mb
movements.
Transosseous acti vation of motor neurons i s accompl i shed by ei ther electri cal or magneti c
stimul ati on. Transcrani al el ectri cal stimul ati on of the motor cortex is a rel i abl e method of el i ci ting
i ntraoperati ve MEPs. It i s achieved by del i veri ng bri ef hi gh-vol tage pul ses through scal p
P.763
el ectrodes. Transcrani al magneti c sti mul ati on i s produced by pl aci ng a magneti c coi l over the
motor cortex. This technique is pai nl ess and noni nvasive and does not require di rect contact wi th
the scalp. Because hi gh-resistance ti ssues such as bone and ski n are transparent to magnetic
fiel ds, small er voltages can be used to stimul ate neural el ements below the surface.
Wi th ei ther electri cal or magneti c sti mulation, there i s concern that repeti tive corti cal sti mul ation
can i nduce epil eptic acti vi ty, neural damage, and cogni ti ve or memory dysfuncti on. Gui del ines for
transcranial MEP sti mulation recommend intermi ttent rather than conti nuous stimul ati on over
several hours and cauti ous use in pati ents wi th a history of sei zures, possibl e skul l fractures, or
implanted metall i c devices. Di srupti ons of the cal vari umthat i s, a skul l fracturecoul d focus the
current toward certai n regi ons of the brai n and potenti al l y cause neural damage. Other situations
of concern are patients with cardi ac pacemakers and central venous or pul monary artery
catheterizati on. Transcranial MEP stimul ati on shoul d probabl y be avoided in these pati ents.
There are several indicati ons for intraoperative monitori ng of MEPs. They are especi all y useful i n
preservi ng motor functi on duri ng procedures in whi ch surgicall y i nduced damage may be speci fi c
to the motor system. For exampl e, surgical removal of intramedul l ary tumors can result i n
sel ecti ve damage to corti cospi nal tracts, and MEPs are used to guide surgi cal resecti on. Duri ng
scol i osi s surgery, a di rect moni tor of motor pathway functi on obvi ates the need for the
intraoperative wake-up test and provi des continuous i nformati on about motor function throughout
the surgi cal procedure. Duri ng cerebrovascul ar procedures and resection of cerebral tumors
invol vi ng the motor cortex or subcorti cal motor pathways, the abi li ty to gui de the surgical
resection by moni toring motor functi on prevents postoperati ve motor defi cits. Paralysi s i s an
unpredictabl e compl icati on that can occur after aorti c aneurysm surgery. Myogeni c MEP moni tori ng
can detect ventral horn i schemia duri ng aorti c reconstructi on, thus al l owing the surgeon to i ni tiate
strategi es to i mprove spi nal cord perfusi on. In al l of these procedures, MEPs shoul d be monitored
in conjunction wi th SSEPs to full y eval uate the functional integri ty of both motor and sensory
pathways.
Motor evoked potenti als are extremel y sensi ti ve to depressi on by anestheti cs.
134
The vol ati l e
agents are powerful depressants of myogenic MEPs. Ni trous oxi de appears to be less suppressive
than other i nhal ed agents. Moderate doses of up to 50% N
2
0 have been used successful l y to
supplement other agents duri ng myogeni c MEP moni tori ng. Benzodi azepi nes, barbi turates, and
propofol also produce marked depression of myogeni c MEP. However, successful recordi ngs have
been obtained duri ng propofol anesthesi a by control l i ng serum propofol concentrati ons and
increasi ng stimul i rates. Fentanyl, etomi date, and ketami ne have l i ttle or no effect on myogenic
MEP and are compatibl e wi th i ntra-operative recordi ng. Muscl e rel axants affect the recorded
el ectromyographi c response by depressi ng myoneural transmi ssi on. By adjusting a conti nuous
infusion of muscle relaxant to maintain one or two twi tches i n a trai n of four, rel i abl e MEP
responses have been recorded.
Although i t appears that MEPs are more sensiti ve to the effects of anestheti c agents, reli able
responses have been recorded with a ni trous oxidenarcoti c technique and wi th agents such as
ketami ne or etomi date. Mul ti sti mul us techni ques can i mprove moni toring duri ng anesthesia wi th
more depressi ve agents such as propofol . As wi th SEPs, hypothermi a, hypoxia, and hypotension
wi l l al ter MEPs under anesthesi a.
Cr ani al Ner ve Moni t or i ng
Potential i njury to the cranial nerves can occur duri ng posterior fossa and l ower brai nstem
procedures. The integrity of these cranial nerves can be preserved by moni tori ng the
el ectromyographi c (EMG) potential of crani al nerves wi th motor components (V, VII, IX, X, XI,
XII). Both spontaneous and tri ggered muscl e acti vi ty can be recorded. Recordi ngs can be obtai ned
by pl aci ng two wire el ectrodes wi thi n the muscle or usi ng surface electrodes. Si mul taneous
spontaneous EMG and compound muscl e action potenti al (CMAP) recordi ngs can be obtai ned by
using i ntramuscular wi re and surface el ectrodes. Intramuscul ar wire electrodes i ncrease the
sensi ti vi ty for detecting spontaneous EMG activi ty, whi l e surface el ectrodes all ow for more reli able
moni toring of CMAP amplitude and morphology. Wi th acci dental surgi cal trespass, spontaneous
neural acti vi ty changes into phasi c bursts or trai n acti vi ty, whi ch suggests i njury potenti al .
Evoki ng the nerves wi th electri cal sti mul ati on faci l itates identi fi cati on and hence preservation of
the crani al nerve. Although i t is possibl e to record EMG potential s duri ng partial neuromuscul ar
bl ockade, i t i s recommended that muscl e relaxants not be admi ni stered during crani al nerve
moni toring.
I nt r acr ani al P r essur e Moni t or i ng
Si nce Lundberg' s
135
report i n 1960, conti nuous ICP monitori ng has been used to gui de the
peri operative management of patients with head injury, large brain tumor, ruptured intracrani al
aneurysm, cerebrovascul ar occl usive di sease, and hydrocephal us. With conti nuous ICP moni tori ng,
it i s possibl e to optimi ze CPP (MAP-ICP) i n cri ti cal l y i l l neurosurgi cal pati ents. It al so all ows earl y
detecti on and prompt treatment of brai n hemorrhage, swel l i ng, and herni ati on. An i mportant intra-
operative i ndi cation for ICP monitori ng is to detect intracranial hypertension i n the mul ti pl e
trauma pati ents during a nonneurosurgi cal procedure.
Techni ques used to moni tor ICP include ventricul ar catheters, subdural -subarachnoi d bol ts or
catheters, vari ous epidural transducers, and intraparenchymal fiberopti c devi ces (Fi g. 27-8). The
intraventri cul ar catheter is the standard method of moni toring ICP. Thi s techni que requi res a small
scal p i nci sion and a burr hol e through the skul l . A soft, nonreacti ve pl astic catheter i s introduced
into the l ateral ventri cl e and connected by steri l e tubi ng fil l ed wi th sal i ne soluti on to an external
transducer. The intraventricul ar catheter measures CSF pressures reli ably. It al l ows therapeutic
CSF drai nage and can also be used for compli ance testing. There are, however, several potenti al
problems with thi s technique. Thi s devi ce depends on the transmi ssion of ICP through fl uid-fil l ed
tubing that can occl ude, thus dampi ng or obl i terati ng the recordi ng. In a pati ent wi th severe brain
swel l ing or a l arge mass l esi on and smal l ventricl es, i t may be techni cal ly diffi cult to locate the
lateral ventri cle. Besi des not being able to pass the catheter i nto the CSF, there i s a possibi l ity of
brai n ti ssue damage,

hematoma, and infecti on. Studi es report a low infecti on rate for the fi rst 4 days after catheter
pl acement. Catheter removal i s, therefore, recommended on or before the fi fth day, with
repl acement at a di fferent si te i f continued ICP moni tori ng is necessary.
The subdural -subarachnoi d bol t usuall y consi sts of some type of hollow screw fixed to the
calvari um, wi th the ti p passi ng through the incised dura. The advantages of the bol t are that i t
P.764
FIGURE 27-8. Techni ques used to measure i ntracranial pressure.
does not require brai n ti ssue penetrati on or knowl edge of ventri cul ar posi ti on and can be pl aced i n
any skull locati on that avoi ds major venous si nuses. There are several disadvantages to use of
this techni que. The bolt cannot be used to lower ICP by CSF drai nage or to test compl i ance
rel iabl y. As wi th the intraventri cul ar catheter, the bolt i s connected to a transducer wi th tubing
fil l ed wi th steri le sali ne. Not onl y can the tubi ng bl ock, but al so brai n substance can obstruct the
ti p of the bol t; i n either situati on, the recordi ng may be damped or lost. Dri l li ng si de hol es just
proxi mal to the ti p of the bolt compensates for this probl em to some extent. Subdural devi ces are
easil y inserted, but can mal functi on i f they are not copl anar to the brai n surface or i f they become
loose. The major compl icati on of thi s procedure i s i nfecti on, commonly meningiti s, osteomyeli tis,
or a local i zed infecti on. Epidural bl eedi ng and focal seizures, if the bolt i s inserted too deepl y, can
al so occur.
Two pri mary types of epidural transducers have been devel oped. One uses a devi ce that has a
pressure-sensi ti ve membrane mounted cl ose to or contacti ng the dura; the other type, known as
the Ladd epi dural transducer, i s based on the pri nci ple of the Numoto pressure swi tch. Al though
the ri sk of infecti on to the brai n i s l ower because of the extradural pl acement, there are several
di sadvantages associ ated wi th usi ng these devices. Pl acement in thi s potenti al space i s more
di fficul t, and there i s a ri sk of bl eedi ng. Techni cal probl ems i n posi tioni ng and cal i brati ng the
transducer i n si tu can al so occur. Another shortcomi ng of the epidural transducer is that
intracranial compli ance testing and therapeuti c CSF drai nage cannot be performed.
Intraparenchymal ICP moni tori ng techniques al l ow direct measurement of brai n ti ssue pressure,
whi ch may be i mportant in edema formati on and regi onal capi l l ary bl ood fl ow. Intraparenchymal
devices use a fi beropti c catheter that i s inserted wi thin cortical gray matter. In compari son to
ventri cul ostomies, these moni tors are easi er to i nsert, have a smal ler di ameter, and are less
di srupti ve of brai n ti ssue. Because there i s no fl ui d column, the risk of infecti on i s lower.
Cerebral monitori ng devices are bei ng devel oped wi th mi ni aturi zed sensors, transducers, and
probes usi ng fi beropti c sol i d state technol ogy. These devi ces can be i nserted i nto the subdural,
intraparenchymal , or intraventri cul ar compartments. Because these are soli d-state monitors, the
problems of infecti on, leaks, catheter occlusion, and dri ft that attend fluid- or ai r-fil l ed systems
are mi ni mi zed or avoi ded. Ani mal and human studi es show that pressure recordi ngs obtained wi th
these devi ces are accurate and rel iabl e. The mai n disadvantage of these devices i s that they
cannot be recal ibrated i n si tu. Another l i mi tation is that they cannot be used for CSF drai nage or
compl i ance testi ng unl ess inserted in conjuncti on wi th a ventri cul ostomy.
New generations of fiberopti c ICP moni tors al l ow si multaneous measurement of ICP, l ocal CBF
usi ng l aser Doppl er fl owmetry, brain tissue oxygen pressure (PO
2
), carbon dioxi de pressure
(PCO
2
), pH, and other metabol i c markers. By si mul taneousl y monitori ng ICP, local CBF, and brai n
ti ssue oxygenati on, early si gns of ischemi a can be i dentified and the effecti veness of therapeuti c
maneuvers more ful l y determined. The vari ous ICP moni tors are sel dom used intra-operatively.
They are most val uable in managi ng cri ti cal l y i l l neurosurgi cal pati ents in the i ntensi ve care uni t.
All of the cl i ni cal ly avai l abl e monitors have recogni zed advantages and disadvantages. Despi te the
problems associated wi th these devi ces, ICP moni toring provi des useful i nformati on for eval uati ng
the pati ent's condi ti on, progress, and need for therapy. Research efforts conti nue to i mprove
moni tori ng techni ques in terms of rel iabi li ty, accuracy, and safety.
Transcranial Doppler Ultrasound
Transcrani al Doppl er (TCD) ultrasound i s used for cli ni cal i magi ng of i ntracrani al vascul ature. TCD
uses a 2-MHz probe, whi ch i s range-gated. The probe i s placed over l ow-densi ty bone regi ons of
the skul l , and the beam i s focused on the desi red vessel . The ul trasoni c beam refl ects off the
bl ood fl owing i n the vessel , produci ng a Doppl er shi ft that i s proporti onal to bl ood fl ow vel oci ty.
Thi s technique can provi de conti nuous assessment of the systol ic, diastol ic, and mean fl ow
velociti es i n the target vessel . Any downstream resi stance is proporti onal to the di fference
between systoli c and di astol i c vel oci ti es. One commonl y used resistance i ndex i s the pul satil i ty
i ndex defi ned as:

TCD does not measure CBF. It determines velocity and di recti on of the movi ng col umn of bl ood i n
a major artery. The TCD i s used to monitor flow vel oci ty in l arge vessel s i n the Ci rcl e of Wil l is and
its major branches. The transtemporal approach above the zygomatic arch al l ows i nsonating the
anteri or, mi ddl e, and posteri or cerebral arteries. The suboccipi tal route, through the foramen
magnum, all ows i nsonati ng the basi lar and vertebral arteri es.
TCD has several appl i cations both i n cri ti cal care and intra-operatively. It can be used to
determi ne the reserve of cerebral bl ood vessel s by measuri ng CO
2
reacti vi ty and autoregul ati on
and to esti mate CPP by usi ng the PI. TCD al so i s used to i denti fy pati ents wi th vasospasm,
hyperemi a, embol i , stenosi s, abnormal col lateral bl ood fl ow, and i nadequate CBF. For i ntra-
operative appl i cation, the probe i s affi xed to the temporal bone with a strap. During crani otomy, a
ski n adhesi ve is appli ed to mount the probe.
Limitati ons of thi s technique i nclude between-subject variation of TCD veloci ties, withi n-subject
vari ati on i f vessel di ameter changes i n response to vasoacti ve agents or condi ti ons, and error
from changing the angl e of insonati on. However, the advantages of TCD are that it i s noni nvasi ve
and nonradi oactive

and provi des conti nuous i nformation about the cerebral circul ati on.
Cer ebr al Oxygenat i on/ Met abol i sm Moni t or s
Brain Tissue Oxygenation
A multi parameter sensor i s avai l abl e for measuri ng brain tissue PO
2
, PCO
2
, pH, and temperature
using a combined electrodefiberopti c system. The sensor was ori ginal l y desi gned for conti nuous
intra-arterial bl ood gas moni tori ng. It i s suppl ied as a steril e, di sposabl e devi ce comprisi ng two
modi fi ed opti cal fibers for the measurements of PCO
2
and pH, a mi ni aturi zed Cl ark electrode for
PO
2
measurement, and a thermocoupl e for determi ni ng temperature. Coupl ed wi th a di al ysi s
catheter, the device permi ts measurement of other metaboli c markers, including l actate, gl ucose,
and excitotoxi c amino aci ds. Thi s sensor is invasi ve, requiring i nserti on i nto the cortex ti ssue of
interest under direct vi sual i zati on. The measurements obtained are l imited to the parenchyma
where the electrode is i nserted.
Jugular Bulb Venous Oximetry
Conti nuous or i ntermi ttent esti mation of the gl obal bal ance between cerebral oxygen demand and
suppl y can be achi eved by jugul ar bul b venous oximetry. Thi s i s done by measuri ng the oxygen
saturation of jugular venous blood (SjVO
2
) through percutaneous retrograde cannulation of the
internal jugular vei n with an i ntravascular catheter wi th embedded opti cal fi bers. Normal SjVO
2
is
60 to 70%. In the absence of anemi a and any change i n oxygen saturati on, i ncreases in SjVO
2
to
above 75% are indi cati ve of absolute or rel ati ve hyperemia; that i s, suppl y i s i n excess of
metaboli c requirement. Thi s can occur as a result of reduced metabol ic need (e.g., a comatose or
brain-dead pati ent) or from excessi ve fl ow (e.g., severe hypercapnia). A val ue l ess than 50%
refl ects i ncreased oxygen extraction and indi cates a potenti al ri sk of i schemi c i njury. This may be
because of i ncreased metabol ic demand (e.g., fever or seizure) not matched by an equival ent
increase in fl ow, or it may be because of an absolute reduction in fl ow. Changes in the
oxygenati on of systemi c bl ood al so i nfluence the saturati on of bl ood i n the jugul ar bul b.
Thi s moni tor is used i ntraoperativel y and postoperati vel y to diagnose cerebral i schemia from
inadequate perfusion pressure or excessi ve hyperventi l ation. Its major li mi tati on i s that i t does
not detect focal ischemia.
Transcranial Oximetry
Near-infrared spectroscopy (NIRS) i s a noni nvasive opti cal method for monitori ng cerebral
P.765
regi onal oxygenati on. It i s based on the pri nci pl e that li ght i n the near-infrared range (700 to 900
nm) readi l y penetrates skin and bone, but refl ects off certai n chromophores i n the brai n, such as
oxy- and deoxyhemogl obi n and cytochrome AA
3
. Therefore, by monitori ng the absorption of li ght
at several wavel engths i n the near-infrared range, brain tissue concentrati ons of oxy- and
deoxyhemoglobi n, total hemogl obin, and hemoglobi n oxygen saturati on can be measured. The
ti ssue fi eld beneath the sensor contai ns capi l lari es, arteri es, and vei ns, refl ecti ng a mi xed
vascul ar saturati on, whi ch NIRS moni tors. Cerebral oxi metry can be used to moni tor i schemia i n
several cl ini cal neurosurgi cal condi ti ons, i ncluding caroti d endarterectomy, head i njury, and
subarachnoi d hemorrhage. Its major l imitati ons include i ntersubject vari abi l ity, vari abl e opti cal
path l ength, potenti al contami nati on from extracranial bl ood, and l ack of a defi nabl e threshol d. At
present, i t i s consi dered a trend monitor, with each pati ent acting as hi s or her own control . In
si tuati ons of potenti al regional i schemia, for exampl e, carotid endarterectomy and temporary clip
appl icati on duri ng intracrani al aneurysm surgery, bi lateral moni tori ng shoul d be used.
NEURORADIOLOGY
Common neuroradi ol ogy procedures are computed tomography (CT), magneti c resonance
i magi ng (MRI), angi ography, and a variety of invasive interventi onal procedures. These
requi re total i mmobi l ity on the part of the pati ent. Therefore, uncooperati ve pati ents, speci fi cal ly
children, fearful adults, and retarded or obtunded pati ents, woul d requi re general anesthesi a. All
the standard equi pment and monitors requi red for the admini stration of a general anestheti c and
possi bl e cardiopul monary resuscitati on must be present.
Comput ed Tomogr aphy Scan
The CT scan produces a seri es of cross-secti onal images by computeri zed processi ng of x-ray
absorpti on measurements (photon attenuation data as measured by sodi um iodi de crystal s
rotati ng about the patient' s head). Performance of a brai n scan requires that the pati ent li e on a
table wi th hi s or her head i nsi de a rotating gantry that makes a 180 arc, produci ng one axi al
sl i ce or cut. Dependi ng on the generati on of the scanner, the rotation may take from a few
seconds to 4.5 minutes per cut. Eight cuts are usual ly required for a compl ete exami nati on of the
head. When contrast enhancement is i ndi cated, the dye may be i nfused i ntravenously and the scan
repeated. The pati ent must remain supi ne and i mmobi l e throughout the enti re scan.
CT scanni ng i s an excel lent modal ity for detecti ng skull fractures and acute subarachnoid
hemorrhage. It is relatively insensiti ve for vi ewing structures wi thi n the posteri or fossa because
image degradation resul ts from artifact produced by the interface of bone and brai n parenchyma.
For trauma pati ents, spi ral acquisi ti on CT i s becomi ng more popul ar. Larger anatomi c regi ons can
be imaged as the pati ent i s moved at a conti nuous, constant speed through the scanni ng fiel d with
the x-ray tube rotati ng conti nuousl y.
Most CT exami nations are performed wi thout an anesthesi ologi st present. Oral or i ntravenous
sedati on i s used for many pediatri c exami nati ons and i s usual ly admini stered by radi ol ogy
personnel . Iodi nated contrast medi um, whi ch is parti cularly valuabl e i n studi es of vascular
malformati ons, vascul ari zed tumors, and bl ood-brain defects, may also be admi ni stered oral l y or
intravenously. When general anesthesi a i s requested, the pati ent' s nothing-by-mouth status
must be determi ned. Other i ssues that need to be resol ved before the admi ni strati on of general
anesthesia are remote access to the pati ent and the establ i shment of moni tori ng and equi pment
that meets the same standard of care that exi sts i n the operati ng room.
The CT scanner uses i onizing radi ati on. The radi ation exposure during CT is similar to that of a
conventi onal skul l radi ograph (1.0 to 2.5 rad). Exposure val ues for personnel attendi ng the
patient are mi ni mal (e.g., 1 to 2 mrad/hr for the anesthesi ol ogi st posi ti oned next to the scan).
However, radi ati on moni toring badges and l ead aprons shoul d be worn by personnel who
parti cipate in CT scanni ng on a regular basi s.
Magnet i c Resonance I magi ng
Magneti c resonance imagi ng is a noninvasi ve di agnosti c technique that i s superi or to CT i n many
CNS disorders. Thi s technique empl oys a strong magneti c fi el d and pul sed radi ofrequency energy
to generate i mages. When a biol ogi c speci men is pl aced withi n a stati c magneti c fiel d, certain
atomic nucl ei

(nuclei wi th an odd number of protons, such as
1
H nuclei ) act l ike magnets and are ali gned. The
atoms are then subjected to a radi ofrequency pul se that defl ects thei r ori entation. When the
radi ofrequency pul se i s di scontinued, the nucl ei rotate back into ali gnment wi th the stati c
magneti c fi el d. The energy rel eased as the nucl ei rel ax is used to create the MR image. The
magnet of the MRI system is in the form of a tube that can accommodate the human body. The
patient must remai n sti ll duri ng investi gati on, whi ch may last 1 hour, to prevent i magi ng artifacts.
The MRI is an extremel y val uabl e di agnosti c tool that provides excel l ent contrast between gray
and white brai n matter. The i mages can be displ ayed in axi al , coronal , or sagi ttal pl anes. Because
there is no dental or bony artifact, the MRI i s superi or to the CT scan i n examini ng the posterior
fossa. Other areas optimal l y i maged by MRI i ncl ude the pi neal gl and region, sel l a and parasel l ar
structures, the l i mbi c system, cranial nerves, i nternal auditory canal , the cerebel l opontine angl e,
and l eptomeni nges. Magneti c resonance angi ography (MRA) provi des i mages of arteri al and dural
si nus blood fl ow. Magneti c resonance spectroscopy provides noninvasi ve bi ochemi cal
measurements of specific brai n metaboli tes and can be hel pful in the earl y detecti on of stroke.
The i ntense magneti c fiel d creates uni que chal l enges for the anesthesi ol ogi st. The high-stati c
magneti c fi el d (0.12 to 2.00 tesl a [T]) and the radi ofrequency energy transmi tted duri ng i mage
acqui siti on may damage or cause mal functi on of el ectrical, electroni c, or mechanical li fe support
and moni toring equi pment. Conversel y, the radi ofrequency energy generated by these devi ces can
interfere with MR si gnal detecti on, produci ng arti facts that degrade the i mage. Another problem
uni que to MRI is that ferromagnetic substances pl aced wi thin the magneti c fi el d are propel led
toward the scanner. A li st of MRI-compati bl e equi pment and moni tors has been publ i shed.
136

Laryngoscopes are not magneti c, but the batteri es are. Therefore, to use a l aryngoscope within
the scanning room, pl asti c- or paper-coated batteri es must be used. A prebent RAE tube i s
recommended owi ng to l imi ted verti cal space wi thi n the scanner. Very l ong breathi ng tubes are
requi red, and ei ther pi pel i ne gases or a remotel y pl aced anesthesi a machi ne can be used.
Alumi num cyl i nders can be used safel y within the scanni ng room. MRI-compati bl e anesthesi a
machines and venti l ators are avail able. The anesthesi a machi ne can be bol ted to the wal l or
modi fi ed by removal of ferromagneti c components. The venti lators are pneumati cal l y driven and
vol ume-cycl ed and have flui dic control s. The ventil ator is compl etel y powered by hi gh-pressure
oxygen del ivered by a wal l source or from l arge cyl inders pl aced outside the imagi ng room, and
el ectroni c parts have been repl aced wi th pl asti c, alumi num, or nonmetal li c al l oys.
The i mpl ementati on of monitori ng duri ng MRI i s di ffi cul t because of remote access to the pati ent
and the i nteracti ons between vari ous moni tori ng devi ces and the MR scanner, as previ ousl y
descri bed. For exampl e, standard ECG moni tors produce probl ems wi th i mage degradati on from
wire l eads acti ng as antennas and wi th arti fact produced by radi ofrequency pul ses and stati c
magneti c fi el ds. Burns under ECG el ectrodes have been reported. MR-compati bl e ECG moni tors,
cables, fasteners, and el ectrodes have been devel oped. However, thi s ECG provi des onl y heart
rate and rhythm and cannot be used to moni tor ischemi a. Additional suggesti ons for i mprovi ng
ECG monitori ng i ncl ude pl aci ng electrodes cl ose together near the three-di mensional center of the
imager and twi sti ng the leads. Both noninvasi ve and invasi ve pressure moni tori ng have been
successful ly used duri ng MRI. Bl ood pressure i s easi l y measured wi th an ordi nary cuff and long
pressure tubi ng wi thout metal connections. The blood pressure dial must be kept away from the
magneti c fi el d. Automated bl ood pressure devi ces wi thout metal connectors have also been used.
Usi ng nonmetal li c components, pressure transducers connected to i ntravascular catheters for
central venous, pul monary artery, and arteri al pressure monitori ng can functi on near the magnet.
Transducers are affixed al ong the side of the magnet at i ts midpoi nt to mini mi ze artifact. Shi el ded
el ectric extensi on cabl es couple the transducers to the moni tors located outsi de the scanni ng
room. There have been reports of i mage degradati on wi th the pul se oxi meter. Placing the oxi meter
a di stance from the magnet and the probe on the pati ent' s toe, whi ch i s usual ly outsi de the
magnet, and usi ng a fi beropti c cabl e may i mprove i mage qual i ty. Moni toring of heart rate and
P.766
respirati on can be achi eved usi ng nonmetal l ic precordi al or esophageal stethoscopes; however, the
drum-li ke noi se of the scanner may obscure auscultated heart and breath sounds. A standard
vascul ar Doppl er has al so been used to moni tor heart rate. Capnography i s possi bl e wi th l ong
tubi ng and hi gh-powered sucti on. Changes i n respi ratory rate are easi ly observed, but the end-
ti dal CO
2
reading may be l ess than the actual val ue. Al though temperature moni tori ng is
parti cul arl y i mportant i n the cold MRI sui te, especi al l y i n pedi atric patients, i t has been di ffi cul t to
implement. The wires conducti ng the si gnal from the thermi stor may function as an antenna for
radi ofrequency si gnal s and produce i magi ng arti fact and burns. Nonferromagneti c disposabl e
temperature stri ps may be used. All efforts to mi ni mize pati ent heat loss should be impl emented:
usi ng bags of warmed i ntravenous fl ui ds, heati ng pads, and ai rway humi di fi cati on and covering the
patient.
Guidel i nes for using the MRI have been i ssued and are updated by the Insti tute for Magneti c
Resonance Safety, Education and Research.
137
It i s recommended that women i n the fi rst tri mester
of pregnancy not be scanned because of possi ble developmental consequences. Patients wi th
demand pacemakers shoul d not be scanned because the varyi ng magneti c fiel d can i nduce el ectri c
currents in the pacemaker wires, whi ch may be mistaken for the natural el ectrical acti vi ty of the
heart, inhi bi ti ng pacemaker output. Metal li c objects such as vascular cl i ps or shrapnel can move
and become di spl aced when exposed to the magneti c fi el d. Pati ents who have a l arge metall i c
implant or prosthesi s can be scanned unti l the heat at the si te of the i mpl ant or prosthesis
becomes uncomfortabl e. There i s a possi bi li ty that i nduced currents can affect myocardi al
contracti l ity or produce arrhythmias. Ful l resuscitati on facil i ti es shoul d be avail able.
P osi t r on Emi ssi on Tomogr aphy
Bi ochemical or physi ol ogic processes i nvol ved i n cerebral metabol i sm can be imaged with posi tron
emissi on tomography (PET). After receiving i ntravenous radionucli de, such as fl uorodeoxygl ucose
(FDG), the pati ent i s scanned i n a speci al i zed detector system. Thi s system detects the posi tron
energy emi tted from the radionucl i de. Computerized reconstruction procedures produce
tomographi c i mages. The i nformati on from PET can be overl ai d on CT or MR i mages to i mprove
anatomic l ocal izati on of detected activity. When the MRI is normal in a pati ent wi th sei zures, PET
mi ght provi de l ocali zi ng informati on pri or to focal resecti on treatment. The injecti on of FDG
renders the pati ent radi oacti ve for 24 hours. The usual protocol i nvol ves two initi al scans lasti ng
15 to 20 mi nutes fol l owed by another scan i n 2 to 3 hours. PET scanners do not requi re
nonferromagnetic monitors and equipment.
Cer ebr al Angi ogr aphy
Angi ography i s used to del i neate the vasculature of the brai n. Catheters are usual ly i ntroduced
through the common femoral artery, whi ch has repl aced di rect caroti d artery puncture.

Di gi tal subtracti on angi ography reduces the required volume of intra-arterial contrast and the
overal l durati on of the procedure.
There are several ri sks and probl ems associ ated wi th angi ography, i ncludi ng an i nci dence of
neurol ogic probl ems related to angi ography itsel f. In addi tion, arteri al spasm, hematoma, and
local i nfection can occur at the si te of needl e puncture. Subinti mal di ssecti on or occlusi on of the
vessel may resul t from injecti on i nto the vessel wal l . Iodi ne-contai ning contrast medi a produce
vasodi l ati on and a burni ng sensati on i n the di stri buti on of the i njected vessel . Septi cemi a,
cerebral embol i sm, anaphylacti c reacti ons to the i odinated contrast materi al , and, rarel y, sei zures
or death are all potenti al compl i cations of cerebral angi ography.
The i ntroduction of low-ioni c and nonioni c contrast materi al has reduced both the di scomfort and
toxi ci ty associ ated with angiography. Because of thi s, patients usuall y do not requi re general
anesthesia and are abl e to tol erate the procedure with mi ni mal or no sedati on. When general
anesthesia i s requested for chil dren or uncooperati ve adul ts, the angi ogram qual i ty may be
enhanced by hyperventi lation. Hypocarbia i s thought to improve study qual i ty by sl owi ng the
cerebral ci rculati on and improvi ng del i neati on of tumor bl ood vessel s, perhaps through an i nverse
P.767
steal phenomenon.
I nt er vent i onal Neur or adi ol ogy
Interventi onal neuroradi ol ogy (INR) has devel oped from tradi ti onal neuroradiol ogy and
neurosurgery to procedures that treat CNS di sease by endovascul ar access.
138
Procedures such as
therapeutic embol izati on and supersel ecti ve angi ography of vascul ar malformations, coi l i ng of
cerebral aneurysms, bal l oon angiopl asty of occl usi ve cerebrovascular disease or cerebral
vasospasm, therapeuti c caroti d occl usion for giant aneurysms and brai n tumors, and others may
be performed. Because these procedures are i nherentl y dangerous, anesthesi ologi sts can hel p
prevent and manage morbi di ty and mortal ity.
Most interventi onal neuroradi ology procedures can be accompli shed wi th consci ous sedation. The
agents chosen for conscious sedati on must al leviate pai n and di scomfort and provi de anxi ol ysi s,
patient immobil i ty, and a rapi d return to consci ousness for neurologi c testi ng. A variety of
sedati on regi mens, most often usi ng a combi nation of mi dazol am, opi oi d, and propofol , have been
successful ly admi ni stered. The goal of drug ti trati on i s to render the pati ent wel l -sedated with a
patent airway.
General anesthesi a i s always admi nistered for smal l chi l dren and uncooperati ve adul t pati ents. In
addi ti on, many neuroradi ologi sts now prefer general anesthesi a to reduce motion arti facts and to
improve the qual i ty of images duri ng hi gh-ri sk procedures, even though i t prevents awake
neurol ogic testing. The specific choi ce of anesthesi a and ai rway control via endotracheal tube or
laryngeal mask ai rway may be gui ded by the condi ti on and physi cal status of the pati ent.
Cannulation of the femoral artery i s the most stimul ati ng porti on of the procedure, and the total
anesthetic requi rement i s usually minimal. Total intravenous techniques or combinations of
inhalation and intravenous agents wi th muscl e rel axant are chosen with the goal of mai ntai ning
adequate systemi c and i ntracrani al hemodynamics and i mmobi l i ty throughout the procedure and
produci ng a rapi d return to consci ousness duri ng emergence.
139

Before i ni tiating anesthesi a, the pati ent i s made comfortabl e with paddi ng under head, neck, and
body, and al l pressure poi nts are protected. Two large-bore intravenous catheters are inserted,
and standard moni toring i s appl i ed. Arteri al pressure i s monitored for i ntracrani al and spi nal cord
procedures and whenever bl ood pressure manipulation is requi red. Awake neurologi c assessment
and other CNS moni tors (e.g., EEG, evoked potenti als, or transcrani al Doppl er) may be used.
During and after these procedures, careful management of coagulation is requi red to prevent
thromboembol i c compl i cations. It i s i mportant to communi cate wi th the radiologi st concerni ng the
degree, ti mi ng, and continuati on of anti coagul ati on. A cl ot wi th devastati ng embol ic potenti al can
easil y develop on a catheter during the procedure, i f hepari ni zation is not adequatel y mai ntained.
At the end of the procedure, protamine may or may not be necessary for hepari n reversal . Special
techni ques such as del i berate hypotension or hypertensi on and hypercapni a may be requested
duri ng certai n procedures.
Compli cati ons during i nstrumentati on of the cerebral vascul ature can be sudden and dramati c.
Simul taneous with ai rway mai ntenance, i t is important to determi ne whether the probl em i s
hemorrhagi c or occl usive. Hemorrhagi c disasters requi re i mmedi ate hepari n reversal wi th
protami ne and l ow normal bl ood pressure. Occl usi ve di sasters requi re del i berate hypertensi on,
ti trated to neurologi c examinati on, wi th or wi thout direct thrombolysi s. Other resuscitati ve
measures that mi ght be i ni ti ated incl ude rapi d fl ui d i nfusi on, 15 head-up position,
hyperventi lation, diuretics, anticonvul sants, hypothermi a (33 to 34C), and thi opental i nfusi on
ti trated to EEG burst suppressi on.
ANESTHETIC MANAGEMENT OF NEUROSURGICAL PATIENTS
The admi ni strati on of anesthesi a to neurosurgical pati ents requi res an understandi ng of the
basic pri ncipl es of neurophysi ol ogy and the effects of anestheti c agents on i ntracranial
dynami cs, as revi ewed i n the previous secti ons of thi s chapter.
P r eoper at i ve Eval uat i on
During the preoperative evaluati on, the patient' s overal l medical condi tion must be considered and
integrated i nto the formul ati on of an anestheti c management pl an. Neurosurgi cal procedures tend
to be l engthy, requi ri ng unusual posi ti oni ng of the pati ent and the insti tution of speci al techni ques
such as hyperventi lation, cerebral dehydrati on, and del i berate hypotension. Not all pati ents can
tol erate the posi ti on desi red by the surgeon; thi s must be addressed and, i f possi bl e, eval uated
preoperati vel y. Furthermore, in pati ents wi th cardi ac di sease, routi ne i nsti tuti on of osmotherapy
or hyperventilation may compromise organ function. Such pati ents must be medi cal l y opti mi zed
and, when i ndi cated, cardi ac monitori ng should be insti tuted. Except for neurosurgi cal
emergenci es (e.g., head trauma or i mpendi ng herni ation), most neurosurgi cal procedures can be
del ayed to treat medi cal l y unstabl e condi tions.
The preoperative evaluati on must i ncl ude a compl ete neurol ogi c exami nati on with special attenti on
to the pati ent' s level of consciousness, presence or absence of i ncreased ICP, and extent of focal
neurol ogic defi cits. The si gns and symptoms frequentl y associated wi th i ntracrani al hypertensi on
are headache, nausea, papi l ledema, uni l ateral pupi l lary di lation, and oculomotor or abducens
pal sy. Wi th advanced stages of i ntracranial hypertension, the pati ent exhi bits a depressed l evel of
consciousness and i rregul ar respi rati on. The cl i ni cal si gns do not rel iabl y i ndi cate the l evel of ICP.
Onl y a di rect CSF pressure measurement can be used to quantitate the pressure; however,
indirect evi dence of elevated ICP can be determined by eval uati ng the MRI or CT scan for a mass
lesion accompanied by a mi dl ine shi ft of 0.5 cm or greater and/or encroachment of expanding
brain on CSF ci sterns.
The l ocati on of the l esion in the supratentori al or i nfratentori al compartment wi ll determine the
cl i ni cal presentati on and

anesthetic management. Supratentori al disease i s usual l y associ ated with problems in the
management of i ntracrani al hypertension, whereas i nfratentori al lesi ons cause probl ems rel ated to
mass effects on vi tal brai nstem structures and el evated ICP as a result of obstructi ve
hydrocephal us.
Fl ui d and el ectrol yte abnormal i ti es are common in pati ents wi th reduced l evel s of consci ousness.
Patients are usuall y dehydrated and devel op el ectrol yte abnormali ties because of decreased fl ui d
intake, i atrogenic water restri cti on, neuroendocri ne abnormal i ti es, and di uresis from di ureti cs,
steroid-rel ated hypergl ycemi a, and x-ray contrast agents. Fluid and electrolyte abnormal iti es must
be corrected before inducti on of anesthesia to prevent cardiovascular instabil i ty.
COMMON INTRACRANIAL PATHOLOGY
Supr at ent or i al I nt r acr ani al Tumor s
Supratentori al tumors (meni ngi omas, gl i omas, and metastatic lesi ons) change intracranial
dynami cs predi ctably. Ini ti all y, when the l esi on i s smal l and sl owly expandi ng, vol ume-spati al
compensati on occurs by compressi on of the CSF compartment and nearby cerebral vei ns, which
prevents i ncreases i n ICP. As the l esi on grows, compensatory mechanisms become exhausted, and
any further increase in tumor mass wil l cause progressi vel y greater increases i n ICP. Pri mary or
metastatic tumors or chronic subdural hematomas can present as chroni c mass lesi ons. Because of
the abi l ity of the i ntracrani al compartment to compensate up to a poi nt, patients may exhi bi t
mi ni mal neurologi c dysfuncti on despi te the presence of a l arge mass, elevated ICP, and shifts i n
the posi ti on of brai n structures.
Significant changes i n ICP can occur wi th supratentori al tumors if they devel op a central area of
hemorrhagi c necroti c tissue or a wide border of brai n edema. As the tumor enlarges, it can
outstri p i ts bl ood suppl y, developi ng a central hemorrhagic area that may expand rapi dl y,
increasi ng ICP. Brai n edema surroundi ng the tumor i ncreases the effecti ve bul k of the tumor and
represents an additi onal porti on of the brai n that i s not autoregul ati ng. In such si tuati ons of
compromised i ntracrani al compl i ance, smal l i ncreases i n arterial pressure may produce large
P.768
increases i n CBF, which can markedl y increase intracrani al vol ume and ICP wi th i ts attendant
compl i cati onscerebral ischemi a and herni ati on. In addi tion to hypertension, other causes of
i ncreased cerebral bl ood volume, such as hypercarbi a, hypoxia, vasodi l ati ng agents, and jugul ar
venous obstructi on, can adversel y affect cerebral hemodynami cs and must be avoi ded
peri operatively.
Anesthetic Techniques and Drugs
The goal of neuroanestheti c care for patients with supratentorial tumors i s to maxi mi ze
therapeutic modali ties that reduce intracrani al vol ume. ICP must be control led before the
cranium is opened, and opti mal operating condi ti ons obtained by producing a sl ack brai n that
faci li tates surgi cal di ssection. Various maneuvers and pharmacol ogi c agents have been used to
reduce brai n bul k (Tabl e 27-9). For exampl e, admini stration of diureti cs or steroi ds,
hyperventi lation, and systemi c bl ood pressure control may be i mpl emented preoperati vel y to
reduce cerebral edema and brai n bul k, thereby reduci ng ICP. The appl i cati on of these methods
sel ecti vely or together, when necessary, i s often accompani ed by marked cl ini cal improvement.
Clinical Control of Intracranial Hypertension. Rapi d brai n dehydrati on and ICP reducti on can
be produced by admi ni steri ng the osmoti c di ureti c, mannitol, or the l oop di ureti c, furosemide.
Manni tol is gi ven as an intravenous i nfusion in a dose of 0.25 to 1.0 g/kg. Its acti on begi ns wi thi n
10 to 15 mi nutes and is effecti ve for approximatel y 2 hours. Larger doses produce a l onger
duration of action but do not necessari ly reduce ICP more effecti vel y. Furthermore, l arger doses
and repeated admi ni strati on can result i n metabol ic derangement. Mannitol i s effecti ve when the
bl ood-brain barrier i s intact. By increasi ng the osmol al i ty of bl ood rel ati ve to the brai n, mannitol
pul ls water across an intact blood-brain barrier from brai n to bl ood to restore the osmol ar
bal ance. When the blood-brain barri er i s di srupted, manni tol may enter the brai n and i ncrease
osmolal ity. Manni tol could pul l water into the brain as the pl asma concentrati on of the agent
decl ines and cause a rebound i ncrease i n ICP. Thi s rebound i ncrease i n ICP may be prevented by
maintai ni ng a mil d fluid defici t. Manni tol has been shown to cause vasodil ati on of vascul ar smooth
muscl e, whi ch i s dependent on dose and rate of admi nistrati on. Manni tol -induced vasodi lation
affects intracrani al and extracranial vessel s and can transi ently i ncrease cerebral blood volume
and ICP whil e si mul taneousl y decreasi ng systemic bl ood pressure. Because manni tol may i ni ti all y
i ncrease ICP, i t shoul d be gi ven sl owl y (10-mi nute i nfusion) and in conjuncti on wi th maneuvers
that decrease intracrani al vol ume (e.g., steroi ds or hyperventi l ati on). Prolonged use of mannitol
TABLE 27-9 Clinical Control of Intracranial Hypertension
Diuretics: Osmotic: Manni tol (0.251 g/kg iv), hypertonic sal i ne (under investi gati on).
Furosemide: 0.51 mg/kg iv alone or 0.150.3 mg/kg i v i n combi nati on wi th mannitol.
Corti costeroids: Dexamethasone (effecti ve for local i zed cerebral edema surroundi ng
tumors; requires 1236 hours).
Adequate venti l ati on: PaO
2

100 mmHg, PaCO

2
3335 mmHg; hyperventi lation on
demand.
Optimize hemodynami cs (MAP, CVP, PCWP, HR): Target normotension and mai ntai n
cerebral perfusi on pressure (CPP = MAP-ICP) to avoi d cerebral ischemia.
Fl ui d therapy: Target normovol emia before anestheti c induction to prevent hypotensi on.
Use glucose-free i soosmol ar crystal l oi d sol uti ons to prevent i ncreases i n brai n water
content (from hypoosmol al i ty) and ischemi c damage (from hypergl ycemi a).
Positi on to i mprove cerebral venous return (neutral , head-up posi tion).
Drug-induced cerebral vasoconstri cti on (e.g., thi opental , propofol ).
Temperature control : Avoid hyperthermia perioperativel y. Consider usi ng mi ld
intraoperative hypothermi a.
Cerebral spi nal fl ui d drai nageto acutel y reduce brai n tensi on.
may produce dehydrati on, el ectrolyte di sturbances, hyperosmol ali ty, and impai red renal function.
Hypertoni c sal ine, another osmoti c di ureti c, is currently under investi gati on.
140
Hypertoni c sal i ne
solutions have been shown to reduce ICP in ani mal models and in human studi es and may be more
effecti ve than other di ureti cs i n certai n cl i ni cal conditi ons, for exampl e, pati ents wi th refractory
intracranial hypertension or i n those who requi re brai n debul ki ng and mai ntenance of intravascul ar
volume.
140, 141
Hypertoni c sal i ne al so can be used as an al ternati ve or adjunct to intraoperati ve use
of mannitol . There are several potential adverse effects of hypertonic sal i ne therapy (Tabl e 27-
10). Significant compl i cations such as central pontine myeli nol ysis and intracranial hemorrhage
have not been reported in human studi es. Di fferent types of hypertoni c sal i ne sol utions with
di fferent methods

of infusi on (bol us and conti nuous) have been reported i n the li terature. Publ ished data are
encouraging, but more studi es are requi red to determi ne dose-response curves and the safety and
effi cacy of these sol uti ons.
Hypertoni c agents, ei ther mannitol or hypertoni c sal i ne, should be admini stered cautiousl y i n
patients with preexi sti ng cardi ovascul ar di sease. In these patients, the transient i ncrease i n
intravascul ar vol ume may preci pi tate left ventri cul ar fai lure. Furosemi de may be a better agent to
reduce ICP i n pati ents wi th i mpaired cardiac reserve.
The l oop di ureti c furosemide reduces ICP by i nducing a systemic diuresi s, decreasi ng CSF
producti on, and resol vi ng cerebral edema by i mproving cel l ul ar water transport. Furosemide
lowers ICP wi thout i ncreasi ng cerebral blood volume or blood osmol al i ty; however, it i s not as
effecti ve as mannitol in reduci ng ICP. Furosemi de can be gi ven al one as a l arge i niti al dose (0.5 to
1 mg/kg) or as a l ower dose with mannitol (0.15 to 0.30 mg/kg). A combinati on of mannitol and
furosemi de di uresi s has been shown to be more effecti ve than manni tol al one i n reduci ng ICP and
brai n bul k but causes more severe dehydration and electrol yte imbal ances. With combi ned
therapy, i t is necessary to moni tor electrolytes i ntraoperati vel y and repl ace potassi um as
i ndi cated.
Corti costeroids reduce edema around some brain tumors; however, steroi ds requi re many hours or
P.769
TABLE 27-10 Hypertonic Saline: Potential Adverse Effects of Intravenous
Administration
CENTRAL NERVOUS SYSTEM SYSTEMIC
Decreased l evel of consciousness Hyperosmol al i ty Hypernatremi a
Sei zures Congesti ve heart fai l ure
Central ponti ne myel i nolysi s
a
Hypokal emi a
Subdural and intraparenchymal hemorrhage
a
Hyperchloremic acidosi s
Coagul opathy
Rebound cerebral edema Phl ebi tis
Renal fai lure
a
Not reported i n human studi es.
days before a reducti on i n ICP becomes apparent. The admi ni strati on of steroi ds preoperati vel y
frequently causes neurol ogi c improvement that can precede the ICP reducti on. One expl anati on for
this i s that the neurol ogi c improvement is accompani ed by parti al restoration of the previ ousl y
abnormal blood-brain barrier. Postul ated mechani sms of action for steroi dal reducti on i n brai n
edema are brai n dehydrati on, blood-brain barrier repair, preventi on of l ysosomal acti vi ty,
enhanced cerebral el ectrol yte transport, improved brai n metabol ism, promoti on of water and
el ectrol yte excretion, and i nhi bi ti on of phosphol i pase A
2
activity. The potenti al compl i cations of
conti nuous perioperative steroi d admi ni strati on are hypergl ycemi a, gl ucosuri a, gastroi ntesti nal
bl eedi ng, el ectrol yte di sturbances, and i ncreased i nci dence of i nfecti on. Therefore, the potential
ri sks and benefi ts of conti nuous steroid administration need to be eval uated in these pati ents.
Hyperventi l ati on reduces brai n vol ume by decreasing CBF through cerebral vasoconstri cti on. For
every 1 mm Hg change in PaCO
2
, CBF changes by 12 mL/100 g/mi n. The duration of effectiveness
of hyperventi lation for l oweri ng ICP may be as short as 4 to 6 hours, dependi ng on the pH of the
CSF. Hyperventi lation is onl y effecti ve when the CO
2
reacti vi ty of the cerebrovasculature is i ntact.
Impai red responsi veness to changes i n CO
2
tensi on occurs i n areas of vasoparal ysis, whi ch are
associated wi th extensi ve i ntracrani al di sease such as i schemi a, trauma, tumor, and infecti on.
The typi cal target PaCO
2
is 30 to 35 mmHg. A PaCO
2
less than 25 to 30 mmHg i n some pathologi c
condi ti ons may be associ ated wi th i schemi a caused by extreme cerebral vasoconstri cti on.
142, 143
By
moni tori ng global cerebral oxygenati on wi th, for exampl e, SjVO
2
, the therapeuti c effecti veness of
hyperventi l ati on can be determi ned and more safel y appl i ed.
The autoregul ati on of CBF has been di scussed, as has the rel ati onshi p between bl ood pressure and
ICP when autoregul ati on i s di sturbed. The therapeuti c goal s are to maintai n CPP and to control
intracranial dynamics so that cerebral i schemia, edema, hemorrhage, and herniation are avoi ded.
Severe hypotension resul ts i n cerebral i schemia and shoul d be treated with vol ume repl acement,
inotropes, or vasopressors as dictated by cl i ni cal need. Severe hypertension, conversely, can
worsen cerebral edema and cause i ntracrani al hemorrhage and herni ati on. The -adrenergi c
bl ockers propranol ol and esmol ol and the combined - and -adrenergi c bl ocker l abetal ol are
effecti ve i n reduci ng systemi c bl ood pressure i n pati ents wi th rai sed ICP wi th mi ni mal or no effect
on CBF or ICP.
Restri cted fl uid i ntake was a traditi onal approach to i ntracranial decompressi on therapy but i s now
rarel y used to l ower ICP. Severe fluid restri cti on over several days i s only modestl y effecti ve i n
reduci ng brai n water and can cause hypovolemia, resul ti ng in hypotensi on, i nadequate renal
perfusi on, electrolyte and aci d-base di sturbances, hypoxemi a, and reducti ons i n CBF. In pati ents
who are dehydrated preoperati vel y, intravascul ar vol ume must be restored to normal before
inducti on of anesthesia to prevent hypotensi on i n response to anestheti c agents and posi ti ve-
pressure ventil ati on. Fl ui d resuscitati on and mai ntenance flui ds i n the routi ne neurosurgi cal
patient are provi ded wi th gl ucose-free i soosmol ar crystal loi d sol uti ons to prevent i ncreases in
brain water content from hypoosmol ali ty. For routine crani otomy, the pati ent receives hourly
maintenance flui ds and repl acement of urine output. Bl ood l oss is replaced at approxi mately a 3:1
rati o (crystal loid:bl ood) down to a hematocrit of approxi matel y 25 to 30%, dependi ng on the
patient' s physiologi c status.
Sol uti ons contai ning gl ucose are avoi ded i n al l neurosurgi cal pati ents wi th normal gl ucose
metaboli sm, si nce these sol utions exacerbate i schemi c damage and cerebral edema.
Hypergl ycemi a augments i schemi c damage by promoti ng neuronal lactate production, whi ch
worsens cel l ul ar i njury. Intravenous fl uids contai ni ng glucose and water (D
5
W
0. 45%
NaCl or D
5
W)
are parti cul arl y probl emati c because the gl ucose i s metabol i zed and the free water remains in the
intracranial fl ui d compartment, resul ting i n brain edema. Brain water can i nterfere wi th surgi cal
exposure and, after closure of the skul l , can compromi se cerebral perfusion. In normal pati ents,
both preoperati ve dexamethasone treatment and general anesthesi ainduced gl uconeogenesi s may
el evate resti ng glucose l evels. Therefore, bl ood gl ucose l evel s shoul d be moni tored duri ng
craniotomy and maintai ned at near low-normal range. Thi s shoul d be accompl ished mainly by
wi thhol di ng gl ucose.
For most neurosurgical patients, a neutral head posi tion, el evated 15 to 30, is recommended to
decrease ICP by i mprovi ng venous drai nage. Fl exi ng or turni ng of the head may obstruct cerebral
venous outfl ow, causi ng a dramati c ICP elevati on that has been shown to resolve wi th resumption
of a neutral head posi ti on. Lowering the head i mpai rs cerebral venous drai nage, which can qui ckl y
resul t in an i ncrease i n brai n bul k and ICP.
The appl i cati on of posi ti ve end-expi ratory pressure (PEEP) to mechani cal l y venti l ated pati ents can
potential ly i ncrease ICP. Thi s effect occurs when PEEP i ncreases mean intrathoraci c pressure,
i mpai ri ng cerebral venous outfl ow and cardi ac output. When PEEP i s required to maintai n
oxygenati on, i t shoul d be appli ed cauti ously and with appropri ate moni toring to

mi ni mi ze decreases i n cardiac output and increases i n ICP. PEEP level s of 10 cm H
2
O or less have
been used wi thout si gni fi cant increases i n ICP or decreases i n CPP. When hi gher l evel s of PEEP are
requi red to opti mi ze the PaO
2
-PEEPCPP rel ati onshi p, both central venous pressure and ICP
moni tori ng are i ndi cated.
The admi ni strati on of pharmacol ogi c agents that increase cerebral vascul ar resistance can acutely
reduce ICP. Thi opental and propofol are potent cerebral vasoconstri ctors that can be used for thi s
purpose. The effects of these agents on CBF, cerebral metabol i c rate for oxygen (CMRO
2
), ICP,
and CPP are revi ewed i n this chapter. These agents are usual l y admi nistered during i nducti on of
anesthesia but may al so be admi ni stered in anti ci pati on of noxi ous sti muli or to treat persistently
el evated ICP in the i ntensi ve care unit.
Although rarely used to reduce ICP, hypothermi a does thi s by decreasi ng brain metabol ism, CBF,
cerebral bl ood vol ume, and CSF producti on.
144
Drugs that central ly suppress shi veri ng, muscl e
rel axants, and mechani cal venti l ation are requi red when hypothermi c techniques are empl oyed.
Intraoperativel y, a modest degree of hypothermi a, approximatel y 34C, has been recommended as
a way to confer neuronal protection duri ng focal i schemia. Hypothermi c techni ques are al so
employed to cool febri l e neurosurgi cal pati ents. Hyperthermi a is parti cularly dangerous i n
neurosurgi cal pati ents because i t increases brai n metabol i sm, CBF, and the propensi ty for cerebral
edema.
To acutel y reduce brai n tensi on, CSF drai nage ei ther by di rect surgi cal puncture of the l ateral
ventri cle or by l umbar spi nal catheter can be empl oyed. Lumbar CSF drainage shoul d be used
cauti ousl y and only when the dura is open and the pati ent i s at l east mi l dly hyperventi l ated to
prevent acute brai n herniation. Brai n tensi on can be effecti vel y reduced by drai ni ng 10 to 20 mL
of CSF.
Premedication
Lethargi c pati ents do not recei ve premedicati on. Pati ents who are al ert and anxi ous may recei ve
an anxi ol yti c (e.g., midazolam 5 mg po) before coming to the operating room. If there i s any
doubt about the pati ent' s level of consciousness, the patient may be gi ven sedation or analgesics
in the operati ng room after an intravenous route i s establ i shed. For the prei nducti on i nserti on of
invasi ve monitori ng devices i n an awake, conversant pati ent, premedicants (e.g., smal l doses of
opi oi ds) should be consi dered to al l evi ate the di scomfort from needl e punctures.
Monitoring
In addi tion to the routine moni tors, measurement of i ntra-arterial blood pressure, arteri al bl ood
gases, central venous pressure, and uri ne output is recommended for all major neurosurgi cal
procedures. An arteri al cannul a i s inserted before i nducti on of anesthesi a to continuousl y monitor
bl ood pressure and to esti mate CPP. When the arteri al pressure transducer i s at mi dhead l evel
(usual l y the l evel of the external auditory meatus), MAP approxi mates the MAP at the l evel of the
ci rcl e of Wi ll i s. Cerebral perfusi on pressure i s cal cul ated as the di fference between MAP and
central venous pressure in pati ents wi thout intracrani al hypertensi on or the ICP in those with
intracranial hypertension. When the crani um i s open, ICP equal s atmospheri c pressure and CPP
equal s MAP. Wi th di rect arteri al pressure moni tori ng, the hemodynami c consequences of the
pharmacol ogic agents admini stered duri ng anesthesi a are recogni zed i nstantl y. In addi ti on, the
arterial catheter provi des ready access for i ntraoperati ve measurement of arteri al bl ood gases,
P.770
hematocri t, serum el ectrol ytes, glucose, and osmol ali ty. Arteri al bl ood gas measurement i s
necessary to verify the adequacy of hyperventi lation. In the el derl y and those wi th
ventil ati on/perfusi on mi smatch, end-ti dal CO
2
may correlate poorl y wi th the PaCO
2
. Therefore, the
di fference between PaCO
2
and end-ti dal CO
2
must be determined for a gi ven pati ent i n a gi ven
positi on. Radi al, femoral , or brachial arteri es are sui tabl e for short-term cannul ati on; however,
after ul nar artery coll ateral bl ood flow i s tested, cannul ati on of the radial artery is preferred.
Because most neurosurgi cal pati ents are dehydrated preoperati vel y and then subjected to
i ntraoperati ve di uresi s, the measurement of cardi ac prel oad and uri ne output is i mportant. A ri ght
atri al catheter reflects cardi ac prel oad and is used to determi ne the preoperati ve fl ui d defi ci t and
rate of intra-operative fl ui d i nfusion. When possi bl e, the central venous pressure catheter shoul d
be inserted through an antecubi tal vei n i nstead of the jugul ar or subcl avi an veins. Thi s avoi ds
i ncreased ICP from both the head-down posi ti on and decreased cerebral venous outfl ow. The
positi on of the antecubi tal central venous pressure can be veri fi ed by chest radi ograph, transducer
pressure waveform, or p-wave configuration on the ECG.
Uri ne output is al so measured as an indicator of peri operati ve fl ui d bal ance. Duri ng crani otomy, a
di uresis occurs i ni tial ly foll owi ng the admini stration of osmotic or loop diuretics. Reduced uri ne
output may reflect either hypovol emi a or release of anti di ureti c hormone.
Preoperati ve ICP moni tori ng is rarely used i n pati ents for el ecti ve supratentorial tumor operati ons.
ICP moni toring i s an i nvasive procedure that can cause bl eeding or i nfecti on. When performed wi th
local anesthesi a before induction, the procedure can be uncomfortabl e to the pati ent.
Muscle Relaxants
An i ncrease i n ICP has been reported after admi ni strati on of succi nylchol ine i n ani mal s and
humans. Intravenous admi ni strati on of succi nylchol ine i s reported to produce activation of the EEG
and i ncreases i n CBF and ICP i n dogs wi th normal brains.
145
These cerebral effects have been
attri buted to succinyl chol i ne-induced i ncreases in muscl e afferent acti vi ty that produce cerebral
stimul ati on. In many, but not al l , pati ents wi th compromi sed i ntracrani al compl iance,
succi nyl choli ne has been shown to i ncrease ICP. Thi s increase can be blocked wi th a full ,
paral yzing dose of vecuronium or a pretreatment (defasciculating) dose of metocuri ne.
144
The
nondepol ari zi ng agent apparentl y el i mi nates the massi ve afferent i nput to the brai n after
succi nyl choli ne.
To achi eve muscl e rel axati on for i ntubati on of the trachea, succi nylchol ine i s not recommended for
el ecti ve neurosurgi cal cases; however, succi nylchol ine remai ns the best agent for achi evi ng total
paral ysi s for the rapi d-sequence i ntubati on of the trachea. Therefore, i n an emergency room or
ICU setting, when there i s a ri sk of aspi ration or a need for i mmedi ate reassessment of neurologi c
status, succi nyl choli ne shoul d be used. Si mul taneously, an effort shoul d be made to control
anesthetic depth to protect agai nst the ICP-el evati ng effects of such noxi ous sti muli as
laryngoscopy, i ntubation, or tracheal sucti oni ng. In the hemipl egi c (or parapl egic) pati ent,
succi nyl choli ne is avoi ded because of the ri sk of hyperkal emi a. Succinyl choli ne-induced
hyperkalemia has also been reported after cl osed head injury and ruptured cerebral aneurysms i n
patients who were not hemi pl egi c or parapl egi c.
Nondepolari zing muscl e rel axants are used duri ng i nducti on and maintenance of anesthesi a in
neurosurgi cal pati ents. Agents that release hi stami ne are avoi ded, however. Histamine alone may
l ower bl ood pressure and increase ICP, thus l oweri ng CPP. When the bl ood-brai n barri er i s
di srupted, hi stami ne can produce cerebrovasodi lation and i ncreases i n CBF. Dependi ng on the dose
and rate of admi ni stration, most of the benzyli soquinol i ni um compounds (d-tubocurari ne,
metocurine, atracuri um, mi vacurium) have the potential to release hi stami ne and thus i ncrease
ICP. Doxacuri um and ci satracuri um produce mi nimal to no hi stami ne rel ease over a wide dose

range. Atracurium in i ntubati ng doses i s reported to have no si gni fi cant effect on ICP, bl ood
pressure, or CPP i n neurosurgi cal pati ents. The rel ease of l audanosi ne by atracuri um does not
appear to have cl i ni cal signi fi cance i n humans. Laudanosi ne has been reported to produce seizure
P.771
acti vi ty i n animal s.
The steroi dal compounds (pancuroni um, pipecuroni um, vecuronium, and rocuronium) may be
better relaxants for neurosurgi cal pati ents because they do not di rectl y affect ICP. Pancuroni um
does not produce an i ncrease i n CBF, CMRO
2
, or ICP i n dogs.
144
However, pancuroni um' s vagol yti c
effects can cause increases i n heart rate and bl ood pressure, whi ch may el evate ICP i n pati ents
wi th di sturbed autoregul ati on. Pi pecuroni um, another l ong-acti ng agent, is reported to have no
si gni fi cant effect on ICP or CPP i n pati ents wi th i ntracranial tumors and no hemodynami c si de
effects. Vecuronium has no effect on ICP, heart rate, or bl ood pressure in neurosurgi cal pati ents.
To achi eve rel ati vel y rapid ai rway control (wi thi n 90 seconds), a pri mi ng dose of vecuronium (0.01
mg/kg) can be admi ni stered fol l owed by a hi gher dose (0.10 mg/kg), or high doses of vecuroni um
(to 0.4 mg/kg) can be safel y admi nistered wi thout hemodynami c consequence. Rocuronium al so
has no effect on ICP i n neurosurgi cal pati ents, but may have some mi l d vagol yti c activity in hi gher
doses (0.9 mg/kg).
Induction, Maintenance, and Emergence
When the patient is brought i nto the operati ng room, a gross neurologi c examinati on shoul d be
repeated and documented because changes i n the pati ent's neurol ogi c status can occur overni ght.
In pati ents wi th el evated ICP by cl inical exam, CT scan, and/or ICP measurement, osmotherapy
may be i ndi cated before i nducti on of anesthesi a. After appropriate moni tori ng devi ces are appl i ed,
the cooperati ve patient i s asked to hyperventil ate whi le preoxygenation is provided. Before
l aryngoscopy and i ntubati on of the trachea, the pati ent i s smoothl y and deepl y anesthetized wi th
agents that reduce ICP. In the presence of elevated ICP, thi opental i s commonly used to induce
anesthesia; however, al ternative agents such as propofol or midazolam can be used dependi ng on
the pati ent's medical condi tion. The fol lowi ng inducti on sequence i s suggested: The intravenous
administrati on of thiopental (3 to 5 mg/kg) or propofol (1.25 to 2.5 mg/kg) i s fol l owed by an
opi oi d (fentanyl , 3 to 5 g/kg) and muscle rel axant. If no airway di fficul ties are anti cipated, a
nondepol ari zi ng muscle rel axant is admi ni stered whil e controll ed hyperventi l ation wi th 100%
oxygen i s i nsti tuted. In pati ents who have been vomi ti ng because of el evated ICP, cricoid pressure
i s appl i ed duri ng mask venti lation. To deepen the anestheti c, fentanyl i s admi ni stered in 50-g
increments to a total dose of 10 g/kg, dependi ng on the bl ood pressure response. Lidocai ne (1.5
mg/kg) is al so admi ni stered intravenousl y 90 seconds before i ntubati on to suppress l aryngeal
refl exes. When the peri pheral muscle twi tch response di sappears, an addi tional 2 to 3 mg/kg bol us
of thiopental i s admi ni stered, and endotracheal i ntubati on i s performed as rapi dl y and smoothl y as
possi bl e. An esmol ol i nfusi on or bol us may al so be used to reduce the heart rate and blood
pressure response to laryngoscopy and intubati on. After induction of anesthesi a, venti lation of the
lung i s control l ed mechani cal l y. Arteri al bl ood gases are measured after intubati on to establ i sh the
arterial end-ti dal CO
2
gradi ent.
Routi ne i nstituti on of hyperventi l ati on i s no l onger recommended i n neurosurgi cal pati ents
because of the risk of cerebral ischemia i n some pathol ogi c conditi ons. In other words, surgi cal
condi ti ons shoul d defi ne the PaCO
2
level for each pati ent. For exampl e, i n patients wi th si gnifi cant
intracranial hypertension or when usi ng volatil e agents, PaCO
2
is usuall y adjusted between 30 to
35 mmHg to reduce brai n bul k.
146
After di rect vi suali zation of the brai n and/or di scussi on wi th the
neurosurgeon, the PaCO
2
level should be adjusted as necessary.
Since anesthetics affect the intracrani al envi ronment, there conti nues to be controversy over the
best choice of anestheti c techni que for neurosurgi cal pati ents, that is, i ntravenous- or volatil e-
based techni ques. In practi ce, the anestheti cs most frequentl y admi ni stered to neurosurgi cal
patients are ei ther propofol -opi oi d or i sofl urane-opi oi d.
31
The opi oi ds sel ected are usuall y fentanyl
or remifentanil . There have been no l arge cl ini cal outcome studi es conducted comparing anestheti c
techniques. Our choi ce of anestheti cs has been based pri mari l y on i nformati on deri ved from
experi mental and cli ni cal studi es of cerebral hemodynami cs (CBF, CMRO
2
), ICP and recovery
characteri sti cs of di fferent agents.
A popular mai ntenance techni que for neurosurgi cal pati ents i s the conti nuous infusi on of propofol
with remifentanil or fentanyl . In brain tumor pati ents, this techni que has been shown to reduce
ICP more effecti vely than either i sofl urane or sevofl urane,
31
and i n nonneurosurgical pati ents,
propofol wi th remi fentani l produced a qui cker emergence than ei ther desfl urane or sevofl urane.
147

Thi s technique woul d seem i deal for neurosurgi cal pati ents; however, questi ons have been raised
regardi ng the ri sk of cerebral hypoperfusi on wi th propofol anesthesia.
148, 149
Studi es suggest that
propofol anesthesi a produces a reduction of CBF l arger than a reduction of CMR, resulting in a
decrease of the CBF/CMR rati o.
149, 150
In suscepti ble patients, the ri sk of cerebral hypoperfusi on
may be even greater when pati ents are hyperventil ated under propofol anesthesi a.
149, 150

Ni trous oxi de, 50 to 70% i n oxygen, i s admi ni stered by some to decrease the total dose of
intravenous agent or the requi red concentration of volatil e agent. The cerebrovascul ar effects of
ni trous oxide are not beni gn,
38, 144
and studies report that at equi potent doses, isofl urane has less
adverse effects on ICP and CBF than ni trous oxi de. In pati ents wi th elevated ICP or l ow
compl i ance, some cl inici ans avoi d the admini stration of either ni trous oxi de or high concentrati ons
of isoflurane (i .e., greater than 1.0%). Al ternati vel y, an opioidthiopental or propofol anestheti c
techni que may be empl oyed wi th mi dazol am or low-dose i sofl urane added for amnesi a. When
severe i ntracrani al hypertensi on exi sts and the brai n i s ti ght despi te adequate hyperventi l ati on
and the admi ni strati on of steroi ds and di ureti cs, a totall y intravenous techni que usi ng a thiopental
infusion (2 to 3 mg/kg/hr) and fentanyl bol uses or i nfusi on (1 to 4 g/kg/hr) i s recommended.
In the usual crani otomy for exci sion of a supratentorial tumor, the conduct of the anestheti c is
ai med at awakeni ng and extubating the pati ent at the end of the procedure to permi t earl y
assessment of surgi cal results and postoperati ve neurologi c fol l ow-up. The ri sks and benefits of an
early versus del ayed recovery i n neurosurgi cal pati ents have been reviewed.
151
The authors
recommend extubati on of the neurosurgi cal pati ent onl y when there is complete systemic and
brain homeostasi s. There are several conditi ons li sted i n Tabl e 27-11 that can del ay awakeni ng in
neurosurgi cal pati ents and shoul d be consi dered pri or to devel oping an extubation plan.
Intracranial hematoma and major cerebral edema are the most feared compl i cations after
intracranial surgery. In a retrospecti ve study of 11,214 crani otomy patients, a relationshi p was
demonstrated between perioperative hypertensi on and the devel opment of postoperati ve
hematomas.
152
Therefore, emergence from anesthesi a shoul d be as smooth as possibl e, avoidi ng
strai ni ng or bucki ng on the endotracheal tube. Bucki ng can cause arterial hypertension and
el evated ICP, which can lead to postoperati ve hemorrhage and cerebral edema. To avoi d bucki ng,
muscle rel axants are not reversed unti l the head dressi ng i s appli ed. Intravenous l i docai ne (1.5
mg/kg) can be admi ni stered 90 seconds before sucti oni ng and extubati on to mi ni mi ze cough,
strai ni ng, and hypertension. Antihypertensi ve agents such as labetal ol and esmol ol al so are al so
administered duri ng emergence to control systemi c hypertension.

The pati ent i s extubated onl y when full y reversed from paral ysi s, and when he or she is awake and
TABLE 27-11 Causes of Delayed Awakening
Preoperati ve decreased level of consciousness
Large intracrani al tumor
Resi dual anestheti cs
Metabol ic or electrol yte di sturbances
Resi dual hypothermi a
Surgical compl icati ons Sei zures
Cerebral edema
Hematoma
Pneumocephal us
Vessel occlusi on/i schemia
P.772
fol l owing commands. If the patient is not responsive, the endotracheal tube remains i n pl ace unti l
the pati ent i s awake and fol lowi ng commands. A bri ef neurol ogi c exami nati on i s performed before
and after extubati on of the trachea. The pati ent i s posi ti oned wi th the head elevated 15 to 30
and transferred to the recovery room wi th oxygen by mask and oxygen saturation moni tori ng.
Close moni toring and care, i ncl udi ng frequent neurologi c examinati ons, are conti nued i n the
recovery room.
Awake Cr ani ot omy
Awake crani otomy wi th functi onal mapping i s recommended for removal of tumors i nvol vi ng the
el oquent cortex. Functi onal mappi ng i s performed by sti mul ati ng the brai n wi th a small el ectri cal
charge. A neuropsychologi st then performs neurocogni tive testing and/or monitors motor
responses duri ng mappi ng and l ater tumor resection. Thi s techni que all ows maxi mal tumor
resection wi th mi ni mal postoperati ve neurol ogi cal defi cits from retracti on, edema and/or resecti on
of el oquent ti ssue. Other advantages i ncl ude avoidance of general anesthesi a and need for more
intensi ve moni tori ng intra-operatively and postoperati vely, a l ow compl i cation rate, and reducti on
in resource uti l izati on (e.g., shorter i ntensi ve care time and total hospi tal stay).
153, 154

Preoperati ve selection, eval uati on, and preparati on of the pati ents for awake craniotomy i s sl i ghtly
di fferent than for general anesthesi a. The pati ent must be cooperati ve and abl e to parti ci pate i n
neurocogni ti ve testi ng. In additi on, the patient must have an uncompl i cated ai rway and be a
candi date for general anesthesi a. Most centers provi de the pati ent wi th detail ed informati on about
the procedure and what to expect i n verbal, written, and vi sual form.
In the operati ng room, there are several chall enges for the anesthesi ol ogi st. As wi th any
craniotomy, opti mal operati ng condi tions providi ng adequate surgical exposure and brai n
rel axation are requi red. For the awake crani otomy, the pati ent must be positi oned very
comfortabl y wi th bol sters and addi ti onal paddi ng. Adequate anal gesia and sedati on are needed for
head frame appl i cation, skin i nci si on, craniotomy, and openi ng of the dura. Duri ng cortical
mappi ng and tumor resecti on, the patient must be ful ly al ert and cooperati ve, and able to
parti cipate in complex neurocogni tive testing.
Several different anesthetic protocol s have been reported for awake crani otomy.
154
These i nclude
neurol ept anesthesi a, propofol wi th or wi thout opi oi d i nfusi ons, and asl eep, awake, asl eep
techniques using l aryngeal mask ai rways. Dexmedetomi di ne, a highl y speci fi c -2 adrenoreceptor
agoni st, has been recommended for use during awake crani otomy.
155
It has the advantage of
provi di ng sedati on and anal gesi a without respi ratory depressi on.
All awake procedures wi th sedation run the ri sk of respi ratory depressi on and poor pati ent
cooperati on. Compl i cations such as seizures, increased ICP, hypertensi on, nausea, and vomi ti ng,
whi ch are more l i kely to occur duri ng craniotomy, also require prompt treatment.
153, 156
Most
anesthetic protocol s i ncl ude prophyl axi s with antihypertensi ves, anti convulsants and antiemeti cs
to prevent these compl i cati ons from occurri ng.
I nf r at ent or i al I nt r acr ani al Tumor s
The peri operati ve management of i nfratentori al tumors poses si gni fi cant surgi cal and
anesthetic chal lenges because of the rel ati vel y confi ned space within the posteri or fossa. The
posterior fossa contains the medull a, pons, cerebel lum, major motor and sensory pathways,
pri mary respi ratory and cardi ovascul ar centers, and lower crani al nerve nucl ei. Because of the
posterior fossa's smal l si ze, a l ocal ized tumor can si gni fi cantl y compromi se these vi tal brai nstem
structures and crani al nerves. Consequentl y, when eval uati ng pati ents with infratentori al tumors,
the anesthesi ol ogi st shoul d be aware that these patients have the potenti al to devel op profound
neurol ogi c damage. Pati ents may exhibi t depressed level s of consci ousness secondary to increased
ICP from obstructi ve hydrocephal us and/or exhi bit si gns of brai nstem compressi on wi th depressed
respirati on and cranial nerve palsi es. Preoperati ve endotracheal i ntubati on and respi ratory support
may be requi red.
Special Anesthetic Considerations
Patient Position. A major chal l enge of infratentori al surgery i s preventi ng further neurol ogic
damage from the positi on of the pati ent and expl orati on. There i s considerabl e controversy among
neurosurgeons as to the best position for infratentori al surgery.
157

Expl orati on of the posteri or fossa has been tradi ti onal l y performed i n the si tti ng positi on because
it provi des excell ent surgi cal exposure and faci l itates venous and CSF drai nage. From the
standpoi nt of the anesthesi ol ogi st, the sitting posi tion provi des better venti l ati on and easi er
access to the chest, ai rway, endotracheal tube, and extremi ti es. Furthermore, facial and
conjunctival edema i s reduced. However, the si tti ng posi ti on i s associ ated wi th si gni fi cant ri sks. In
ol der or debil i tated pati ents, the si tti ng posi ti on can produce cardi ovascul ar i nstabi l i ty, resul ting
in hypotension wi th cerebral and cardi ovascul ar compromi se. A signi ficant risk of venous air
embol i sm occurs i n patients operated on in the si tti ng positi on, and an attendant ri sk of
paradoxi cal air embol ism may al so occur i n pati ents with a patent foramen ovale or other right-to-
l eft shunt.
Other probl ems associ ated wi th the si tti ng positi on are peripheral nerve i njury, pneumocephalus,
jugular venous obstructi on, and quadri pl egi a. Peri pheral nerve i njuries to the ul nar, sci ati c, or
lateral peroneal nerves can resul t i f care i s not taken in posi tioni ng and paddi ng the respecti ve
pressure poi nts. Pneumocephal us occurs frequentl y in pati ents who have surgery performed in the
si tti ng posi ti on.
157
Pneumocephal us may devel op i nto tensi on pneumocephal us postoperati vely,
producing seri ous neurologi c dysfuncti on. Nitrous oxi de has been impli cated i n the pathogenesis of
tensi on pneumocephal us.
157
Because of this, when used, ni trous oxide shoul d be di sconti nued
before dural and crani al cl osure and avoi ded i f surgery recurs withi n 14 days. Jugul ar venous
obstruction causi ng swell i ng of the face and tongue may resul t from hyperfl exi on of the neck. To
avoi d thi s, head fl exi on shoul d be l i mi ted by pl aci ng two

fingers between the mandi ble and sternum. Paraplegi a, tri pl egi a, and quadri pl egi a have been
reported foll owing surgery in the sitting posi tion. Thi s compl i cation has been attri buted to
mechani cal compressi on of the cervical spi nal cord or vertebrobasi lar blood vessel s and stretchi ng
of spi nal cord bl ood vessel s, causi ng i schemia duri ng head fl exi on. If hypotensi on occurs, the
brainstem and cervi cal spi nal cord are rendered even more vul nerabl e to an i schemic i nsult.
Duri ng posi ti oni ng for posteri or fossa expl orati on, cases of posi ti on-rel ated brai nstem and cervical
spi nal cord ischemia have been reported. Therefore, fl exion of the head on the cervi cal spi ne may
be hazardous i n some patients wi th l arge posterior fossa tumors and in elderly or arthri ti c
patients. A preoperati ve examinati on of the mobi l ity of the cervi cal spine, i ncl udi ng a revi ew of
radiol ogi c studi es to determine the width of the cervi cal canal, shoul d be performed to establ i sh
whether the pati ent can tol erate the posi ti on requi red for surgery. In additi on, the appli cati on of
SEP moni tori ng duri ng posi ti oni ng for surgery may be used to detect positi on-rel ated ischemia.
Other posi ti ons used for posteri or fossa expl orati on are the lateral, prone, and park bench or
three-fourths prone posi tions. These al ternative posi ti ons have been advocated because of the
lower incidence of ai r emboli and greater cardiovascular stabil i ty associ ated wi th them. Potenti al
di sadvantages of these posi ti ons are mal i gnant cerebell ar edema and venous hemorrhage. To
date, there is no evidence that operati ve positi on affects postoperati ve outcome. In a study that
revi ewed 579 posteri or fossa crani ectomi es, patients i n the sitting posi ti on had less bl ood l oss and
postoperative crani al nerve dysfuncti on than pati ents operated on in the hori zontal positi on
(supi ne, prone, l ateral , and park bench), and there was no difference in the i nci dence of
hypotensi on and postoperative cardiopul monary compl i cati ons between groups.
158
The i nci dence of
venous air embol ism in thi s seri es of patients was signi fi cantl y greater i n si tti ng versus hori zontal
patients (45 vs. 12%), but i t was not associated wi th a si gni fi cantl y increased morbidi ty or
mortal i ty.
158
The authors concl uded that there are si gni fi cant advantages and di sadvantages to
both si tti ng and hori zontal posi ti ons and that these positi ons can be used safel y.
Because of various advantages and disadvantages to both si tti ng and hori zontal positi ons, no one
best posi ti on exists for all patients requi ri ng expl orati on of the posteri or fossa. The selection of
the most appropri ate posi ti on for an i ndi vi dual pati ent shoul d be based on the l ocati on of the
P.773
tumor, surgi cal exposure, the pati ent' s medi cal conditi on, and considerati on of the ri sks and
benefi ts.
Monitoring. Duri ng posteri or fossa expl orati on, surgical retracti on or mani pul ati on of the
brainstem or crani al nerves can cause si gni fi cant cardi ac dysrhythmi a or alterations i n blood
pressure. Adequate warni ng of brainstem compromi se i s obtained by moni tori ng the ECG for
al terati ons in cardi ac rate and rhythm. In addi tion, direct arterial pressure moni tori ng provi des
conti nuous i nformati on on sudden changes i n systemi c bl ood pressure and an esti mate of CPP. (To
estimate CPP in the si tti ng posi ti on, the arterial transducer should be zeroed to the hi ghest point
on the skul l .) The hemodynami c consequences of dysrhythmi as or ai r emboli sm are al so instantl y
recogni zed wi th di rect arteri al pressure moni tori ng.
El ectrophysi ol ogic monitori ng of SEPs i s used to detect i schemi a and compromi se of the brai nstem
or crani al nerves. For example, BAEPs are moni tored during surgery for acousti c neuroma to hel p
preserve functi on of crani al nerve VIII or duri ng posteri or fossa procedures to moni tor brai nstem
ischemi a. Dependi ng on the tumor's l ocation, SSEPs may al so be used to detect brai nstem
compromise. Posi tion-rel ated i schemia has been observed during moni toring wi th ei ther BAEPs or
SSEPs. El ectromyography is used during resecti on of acousti c neuromas and microvascular
decompression to test seventh nerve functi on when the face i s not accessi ble to palpation or
visual assessment.
Venous Air Embolism. Venous air embol ism may occur whenever the operati ve fi eld is el evated 5
cm or more above the ri ght atrial level. Whereas the i ncidence of ai r embolism i s on average 40 to
45% i n pati ents operated on i n the si tti ng posi ti on, entrai nment of ai r al so occurs during
operati ons performed i n the l ateral , supi ne, or prone posi ti ons. The pri mary pathophysi ol ogi c
event i n venous ai r emboli sm is i ntense vasoconstri cti on of the pul monary circul ati on, which
resul ts i n venti lation/perfusion mi smatch, intersti ti al pul monary edema, and reduced cardiac
output as pul monary vascul ar resi stance i ncreases.
Air may al so pass directl y through the pul monary circul ati on or through right-to-left i ntracardi ac
shunts (e.g., probe-patent foramen oval e) to the coronary and cerebral ci rcul ation when right
atri al pressure exceeds l eft atrial pressure. A patent foramen oval e exi sts i n 20 to 30% of the
popul ati on on autopsy study. In the si tti ng posi ti on, a reported 50% of pati ents devel op ri ght
atri al pressure greater than l eft atrial pressure and thus have the potenti al for paradoxi cal ai r
embol i sm. The cal culated ri sk of paradoxi cal ai r embol ism is 5 to 10%. Preoperati ve screeni ng
with precordi al two-di mensional contrast echocardi ography duri ng a Val sal va maneuver and cough
has been suggested as a method to i denti fy patients with patent foramen ovale. An alternati ve
technique is to perform contrast TEE with a ventil ati on maneuver after i nducti on of anesthesi a,
but before surgery.
159
If a patent foramen ovale is detected with either screeni ng method, a
positi on other than si tti ng is recommended for surgery because of the risk of paradoxi cal ai r
embol i sm.
Moni tors used for detecti ng venous ai r embol i sm are l i sted i n Tabl e 27-12. The two-di mensional
transesophageal echocardi ogram detects ai r bubbl es wi th an echocardi ographi c probe pl aced
behind the heart. The transesophageal echocardiogram is sl ightl y more sensi ti ve than the
precordi al Doppl er, but i s invasive and cumbersome. The transesophageal echocardi ogram has the
advantage of moni toring air i n the ri ght and left cardi ac chambers and the aorta, and thus can be
used to detect both venous and arteri al ai r emboli sm.
The precordi al Doppl er ul trasound transducer i s the most sensi tive noni nvasi ve moni tor of venous
ai r embol i sm. It detects amounts of ai r as smal l as 0.25 mL. The transducer i s posi ti oned al ong
the ri ght parasternal border between the thi rd and sixth i ntercostal spaces to maxi mi ze audi bl e
si gnal s from the right atri um. Proper pl acement i s confi rmed by rapi d i njecti on of 510 mL of
sali ne into a right atrial catheter. The resul tant turbulent fl ow changes the Doppl er sounds to a
hi gh-pi tched noi se si mi l ar to the sounds produced by intravascul ar ai r.

Pul monary artery (PA) catheteri zati on has been advocated for patients who undergo surgery i n the
si tti ng positi on. Passage of ai r i nto the pul monary circul ati on l eads to mechani cal obstructi on and
refl ex vasoconstri cti on from l ocal hypoxemia. The PA catheter detects the resul tant hypertension.
(The change i n pul monary artery pressure correl ates wi th the hemodynami c si gni fi cance of the
embol us because pul monary artery pressure increases proporti onal l y wi th the vol ume of ai r
enteri ng the pul monary arteri es.) Pulmonary artery pressure measurement i s sl i ghtl y more
sensi ti ve than capnography for detecti ng venous ai r embol i sm, but i t i s invasi ve. The PA catheter
lumen is poorl y designed for ai r aspi rati on. In addi ti on, the fi xed di stance between the PA catheter
ti p and the ri ght atri al port makes i t diffi cult to posi ti on for both pul monary capi l l ary wedge
pressure measurement and air aspi rati on. The catheter can be used to identify patients at risk for
paradoxi cal air embol ism, that i s, pati ents who devel op ri ght atri al pressure greater than
pul monary capi l l ary wedge pressure. When thi s occurs, measures to elevate pul monary capi l lary
wedge pressure, such as volume l oadi ng or reposi ti oni ng, are undertaken.
In the operati ng room, exhal ed gases can be measured by infrared anal ysi s, mass spectrometers,
and anal yzers based on Raman scattering. The infrared absorpti on techni que i s the most popular
method of measuri ng the concentrati on of CO
2
i n the ai rway. The capnograph i s very useful for
di agnosi ng venous ai r embol i sm. Smal l volumes of i ntravascular air produce a
ventil ati on/perfusi on mi smatch, whi ch i s reflected in a reduced end-ti dal CO
2
. The capnograph
compl ements the capabi li ties of the precordial Doppl er by di fferenti ating hemodynami cal l y
insi gni fi cant emboli that are heard wi th the Doppl er from si gni fi cant embol i . Doppler sounds
without reduction in end-ti dal CO
2
usual ly i ndi cate insignificant amounts of air.
End-tidal N
2
moni toring i s speci fic for detecting air but i s sl i ghtly l ess sensi ti ve than end-ti dal CO
2

in detecting subcli ni cal ai r embol i sm. As i ntravascular ai r i n the pul monary ci rculation crosses the
capil l aryal veolar membrane, i t is exhaled, i ncreasi ng the end-ti dal N
2
concentrati on. The
advantage of knowing the val ue of the end-expi red N
2
is the abi l ity to cal cul ate the vol ume of air
entrained. When a pati ent i s ventil ated with an airoxygen mixture, the increase in end-ti dal N
2

with venous ai r embol i sm may not be evi dent. In addi tion, other causes of i ncreases in end-ti dal
N
2
must be eli mi nated, such as a l eak in the breathi ng ci rcuit or an i ncomplete seal around the
TABLE 27-12 Monitors for Detection of Venous Air Embolism
P.774
endotracheal tube cuff.
A central venous pressure catheter is i nserted whenever there is a ri sk for venous ai r embol i sm.
When the catheter i s correctl y positi oned, entrai ned air can be aspirated from the ri ght atrium. It
is suggested that the opti mal positi on for the tip of a si ngl e ori fi ce catheter i s 3.0 cm above the
superi or vena cava and the ri ght atri al juncti on. The posi tion of the ri ght atrial catheter may be
confi rmed by a chest fi l m, by usi ng a sali ne-fil l ed catheter as a unipol ar l ead and fol l owing the
confi gurati on of the P waves on the ECG, or by transducing a venous waveform. Mul ti ori fi ce ri ght
atri al catheters are more effective than singl e-orifice catheters i n aspi rati ng ai r from the
ci rculati on.
Earl y di agnosi s of air embol ism is essenti al for successful treatment. The precordi al Doppl er uni t
is consi dered the basi c moni toring devi ce for detecti on of air embol ism and i s most effecti ve when
used in conjuncti on wi th end-ti dal monitori ng. The cl inical si gni fi cance of ai r embol i sm detected by
Doppl er ul trasonography can be assessed by a decrease i n end-expi red C
2
or an i ncrease i n
pul monary artery pressure. A Doppl er in conjunction wi th ei ther a capnograph or a PA catheter
usual l y detects ai r before physi ol ogi c al terati on begins. Treatment i s directed at preventi ng
further influx of air. Whenever air embolism is suspected, the surgeon i s noti fi ed immedi atel y. The
surgi cal fi el d is flooded wi th sal i ne and packed, and bone edges are waxed. Ni trous oxi de, i f
present, i s di sconti nued to prevent further expansion of emboli zed ai r. Neck veins are compressed
as a means of i ncreasing jugular venous pressure, whi ch prevents further ai r entry and helps to
local ize the source of air. Aspi rati on of ai r from the ri ght atri al catheter i s attempted. With
si gni fi cant ai r embol i sm, patient positi on shoul d be changed to lower the head to heart l evel when
possi bl e. If necessary, vasopressors and volume i nfusi on are admi ni stered to treat hypotension.
Positi ve end-expiratory pressure or Valsalva maneuver are avoi ded because they increase ri ght
atri al pressure and the l i keli hood of paradoxi cal embol us from venous air emboli sm.
Anesthetic Management. When sel ecti ng an anestheti c technique for patients i n the sitting
positi on, conditi ons of particul ar concern are cardi ovascul ar stabi li ty and ri sk of air embol ism. In
changing an anesthetized pati ent from the supi ne to sitting posi ti on, a mil d transient postural
hypotensi on occurs i n about one thi rd of cases and marked hypotension in about 2 to 5% of
cases.
144, 157
General anesthesi a wi th posi tive-pressure ventil ati on i s associ ated wi th a reducti on i n
bl ood pressure mai nl y caused by a decrease i n cardi ac output. As pati ents are pl aced i nto the
si tti ng posi ti on, venous return i s i mpeded, causi ng further reducti ons i n cardi ac output and bl ood
pressure. Therefore, efforts are directed at promoti ng venous return and mai ntai ni ng cardi ac
output duri ng the anestheti c management of these pati ents. An anestheti c technique that causes
the least impai rment of cardi ovascul ar performance shoul d be admi ni stered when pati ents are
pl aced in the si tting posi tion. Measures to avoid hypotensi on are al so insti tuted. These incl ude
adequate preoperati ve hydrati on, wrappi ng the l egs wi th el asti c bandages, and fl exi ng the
patient' s hips and knees at heart level . The pati ent's posi ti on i s sl owl y changed, ti trati ng posi ti on
agai nst systemi c bl ood pressure. Admi nistrati on of fluids (balanced sal t sol uti ons) and smal l
amounts of vasopressors may be necessary.
The choice of anesthetic techni que must take into account the hemodynami c consequences of the
sel ected surgical posi ti on and the requi rements of faci al or evoked potenti al moni tori ng. In si tti ng
positi on cases, the use of ni trous oxi de remai ns controversi al because of the potenti al to expand
embol i zed ai r or contri bute to tensi on pneumocephal us.
144, 157
Because of these concerns, an
anesthetic techni que wi thout ni trous oxide is usual ly admi ni stered, for exampl e, ai roxygen,
potent i nhal ati on agent wi th opi oids and muscle rel axant. When el ectrophysiol ogi c moni toring i s
insti tuted, a propofol -based i ntravenous techni que wi th opioid and muscl e rel axant i s
recommended, and for faci al nerve moni tori ng, thi s technique wi thout suppl ementary
administrati on of muscle rel axant provi des successful moni toring condi tions.
Postoperative Concerns. The potenti al for si gnifi cant cardiorespi ratory and neurol ogi c
deteri orati on exists i n the immedi ate postoperati ve period fol lowi ng posteri or fossa expl orati on.
Therefore, direct arterial pressure and ECG moni tori ng shoul d be conti nued for the fi rst 24 to 48
hours postoperati vel y, and neurol ogi c exami nati ons shoul d be performed frequentl y.
Central apnea requi ring postoperati ve venti l atory support may result from damage to respi ratory
centers caused by extensi ve posterior fossa expl orati on. If respi ratory centers have been
mani pul ated but not destroyed, respi ratory i mpairment is temporary. Postoperati ve i mpai rment of
swal lowi ng and pharyngeal sensati on may occur secondary to stretch or mani pul ati on of crani al
nerves IX, X, and XII. These pati ents are at i ncreased ri sk for aspi ration pneumoni a or hypoxi a
and therefore should remai n i ntubated unti l ai rway protective refl exes return.
Systemi c hypertensi on frequentl y occurs after posteri or fossa surgery and requi res i mmedi ate
treatment to prevent brai n edema and hematoma formation. Postoperati ve hypertension usual ly
resol ves wi thi n the fi rst 24 hours. Atri al

and ventricul ar ectopi c beats may al so occur wi thin the first 24 hours.
Because of the proxi mi ty of respi ratory and cardi ovascul ar centers, any edema, hematoma, or
infarcti on of the brainstem and cerebel lum can produce seri ous compromise. When a pati ent fai ls
to awaken sati sfactori ly from anesthesi a, bleedi ng or acute swel l ing of the structures in the
posterior fossa must be suspected. In addi ti on, pati ents who are awake and tal ki ng may become
unresponsi ve secondary to obstructive hydrocephal us or brai nstem compressi on. Decreased l evel
of consciousness i s an earl y reli able si gn of brainstem compressi on. More seri ous signs are
systemi c hypertensi on, bradycardia, and irregul ar or absent respi rati ons. Reintubati on and prompt
surgi cal i nterventi on to reli eve pressure on the brainstem are necessary.
The preoperative level of consciousness and i ntra-operative condi tions wil l determi ne whether the
patient is extubated at the end of the procedure. A pati ent wi th a depressed l evel of consciousness
preoperati vel y shoul d not be expected to improve i mmediately after surgery. In general , pati ents
who requi re preoperati ve mechani cal ventil ati on usual l y requi re postoperati ve mechani cal
ventil ati on. Furthermore, i f the surgi cal procedure i s extensive, produci ng an engorged, swoll en
brain, postoperati ve mechanical venti lation is usual l y necessary.
P i t ui t ar y Tumor s
The pi tuitary gland is l ocated at the base of the skull i n the sel l a turci ca, a bony cavi ty wi thi n the
sphenoi d bone, and i t i s di vi ded i nto anteri or (adenohypophysi s) and posteri or (neurohypophysi s)
l obes. A fol d of dura (the di aphragma sel l a) on the superi or surface of the sel l a is pi erced by the
infundibul ar stal k, whi ch connects the posterior l obe of the pi tui tary gl and to the hypothal amus.
The hypothal amus regul ates hormone rel ease from the anterior pituitary through regulatory
pepti des (hypothal amic rel easing and i nhi biti ng factors) that reach the anteri or pi tuitary by a
compl ex portal vascul ar system. Control of hypothalami c secreti on i s complex and occurs from
neuronal and chemi cal i nfl uences, incl udi ng feedback from target organ hormones. The l arger
gl andular anteri or pi tuitary secretes at l east seven hormones. The small er posteri or pi tui tary
stores and secretes two hormones, anti di ureti c hormone and oxytocin, whi ch are synthesi zed in
special ized hypothalamic neurons and transported as granul es in axons down the pitui tary stal k to
the posteri or pi tui tary gland. The anteri or and posteri or pi tuitary hormones are li sted in Tabl e 27-
13.
P.775
TABLE 27-13 Pituitary Gland Hormones
ANTERIOR PITUITARY POSTERIOR PITUITARY
Growth hormone Anti di ureti c hormone
Prolacti n Oxytocin
Gonadotropi ns:
Pi tui tary tumors can be di vi ded i nto two general categori es, nonfunctioni ng and hypersecreti ng.
Nonfunctioni ng pituitary tumors are usuall y diagnosed when they become l arge and produce
symptoms rel ated to mass effects by impi ngi ng on adjacent structures. Headache, i mpaired vi sion,
crani al nerve pal si es, i ncreased ICP, and hypopituitari sm may resul t. The most common
nonfuncti oni ng tumors are chromophobe adenomas, crani opharyngi omas, and meningiomas. As
these tumors enl arge, they can cause selective or gl obal i mpai rment of pi tui tary function by
compressi ng the normal gl and. A sudden enl argement of the pitui tary caused by spontaneous
hemorrhage or i nfarcti on i nto the tumor produces a symptom complex known as pitui tary
apoplexy, a li fe-threatening conditi on characteri zed by acute neurologic defici ts and a rapi d
decl ine i n pi tui tary function. Therapy incl udes rapi d admi nistrati on of corti costeroi ds and
emergency surgi cal decompression.
Functi oni ng pi tui tary adenomas produce an excess of one or more of the anteri or pi tui tary
hormones, and therefore are usual ly di agnosed when the tumors are smal l . The most frequentl y
occurri ng are prol acti nomas foll owed by growth hormone- and adrenocorti cotropi n-secreti ng
adenomas. Adenomas secreti ng thyrotropi n or foll i cl e-stimul ati ng hormone and l uteini zi ng
hormone are rare. Adenomas secreti ng both growth hormone and prol acti n are common, however.
Prolactinomas may produce the amenorrhea-gal actorrhea syndrome in femal es and decreased
l i bi do and i mpotence i n mal es. Excessive production of growth hormone before puberty results i n
gi ganti sm; after puberty, i n acromegal y. Cushi ng' s di sease devel ops from an adrenocorti cotropi n-
secreting adenoma that causes bil ateral adrenal hyperpl asi a.
Preoperative Evaluation. The preoperati ve evaluation of pati ents wi th pi tuitary tumors requi res
an assessment of endocrine functi on and associated medi cal di sorders. Endocri ne tests are
performed i n the basal state and are suppl emented by appropriate provocative tests (Tabl e 27-
14). These tests di agnose hyperfuncti oning or hypofunctioni ng tumors, the extent of endocrine
di sturbance, and the adequacy of treatment.
Foll i cl e-stimul ati ng hormone
Lutei ni zi ng hormone
Adrenocorti cotropi n (ACTH)
-Lipotropi n
Thyrotropi n (TSH)
TABLE 27-14 Preoperative Endocrine Studies for Pituitary Tumors
ANTERIOR PITUITARY FUNCTION TESTS
Basal level s of pi tui tary hormones: GH, prol acti n, ACTH, TSH, FSH, LH
Serum l evel s: cortisol (AM and PM), thyroxi ne, testosterone, estradi ol
Uri nary l evel s: 17-ketosteroi ds, 17-hydroxycorti costeroids, free corti sol , estrogens
In Cushing' s disease, the i ncreased corticotropi n and corti sol can produce mul ti pl e systemi c
effects such as di abetes mel li tus wi th insul in-resistant hyperglycemia, hyperal dosteroni sm wi th
hypokalemia and metabol ic alkal osi s, hypertension, mi l d congestive heart fai lure, and obesi ty.
These pati ents requi re preoperati ve eval uati on and management of hypertensi on, di abetes, and
el ectrol yte i mbalances, as wel l as a cardiovascular evaluati on for ischemic heart disease and
congesti ve heart fail ure.

Patients with acromegal y exhibit a general overgrowth of skel etal , connecti ve, and soft ti ssues.
Hands and feet become markedl y enl arged and facial features become coarse. Al l major organs
increase i n si ze, i ncl udi ng the heart, lungs, l i ver, and ki dneys. These pati ents al so requi re an
eval uation for systemi c hypertension, diabetes, i schemi c heart di sease, cardiomegal y, and
congesti ve heart fail ure, with appropriate medi cal management insti tuted before surgery.
Significant anatomi c ai rway changes can occur i n acromegal ics, maki ng ai rway management
di fficul t. Faci al bone hypertrophy, parti cul arl y of the mandi bl e and nose, thi ck tongue and l i ps,
and hypertrophy of nasal turbinates, soft palate, tonsi l s, epi gl ottis, and larynx create di ffi cul ties
with mask fi t and vi suali zation of the l arynx. Gl ottic stenosi s caused by soft tissue overgrowth
may cause preoperati ve hoarseness and dyspnea. These pati ents usuall y require a small er
endotracheal tube than anti ci pated based on the si ze of the pati ent's faci al features, and may be
predi sposed to postextubati on edema. Stretching or compression of the recurrent l aryngeal nerves
from laryngeal soft tissue or thyroi d gland enl argement may result i n vocal cord paral ysi s.
Because of these anatomi c changes, a thorough preoperati ve airway examinati on i s required.
Patients compl ai ni ng of hoarseness, dyspnea, or i nspi ratory stri dor shoul d undergo i ndi rect
laryngoscopy and x-ray exami nation of the neck to anal yze ai rway conformati on and l umen
di ameter. Based on this eval uati on, preparations for diffi cult ai rway management and intubati on
should be anti cipated. For pati ents wi th di ffi cul t ai rways and gl otti c abnormal i ti es, an awake
fi beropti c i ntubati on i s recommended. Thi s obviates the need for a tracheostomy i n al l but the
most severe cases. Patients wi thout upper airway or vocal cord i nvol vement can be managed in
the routi ne manner.
Pressure effects on the normal pi tuitary gland from parasel lar tumors or other l esi ons can cause
panhypopituitari sm. Pati ents who have panhypopi tui tari sm requi re repl acement therapy wi th
appropriate hormones. These pati ents should be euthyroid before surgery. Gl ucocorti coi d
repl acement i s required when thyroxi ne replacement i s begun to avoi d stressing the i nsuffi ci ent
adrenocorti cal axis. Because gl ucocorti coi ds are al so necessary to facil i tate renal excreti on of a
water load, di abetes i nsi pi dus i s usuall y not observed in the pati ent wi th pi tui tary i nsuffi ci ency
unti l corti sol repl acement therapy i s insti tuted. Preoperati vel y, the pati ent wi th
panhypopituitari sm wi l l be receiving oral steroi d and thyroxi ne therapy and, when i ndi cated,
intranasal insti l lati on of synthetic vasopressi n.
Provocati ve and suppressi on tests as i ndi cated: GH reservegl ucagon sti mul ati on
GH suppressiongl ucose suppression (acromegaly)
Prol acti n reservechlorpromazi ne or thyrotropi n-rel easing hormone provocati ve
testi ng
Low- and hi gh-dose dexamethasone suppression (Cushi ng' s syndrome)
Metyrapone test (Cushi ng' s syndrome)
POSTERIOR PITUITARY FUNCTION TESTS
ADH reserve: Serum and urine osmol al i ty before and after 812 hours' water
depri vati on.
P.776
During the preanesthetic eval uation, the si ze and l ocati on of the tumor and i ts effect on
intracranial dynamics shoul d be determi ned. Pi tui tary mi croadenomas do not produce mass
effects. Pi tui tary tumors with suprasell ar extension, crani opharyngi omas, and other suprasel l ar
tumors may exert a mass effect. In these patients, the CT scan or MRI and the neurologic
examinati on are evaluated for si gns of i ncreased ICP. Al l pati ents schedul ed for pi tui tary surgery
are given suppl emental short-acti ng glucocorticoi d therapy peri operati vel y. Because the surgery
invol ves manipul ation or removal of the anteri or pi tuitary, transient or permanent defi ciency of
adrenocorti cotropin and corti sol secreti on may resul t. To assess function of the opti c nerves and
chiasm, a visual exami nati on, incl udi ng exami nati on of the vi sual fiel ds, i s performed. When
transsphenoi dal surgery i s pl anned, an otol aryngol ogic exami nati on of the nasal passages and
nasopharynx is al so performed, and a nasal cul ture i s obtained to gui de anti bi oti c therapy i n the
event of postoperati ve infecti on.
Surgical Considerations. Si nce the introducti on of the operati ng microscope, transsphenoi dal
exci si on has been recommended for al l pitui tary tumors that do not have marked suprasel l ar
extensi on. Advantages of the transsphenoi dal approach i nclude the fol lowi ng: lower morbi di ty and
mortal i ty rates with decreased i ncidence and severi ty of di abetes i nsi pi dus; el i mi nation of frontal
lobe retracti on and external scars; magni fi ed vi suali zation and removal of smal l tumors, whi ch
spares normal ti ssue; decreased frequency of bl ood transfusi ons; and shorter hospi tal izati on.
Rel ati ve disadvantages i ncl ude the possi bi li ty of CSF leakage and meningi ti s (whi ch i s rare wi th
the use of antibi oti cs), i nabi li ty to vi sual i ze neural structures adjacent to a l arge tumor,
inaccessi bi l i ty of tumors extendi ng i nto mi ddl e and anteri or fossae, and the possi bi li ty of bl eeding
from cavernous sinuses or carotid arteri es (which can l ead to intracrani al hemorrhage, brai nstem
compressi on, and si gni fi cant bl ood l oss). The transcrani al approach to the sell a permits direct
visual i zati on of suprasel lar structures: the vascular sinus ring, opti c chiasm, hypothal amus, and
pi tui tary stal k. Thi s approach i s recommended for pi tui tary tumors of uncertai n di agnosi s and
those that have significant suprasell ar extensi on wi th optic nerve or hypothal amic i nvol vement.
Wi th thi s approach, there i s potenti al for damage to the olfactory nerves, frontal l obe vascul ature,
and opti c nerves and chi asm. In addi ti on, the i nci dence of permanent di abetes i nsi pi dus and
anterior pitui tary i nsuffi ciency is increased.
Anesthetic Considerations. The anesthetic management of patients undergoi ng pi tui tary surgery
is not fundamentally different from that of pati ents undergoi ng other crani otomies. Basi c
neuroanesthetic principl es appl y whether the transsphenoi dal or transcranial approach i s used.
Wi th the transcranial approach, however, i ntra-operative measures to control ICP are i nsti tuted
because of pressure effects, the necessi ty for brain retraction, and the potenti al for greater bl ood
loss.
During transsphenoi dal procedures, central venous pressure is not routi nel y monitored. When the
patient is posi tioned wi th a si gnificant head-up ti l t, however, air embol ism may occur duri ng this
procedure. Therefore, precordial Doppler moni toring and ri ght atrial catheteri zation are
recommended for detecti on and treatment of ai r embol i sm when a si gni fi cant surgi cal si tecardi ac
gradient (15 or more) exi sts.
Evoked potenti al moni tori ng of VEPs may be used duri ng pi tui tary surgery to monitor direct
compressi on or compromi se of bl ood suppl y to opti c nerves and chi asm. Techni cal di ffi cul ties that
cause i ntra-operative recordi ng probl ems include changes i n pupi l si ze, devi ati on of eyes, goggl e
si ze and bul ki ness, and sti mul us del ivery (l i ght fl ashes). Because VEPs are entirely corti cal i n
origi n, they are al so more vulnerabl e to the effects of general anestheti cs.
For transsphenoi dal procedures, a subl abi al incisi on and di ssecti on through the nasal septum i s
performed; therefore, oral endotracheal i ntubation is requi red. The nasal septum can be prepared
wi th 4% cocai ne pl edgets pl aced i n the nares, fol l owed by i njection of 2% li docai ne with
epi nephri ne 1:200,000 into the submucosa. Thi s combi nati on devel ops a di ssecti on pl ane,
decreases bl eedi ng, and buffers the hypertensi ve response to nasal di ssecti on. Ini tial ly, the
cocai ne and epi nephri ne may cause hypertension, tachycardi a, and dysrhythmi as, and drugs to
treat these responses should be avai labl e. After oral endotracheal intubati on wi th a RAE tube, the
oropharynx i s packed with sal i ne-soaked gauze to mi ni mi ze bl ood pool i ng i n the gl otti s,
esophagus, and stomach. Intra-operative C-arm fluoroscopy of the skull (l ateral vi ews) i s used
duri ng thi s procedure, renderi ng the pati ent' s head and arms relativel y inaccessi ble once the
patient is draped.
Potential i ntraoperati ve compli cati ons during transsphenoi dal procedures relate to the anatomic
landmarks surrounding the sell a turci ca. The cavernous si nuses occupy the l ateral wall s of the
sel la and contain venous structures, the i nternal carotid artery, and crani al nerves III, IV, V, and
VI. The opti c chi asm, wi th i ts associated opti c nerves and tracts, l ies di rectly above the
di aphragma sel l a i n front of the pituitary stalk. Surgi cal mani pul ati on i n the regi on surroundi ng
the sel l a can resul t in the fol lowi ng: hemorrhage from the venous si nuses or i nternal caroti d
artery, arterial spasm or thrombotic occl usi on

secondary to arteri al manipul ati on, venous ai r emboli sm i f head-up ti lt i s excessive, crani al nerve
weakness secondary to trauma or stretchi ng, and vi sual compl i cati ons secondary to damage of the
optic nerve or chiasm.
160

The chosen anestheti c techni que shoul d permi t gross visual acuity exami nati on before pati ent
extubati on. If vi si on is the same or i mproved, extubati on can proceed. If acui ty is worse, further
di agnosti c studi es and emergent decompressi ve surgery may be required. After transsphenoi dal
surgery, the pati ent wi l l awaken wi th nasal packi ng, necessi tati ng mouth breathing
postoperativel y. Therefore, these pati ents must be ful ly awake and fol lowi ng commands before
extubati on of the trachea.
Postoperative Concerns. In the i mmediate postoperati ve peri od after ei ther transsphenoi dal or
transcranial procedures, the pri mary concerns are corti costeroi d coverage and fl ui d bal ance.
Dexamethasone fol lowed by prednisone i s gi ven for 5 days after surgery or until postoperati ve
testi ng shows an i ntact pi tuitaryadrenal axi s. Flui d bal ance i s assessed by stri ct attention to
hourl y fl ui d i ntake and output and uri ne speci fi c gravi ty. Devel opment of di abetes i nsi pi dus i s
uncommon during surgery but may occur earl y i n the postoperative course. Di abetes insipi dus i s
commonly seen duri ng the first 12 hours postoperativel y and usual ly l asts for 2 to 4 days.
Diagnosis i s based on the foll owi ng: pol yuri a (2 to 15 L/day), hypernatremi a, high serum
osmolal ity (300 mOsm/kg), decreased urine osmol ality (200 mOsm/kg), and decreased uri ne
specific gravity (1.005 or l ess). Therapy includes repl acement of uri ne losses wi th i ntravenous
flui ds. When uri ne volumes are excessi ve, exogenous vasopressi n is gi ven, for example, aqueous
vasopressi n (5 to 10 IU, i v or i m, q 6 hr) or the syntheti c analog of ADH, desmopressi n acetate
(0.5 to 2 g, i v, q 8 hr; 1 to 4 mg, sc q 6 to 12 hr; or nasal i nhalati on 10 to 20 g).
Other compl i cations of pi tui tary tumor surgery include CSF rhinorrhea, hypothalamic i njury or
stroke, cerebral i schemi a, and meni ngi ti s. After transsphenoi dal surgery, pati ents must be
careful ly moni tored in the recovery room for ai rway obstructi on caused by bl eedi ng and secreti ons
in the pharynx. Frequent neurol ogic exami nati ons are performed to note any changes i n mental
status. Patients who have had an uncompli cated hospital course after transsphenoidal surgery are
often di scharged wi thi n 5 to 6 days.
Cer ebr ovascul ar Mal f or mat i ons
Intracranial Aneurysms
SAH from rupture of an i ntracrani al aneurysm i s a devastati ng disease, affecting an estimated
27,000 Ameri cans annual ly.
161, 162
Despi te consi derabl e advances i n the management of these
patients, outcome remai ns poor wi th overal l mortali ty rates of 25% and si gni fi cant morbi dity
among approxi matel y 50% of survi vors. In the most recent studi es, the overal l incidence of SAH i s
8 to 10 per 100,000 peopl e. The peak i nci dence for rupture is in the fifth and si xth decades of l i fe
and is greater for women than men. Several potenti al ri sk factors for aneurysm rupture have been
identi fi ed (Tabl e 27-15).
P.777
TABLE 27-15 Potential Risk Factors for Aneurysm Rupture
The management of pati ents with unruptured i ntracranial aneurysms (UIAs) remai ns
controversi al.
162, 163, 164, 165
The Internati onal Study of Unruptured Intracranial Aneurysms (ISUIA)
was recentl y publ i shed.
165
Four thousand, si xty pati ents were assessed1,692 di d not undergo
aneurysmal repai r, 1,917 underwent open surgery, and 451 underwent endovascul ar procedures.
The study revealed that rupture rates were often equal ed or exceeded by the ri sks associ ated wi th
surgi cal or endovascul ar repai r of comparabl e l esi ons. Pati ents' age was a strong predi ctor of
surgi cal outcome; the si ze and l ocation of an aneurysm predi cted both surgi cal and endovascul ar
outcomes.
A pati ent wi th aneurysmal SAH is cl assified accordi ng to the Hunt and Hess Cl assificati on (Tabl e
27-16) or the Worl d Federati on of Neurosurgeons (WFNS) SAH scal e (Tabl e 27-17). These
cl assi ficati ons are used by neurosurgeons to esti mate surgi cal ri sk and outcome. Hi gher grades, or
patients who are cli nicall y more impai red, are associ ated with the presence of cerebral vasospasm,
intracranial hypertension, and i ncreased surgi cal mortal ity. In general , the poorer the grade on
hospi tal admi ssi on, the worse the prognosis.
Ci garette smoki ng
Hypertension
Alcohol consumption
Cocaine and amphetami ne abuse
Oral contracepti ve use
Pl asma chol esterol >6.3 mmol /l
Geneti c condi tions, e.g., ADPKD
Fami l ial (first-degree rel ati ves)
TABLE 27-16 Hunt and Hess Classification of Patients with Subarachnoid Hemorrhage
GRADE CRITERIA
0 Unruptured aneurysm
I Asymptomatic, or mi ni mal , headache and sl i ght nuchal ri gi di ty
II Moderate to severe headache, nuchal rigi di ty, no neurol ogi c defi ci t other
than crani al nerve pal sy
III Drowsiness, confusi on, or mi l d focal defi ci t
IV Stupor, moderate to severe hemiparesi s, earl y decerebrati on, vegetati ve
di sturbance
V Deep coma, decerebrate ri gi di ty, mori bund
The presence of bl ood i n the subarachnoi d space causes an abrupt, marked ri se in ICP, whi ch
often resul ts i n systemi c hypertension and dysrhythmi as. The abrupt increase i n ICP accounts for
the acute onset of a sudden, severe headache. The cl assic presentation of aneurysmal SAH i s that
of severe headache associ ated wi th stiff neck, photophobi a, nausea, vomi ti ng, and often transient
loss of consci ousness. With this presentation, the di agnosi s of SAH i s obvi ous. In about 50% of
patients, a smal l bleed or warni ng leak precedes a major aneurysmal rupture. Warning
symptoms and si gns tend to be mil d and nonspecific (headache, dizzi ness, orbi tal pai n, sli ght
motor or sensory disturbance) and are general l y i gnored or mi sdi agnosed by both pati ent and
physi ci an.
(Adapted from Hunt WE, Hess RM: Surgical ri sk as rel ated to ti me of interventi on i n the
repair of intracrani al aneurysms. J Neurosurg 28:14, 1968.)
TABLE 27-17 World Federation of Neurosurgeons (WFNS) SAH Scale
WFNS GRADE GCS SCALE
a
MOTOR DEFICIT
I 15 Absent
II 1314 Absent
III 1314 Present
IV 712 Present or absent
V 36 Present or absent
SAH = subarachnoid hemorrhage; GCS = Glasgow Coma Scal e.
a
Refer to Tabl e 27-20 for defi niti on of scal e.
(Adapted from Drake CG, Hunt WE, Sank K et al : Report of Worl d Federati on of
Neurologi cal Surgeons Commi ttee on a uni versal subarachnoi d hemorrhage grading
scal e. J Neurosurg 68:985, 1988.)
The di agnosi s of SAH i s made by the combi nati on of cli ni cal fi ndi ngs and a noncontrast CT scan of
the head. When performed wi thi n a day of aneurysm rupture, CT reveal s hi gh-densi ty (white)
bl ood cl ot i n basal subarachnoid ci sterns i n about 95% of pati ents. Thi s has traditi onal l y been
fol l owed by sel ected cerebral angiography to document the presence and anatomi c features of the
aneurysm. More recentl y, spi ral CT angiography (CTA) has been used for detecti on and eval uation

of intracranial aneurysms. Compared to conventional angi ography, the mi ni mal ly i nvasive CTA has
hi gh specifi ci ty, sensi tivity and di agnosti c accuracy i n detecti ng i ntracranial aneurysms.
Aneurysms are cl assified according to l ocation and size. They arise at a branch of bi furcati on,
usuall y at a point where a major vessel makes a turn changi ng the axi al fl ow of blood.
Complications. There are several potenti al compli cati ons of SAH and surgi cal treatment of
aneurysms (Tabl e 27-18). The most important of these are i ntracrani al hypertensi on, rebl eedi ng,
vasospasm, and hydrocephal us.
Rebl eeding occurs most commonl y duri ng the fi rst 24 hours foll owi ng i niti al SAH. The chance of
rebl eedi ng i s about 4% wi thi n the first day; after 48 hours, i t i s 1.5% per day, wi th a cumulative
rebl eedi ng rate of 19% by the end of 2 weeks.
166
Recurrent aneurysmal hemorrhage i s a
devastati ng compl i cation associ ated wi th i ncreased morbi di ty and mortal ity.
Because of the inci dence of rebleedi ng with conservative management of SAH, early aneurysm
cl i pping (days 0 to 3) is currentl y recommended for pati ents who are al ert on admi ssi on. The
debate over early versus late surgery was largel y resol ved fol lowi ng the report of The
Internati onal Cooperative Study on the Ti mi ng of Aneurysm Surgery (ICSTAS).
167, 168
In thi s tri al ,
overal l management resul ts demonstrated a si mil ar mortal ity (20%) and good outcome (60%) for
patients with surgery pl anned for earl y (0 to 3 days) and l ate (11 to 14 days) interval s. The l east
favorabl e outcome and hi ghest mortal i ty occurred i n pati ents wi th pl anned surgery for days 7 to
10 after SAH. Pati ents who were alert on admi ssi on did best wi th earl y surgery. When onl y the
North American pati ents were analyzed, earl y surgery (days 0 to 3) provi ded the best results i n
l ower grade pati ents.
168
There was no di fference in the i nci dence of i ntra-operative rupture
between early and late surgery, and al though there was a relationshi p between ti ghtness of the
brain duri ng surgery and the i nterval from SAH to operati on, aneurysm di ssection was no more
difficult in early than i n late surgery.
168
The ti mi ng of surgery does not i nfluence the risk for
cerebral vasospasm.
Cerebral vasospasm is a major cause of morbi di ty and mortal ity i n SAH patients.
167
Angi ographi c
evidence of vasospasm can be detected i n up to 70% of pati ents. However, cl i ni cal vasospasm
with ischemic defi cits i s observed in approxi matel y 30% of pati ents, most often between days 4
and 12, wi th a peak at 6 to 7 days fol l owi ng SAH.
167
The cl inical syndrome of vasospasm is often
P.778
TABLE 27-18 Potential Complications of Subarachnoid Hemorrhage
Rebl eedi ng
Vasospasm
Intracranial hypertension
Hydrocephal us
Hyponatremi a/vol ume contraction
Sei zures
heral ded by worsening headache and i ncreasi ng bl ood pressure. It i s characterized by progressi ve
symptoms of confusion and l ethargy, fol lowed by focal motor and speech i mpai rments
correspondi ng to the arterial terri tory involved. The syndrome may resolve gradually or progress
to coma and death wi thi n a peri od of hours to days. The di agnosi s of vasospasm i s confi rmed by
angi ography. The transcranial Doppl er (TCD) i s a safe, repeatabl e, noninvasi ve method to i denti fy
and quanti fy vasospasm and can be used to evaluate the effecti veness of various therapi es.
The mechanism responsi bl e for vasospasm i s unknown; however, structural and pathol ogic
changes have been demonstrated i n the vessel wall . There is al so evi dence that vasospasm after
SAH correl ates wi th the amount of blood in the subarachnoi d space, and removal of extravasated
bl ood decreases the occurrence and severi ty of i schemic defi cits. The component i n bl ood
impli cated in causing cerebral arteri al vasospasm i s oxyhemogl obi n.
Many drugs have been i nvesti gated for prevention or treatment of vasospasm but most are
ineffecti ve. The cal cium channel bl ocker ni modi pine has become standard prophyl acti c therapy.
However, the efficacy of prophyl acti c ni modi pine after SAH has been seri ously chal l enged.
102
A
meta-anal ysi s showed a reduction in vasospasm i n ni modi pi ne groups, but a correspondi ng
reduction in mortali ty was sl ight and not stati sti cal l y signi fi cant compared to control groups.
Tri pl e-H therapyhypervol emi a, hypertensi on, and hemodi l uti onhas become the mainstay of
treatment for i schemi c neurol ogic defi cits caused by cerebral vasospasm.
170, 171
To i mprove
cerebral bl ood fl ow to areas of i mpai red autoregul ati on, cerebral perfusi on pressure is i ncreased
by intravascul ar vol ume expansi on and i nduced hypertensi on. Intravascul ar vol ume expansion is
accompl i shed wi th i nfusi on of crystal l oi d, coll oi d, or blood to a pul monary capi l lary wedge
pressure of 12 to 18 mmHg or a central venous pressure of 1012 mmHg. If thi s regi men does not
reverse the defici t, a vasopressor (e.g., dopami ne) i s i ntroduced to rai se systemi c bl ood pressure
unti l the neurologi c defici ts subsi de or reverse. This therapy can worsen cerebral edema, increase
ICP, and cause hemorrhagi c infarcti on. Systemi c compli cati ons incl ude pul monary edema and
cardi ac fai l ure i n patients at ri sk. Hemodi l ution, the l ast component of tri ple-H therapy, decreases
bl ood vi scosi ty and i mproves cerebral blood fl ow. The optimal hematocri t thought to maxi mi ze the
oxygen del ivery to ti ssues has been esti mated at 33%, but may be hi gher in i schemic brain. A
randomi zed controll ed tri al of tripl e-H therapy has not been undertaken,
170
and there is
uncertainty about its effi cacy i n reduci ng the occurrence of del ayed i schemi c defici ts and death
after SAH.
171

Another method for treati ng symptomati c vasospasm i s cerebral angiopl asty. Translumi nal
angioplasty can be used to di l ate constri cted major cerebral vessel s i n pati ents who are refractory
to conventi onal treatment.
144
Supersel ecti ve i ntra-arteri al i nfusi on of papaveri ne di l ates di stal
vessel s not accessibl e to angiopl asty. However, intra-arteri al papaveri ne may be neurotoxi c. There
is a move away from its use in favor of intra-arterial verapami l .
172
Transl uminal angi oplasty
procedures are usual l y performed under general anesthesi a to minimize movement and permit
accurate placement of the intra-arterial ball oon used to di l ate the cerebral vessel s. The risks of
angioplasty i nclude aneurysm rupture, i nti mal dissecti on, vessel rupture, ischemia, and i nfarcti on.

Intracranial hypertension is present to some degree i n most pati ents foll owing an SAH. In the
uncompl icated case, intracrani al hypertensi on does not requi re specific treatment. Intracrani al
pressure graduall y returns to normal by the end of the first week. If an intracerebral hemorrhage,
intraventri cul ar hemorrhage, vasospasm, or hydrocephal us devel ops, intracranial hypertension
may be severe and requi re treatment. Pati ents may requi re emergency ventri cul ostomy, steroi ds,
di uretics, or i ntubation and hyperventi l ati on. Intracrani al pressure shoul d be l owered gradual l y,
especi al l y i n pati ents wi th uncl i pped aneurysms. Abrupt l oweri ng of ICP by l umbar puncture,
ventri cul ar drai nage, or rapi d i nfusi on of manni tol can i nduce rebl eedi ng.
Acute (obstructi ve) hydrocephalus after SAH compl icates approxi matel y 20% of cases.
173
Al though
controversi al, ventri cul ostomy has been recommended for treating acute hydrocephal us i n pati ents
with dimi ni shed l evel of consciousness after SAH.
173
Ventri cul ostomy has been associ ated wi th
i ncreased bl eedi ng and i nfecti on.
P.779
Endovascular Treatment of Cerebral Aneurysms
Endovascular emboli zati on i s a therapeuti c al ternative to surgi cal cl i pping of some cerebral
aneurysm. Ini tial ly, onl y pati ents wi th high ri sk or inaccessi ble aneurysms and/or co-morbi d
medical condi tions were candi dates for INR procedures. These procedures are now recommended
for treatment of unruptured intracrani al aneurysms, dependi ng on aneurysm l ocati on, size and age
of pati ent.
165

A randomi zed trial comparing cli ppi ng and coi li ng of ruptured aneurysms was recentl y publ i shed
[The International Subarachnoi d Aneurysm Tri al (ISAT)].
174
The study enrol led 2,143 patients
treated at 43 centers, mostly i n Europe. The study was stopped earl y by the data safety and
moni tori ng committee. At stopping, 801 pati ents were treated by endovascul ar therapy and 793
patients were treated surgi cal l y and fol l owed for 1 year. Death or dependency occurred i n 23.7%
of endovascul ar cases and 30.6% of surgi cal cases; a rel ati ve risk reduction of 22.6% wi th
endovascul ar therapy (p = 0.0019) was reported.
174
Thi s study has been cri ti cized for not
i ncl udi ng a representati ve popul ati on, studyi ng onl y ruptured aneurysms, and poor surgi cal resul ts
and fol l ow-up.
175

The endovascular technique most commonly performed for occlusion of cerebral aneurysms i s
inserti on of Gugli el mi detachable coi ls (GDC). The fiel d is rapidl y evol vi ng and new techniques
(microball oons, neurovascul ar stents) and investi gati onal devices (li qui d embol ic agents, bi oacti ve
coi l s) are bei ng devel oped and i nvesti gated. An anesthesi ol ogist i s present for most of these
procedures to monitor the pati ent, to provide appropriate anesthesi a for the procedure, and to
manage compl i cations that ari se. The reader i s referred to an earli er section in thi s chapter for
di scussi on of anesthetic management during INR procedures.
Preoperative Evaluation. When the neurologi c examinati on i s performed, the pati ent' s cli ni cal
grade is noted (see Tabl e 27-17). The pati ent' s CT scan or MR i mage i s evaluated to assess the
presence and severi ty of i ntracrani al hypertension. The severi ty, acuteness, and stage of the SAH
as wel l as the presence of intracrani al hypertensi on and the ti mi ng of surgery wil l determi ne the
anesthetic management. Because the circle of Wi l li s i s proxi mal to the hypothalamus, an SAH i n
this area can cause a vari ety of di sturbances rel ated to hypothalami c dysfuncti on (e.g., ECG
changes, temperature i nstabi l ity, vari ous changes in endocri ne [pi tui tary] functi on, vari ous
el ectrol yte di sturbances). Sympathetic overactivity and oversti mul ation of both adrenal cortex and
medul l a can contribute to hypertension and di abetes, requi ring treatment wi th insul in.
El ectrol yte abnormali ties frequentl y occur secondary to the syndrome of i nappropri ate antidi uretic
hormone (SIADH) secreti on or di abetes i nsi pi dus. Hyponatremi a is the most common el ectrol yte
di sturbance detected and i s often associ ated with a hi gh uri nary sodi um and osmol al i ty, which is
expected wi th SIADH. Unli ke a pati ent with SIADH, however, the pati ent wi th SAH usual l y has a
contracted i ntravascul ar vol ume despi te hyponatremia. This cerebral salt-wasting syndrome may
be caused by rel ease of atrial natri ureti c factor from damaged brai n. The recommended therapy i s
to maintai n normovol emi a with isotoni c sal i ne sol uti ons. Other factors contri buti ng to
intravascul ar vol ume contraction i n these pati ents are supi ne di uresi s secondary to i ncreased
thoraci c bl ood vol ume, negati ve ni trogen bal ance, decreased erythropoiesis, increased
catechol amine l evels, and iatrogeni c blood loss. Flui d bal ance and el ectrol yte abnormali ties shoul d
be corrected pri or to surgery.
Most aneurysm surgery requires si gni fi cant intravascul ar vol ume shi fts (di uresi s foll owed by
vol ume l oadi ng) and extensi ve systemic bl ood pressure mani pul ati ons (del i berate hypotensi on or
hypertensi on). Therefore, pati ents wi th a hi story of hypertension, ischemic heart di sease, and/or
congesti ve heart fail ure must be in opti mal conditi on to tolerate the hemodynami c changes
requi red for thi s surgery. Dependi ng on the degree of cardiovascular disease, i nadvertent or
del i berate hypotensi on may be poorly tol erated. When patients have si gni fi cant hypertensi on, the
bl ood pressure shoul d be l owered gradual l y to normotensive l evels to avoi d cerebral i schemi a.
Agents such as propranolol , l abetal ol, or esmolol are used i n neurosurgi cal pati ents because these
agents do not affect cerebral bl ood vol ume or ICP. When the systemi c bl ood pressure i s l owered, a
criti cal l evel bel ow whi ch neurol ogi c defi ci ts occur may be observed. Systemi c bl ood pressure
bel ow thi s l evel should be avoi ded i ntra-operatively.
El ectrocardiographi c abnormal i ti es are commonl y associated wi th ruptured cerebral aneurysms.
The ECG changes include ST-segment depressi on or elevation, T-wave i nversi on or fl attening, U
waves, prolonged Q-T intervals, and dysrhythmi a. The ECG changes are not necessari ly associ ated
with increased operati ve morbidi ty and mortal i ty or consi stent increases i n serum myogl obi n or
creati ne ki nase. They usual ly resolve wi thin 10 days fol lowi ng SAH and requi re no speci al
treatment. When i ndicated, cardi ac troponi n-I l evel s shoul d be drawn to determine the cli nical
si gni fi cance of these abnormal i ti es. When cardiac dysrhythmi a and occasional frank subendocardi al
ischemi a resul t i n cardi ac fail ure, appropri ate treatment must be i nsti tuted.
Anesthetic Management. The anesthetic goal s for intracranial aneurysm surgery are to
avoi d aneurysm rupture, mai ntai n cerebral perfusi on pressure and transmural aneurysm
pressure, and provi de a sl ack brain. Patients in WFNS scale I or II who appear anxi ous shoul d
recei ve premedi cati on. Cerebral perfusi on pressure i s mai ntai ned by usi ng drugs in doses that
avoi d sudden or profound decreases i n systemi c blood pressure or i ncreases i n ICP. Si mi larly,
transmural pressure, whi ch i s defi ned as the difference between mean arteri al pressure and ICP,
must be mai ntai ned. (The pressure wi thi n an aneurysm i s equal to the systemi c bl ood pressure.)
The rel ati onshi p between transmural pressure and wal l stress or tensi on of the aneurysm i s l inear.
An i ncrease i n mean arteri al pressure or fal l i n ICP wi ll increase transmural pressure, wal l stress,
and ri sk of aneurysm rupture. Methods to control brai n vol ume and ICP, such as hyperventil ati on,
di uretics, spinal drai nage, and head positi on, faci l i tate surgi cal exposure and mi ni mize the
retracti on pressure that can cause tissue i njury.
Standard moni tori ng pl us an arteri al pressure catheter i s routi nel y used. A CVP or PA catheter i s
recommended i n WFNS scal e III or hi gher to provi de a more accurate measure of the pati ent' s
vol ume status and cardi ac function intraoperati vely

and postoperati vely i n the preventi on or management of cerebral vasospasm. Electrophysi ol ogic
moni tori ng wi th the EEG or SSEPs may be used to moni tor the adequacy of cerebral perfusion
duri ng i nduced hypotensi on or temporary/permanent aneurysm cl i p appli cati on. When barbi turates
are admini stered for brai n protection, the EEG is used to gui de the dose required to achi eve a
burst suppressi on pattern.
To mini mize the risk of hypertension and aneurysmal rupture duri ng i nduction of anesthesi a,
intravenous l idocai ne and the -adrenergi c antagoni st esmol ol or l abetal ol are recommended.
Foll owi ng i nducti on, ventil ati on i s mechani cal l y controll ed to maintai n normocarbia i f ICP is
normal . If intracrani al hypertensi on i s present, the PaCO
2
can be l owered to 3035 mmHg. A deep
pl ane of anesthesia must be establ i shed pri or to i nserti on of head pi ns, scal p i ncisi on, turni ng the
bone fl ap, and opening the dura i n order to avoi d a hypertensi ve response. When i ntracrani al
hypertensi on i s present, anesthesi a shoul d be deepened wi th additi onal doses of thi opental and
fentanyl unti l the skull i s opened. Several techni ques can be i nstituted duri ng aneurysm surgery to
provi de a sl ack brain and faci li tate di ssecti on. These are hyperventi l ation of the l ungs, osmoti c
di uresis, barbiturate admi ni strati on, and CSF drai nage duri ng the procedure. A l umbar
subarachnoi d catheter or spi nal needl e is i nserted after inducti on to al l ow CSF drai nage duri ng the
procedure. Excessi ve l oss of CSF must be avoided duri ng i nsertion of the l umbar drai n because i t
can decrease ICP, thus increasi ng aneurysmal transmural pressure and the potenti al for rupture.
Removal of CSF after openi ng the dura i s done cauti ousl y wi th gui dance by the surgeons.
The drugs most frequently used to maintai n anesthesia duri ng aneurysm surgery are fentanyl or
remi fentani l and propofol infusi ons in conjunction with 0.5 MAC of a potent inhalation agent in
oxygen and nondepolari zi ng muscl e rel axant. The total dose of fentanyl shoul d not exceed 10 to
12 g/kg, unless postoperati ve venti l ati on is planned. In condi ti ons of poor i ntracrani al
compl i ance, a continuous i nfusion of thi opental (1 to 3 mg/kg/hr fol lowi ng a bol us dose of 5
mg/kg) may be substi tuted for propofol as the pri mary anestheti c. Potenti al di sadvantages to
usi ng thi opental are bl ood pressure i nstabi li ty and prolonged recovery from anesthesi a. Wi th this
P.780
technique, a pul monary artery catheter shoul d be inserted to monitor and optimi ze cardi ovascul ar
performance and i ntravascul ar vol ume. Fol lowi ng an uneventful aneurysm cl ip appl icati on, the
thiopental i nfusi on is disconti nued to prevent a del ay i n recovery.
Pri or to aneurysm cli ppi ng, isotoni c crystal l oi d sol uti ons wi thout glucose are admi ni stered to
repl ace overni ght fl ui d l osses and provi de hourl y mai ntenance fl ui d requi rements. When the
aneurysm i s secured, i ntra-operati ve fl ui d defi ci ts are repl aced and addi ti onal vol ume i s
administered. At the ti me of aneurysm di ssection, bl ood i s avai l abl e for transfusion i n case the
aneurysm ruptures. A bol us of thi opental (3 to 5 mg/kg) may be gi ven before temporary occlusi on
of a major i ntracrani al vessel and before aneurysm cli ppi ng. If temporary occl usi on l asts longer
than 10 mi nutes, recircul ati on shoul d be establi shed, and addi ti onal thiopental administered
before reappl yi ng the temporary cl i p. Fol l owi ng aneurysm cl ippi ng, the central venous pressure
and pul monary capi l lary wedge pressure are raised to 10 to 12 mmHg or 12 to 18 mmHg,
respectively, wi th crystall oid, col loid, or bl ood. A postoperati ve hematocrit of 30 to 35% i s
desi rabl e. As discussed previ ously, i ntravascular volume expansi on wi th hemodi l ution is
recommended to reduce the ri sk of postoperati ve cerebral vasospasm.
When consideri ng the use of del i berate hypotension during aneurysm dissecti on, the riskbenefi t
rati o must be assessed for each patient. The potenti al benefit of deli berate hypotension must be
weighed agai nst the risk of causi ng cerebral i schemi a or i schemi a to other organs. Pati ents wi th a
hi story of cardi ovascul ar disease, occl usi ve cerebrovascular disease, i ntracerebral hematoma,
fever, anemi a, and renal disease are not good candidates for del i berate hypotensi on. Such
pati ents shoul d onl y be subjected to moderate reducti ons i n systemic bl ood pressure (20 to 30
mmHg), if at al l. When del i berate hypotensi on i s requi red, the best choice among the agents l i sted
i n Tabl e 27-19 i s probabl y the drug or drug combinati on wi th whi ch you have the most experi ence.
Commonl y used agents to i nduce hypotension have been sodium ni troprusside, isoflurane, and
esmol ol .
TABLE 27-19 Dosage, Mechanism of Action, Advantages, and Disadvantages of Commonly
used Agents for Inducing Hypotension
DRUG DOSAGE MECHANISM
OF ACTION
ADVANTAGES DISADVANTAGES
Sodi um
ni troprusside
0.510
g/kg/mi n
Ni tri c oxide-
mediated
di rect
vasodil atati on
Rapi d
onset/offset
ti trati on
control
Cyani de toxi city
ICP
Rebound
hypertensi on
Coagul ati on
abnormali ties
Pul monary
shunti ng
Ni troglycerin 110
g/kg/mi n
Ni tri c oxide-
mediated
di rect
vasodil atati on
Rapi d
onset/offset
ti trati on
control
ICP
Rebound
hypertensi on
Coagul ati on
abnormali ties
Pul monary
shunti ng
Tri methaphan 15 mg/mi n Gangl i onic Rapi d Histamine release
Overal l , del iberate hypotensi on has decli ned i n use and has been repl aced by temporary cl i ppi ng.
The temporary occlusi on of a feedi ng artery produces an acute reduction in focal bl ood fl ow and a
sl ack aneurysm, thus eli mi nating the need for del i berate hypotensi on and its systemi c effects.
Dependi ng on the l ocati on of the aneurysm, either somatosensory evoked potenti al s or brai nstem
auditory evoked potential s can be used to moni tor the safety of temporary occl usi on.
The major intraoperative compl i cation of aneurysm surgery i s hemorrhage. When an aneurysm
ruptures i ntra-operatively, there is potenti al for major i schemi c damage from hypotensi on and the
surgi cal efforts to control bleedi ng. Hemorrhagi c death i s also possibl e. When the l eak i s smal l and
the dissecti on i s compl ete, it may be possibl e for the surgeon to gai n control wi th sucti on and
then apply the permanent cl ip to the neck of the aneurysm. Al ternati vel y, temporary cl ips can be
appl i ed proxi mal and di stal to the aneurysm to gai n control . Thiopental may be gi ven to provi de
some protecti on pri or to the pl acement of the temporary cl i p. Duri ng temporary occl usion,
bl ockade onset/offset Cerebral compromi se
bel ow MAP 55 mm
Hg

Pseudocholi nesterase
Esmolol 0.20.5
mg/kg/mi n
l oadi ng dose
50200
g/kg/mi n
-adrenergi c
bl ockade
Rapi d
onset/offset
Limited effi cacy
Cardi ac depressi on
Bronchospasm
Labetalol 20 mg test
dose
0.52
mg/min
(total 300
mg)
- and -
adrenergi c
bl ockade
Reduced
probabi l ity of
adverse
effects
Limited effi cacy
Bronchospasm
Prostagl andi n
E
1
0.10.65
g/kg/mi n
Di rect
vasodil atati on
Rapi d onset
Reflex
tachycardi a
Stable CBF
Sl ow offset
Bradycardi a
Hyperthermi a
Ni cardipi ne Begin 5 mg/h
infusi on,
max 15 mg/h
Coronary and
peri pheral
vasodil atati on
Rapi d onset
Reflex
tachycardi a
Sl ow offset
Resi sts
anti hypotensive
therapy
Pul monary
shunti ng
Inhalation
anesthetics
Ti trate by
inspi red
concentration
Vasodi l atati on
and
myocardial
depressi on
Provi des
surgi cal
anesthesia
ICP
Cerebral edema
Vi tal organ bl ood
fl ow
normotension should be mai ntai ned to maxi mi ze coll ateral perfusi on. If temporary occlusi on i s not
pl anned or not possi ble and blood loss is not si gni fi cant, the mean arterial pressure may be
transi entl y decreased to 50 mmHg or l ower to faci l itate surgi cal control . When bl eeding i s
excessive, aggressi ve fluid resuscitati on and bl ood transfusion must commence i mmediately.
Admi ni strati on of cerebroprotective agents may not be possi bl e because of associ ated
hemodynamic effects. Under these condi tions, del iberate hypotensi on i s not advised as the
intravascul ar vol ume must be restored first.
Intraoperative Cerebral Protection. Thi opental has been the drug of choice for intra-operative
cerebral protecti on during aneurysm surgery. In animal model s, barbi turates have shown
protecti on during i ncompl ete focal i schemi a but not during gl obal i schemia.
144
Barbi turates are the
only agents shown to be useful i n humans.
144

Many practi tioners i nsti tute mi l d i ntraoperati ve hypothermi a (32 to 34C) during aneurysm
surgery to enhance the brain's abi li ty to tol erate ischemia. Unfortunatel y, i ts val ue remai ns
unproven. An NIH supported multi center tri al of the use of mi l d i ntraoperati ve hypothermi a
(IHAST, The International Hypothermi a i n Aneurysm Tri al) was completed i n 2003.
72
The
investi gators found no al terati on i n outcome, when pati ents recei ved i ntraoperati ve cool ing prior
to aneurysm cl i ppi ng.
176

Emergence. The pri mary goals at the concl usi on of surgery are to avoid coughi ng, straini ng,
hypercarbi a, and hypertension. For pati ents i n Grades I and II who have no intra-operative
compl i cati ons, the endotracheal tube shoul d be removed in the operating room and a neurologic
examinati on performed. Patients who have i ntraoperati ve compl i cati ons or have depressed
consciousness preoperati vel y (Grades III toV) shoul d remai n intubated and recei ve mechani cal
ventil ati on unti l thei r neurologi c status i mproves.
Postoperative Concerns. Vari ati on i n systemi c bl ood pressure i s common postoperati vely and
contri butes significantly to morbidi ty and mortal i ty i n pati ents fol lowi ng aneurysm repai r. Causes
of hypertension i ncl ude preexi sti ng hypertensi on, pai n, and CO
2
retention from resi dual
anesthesia. The treatment of postoperati ve hypertensi on is criti cal to prevent the formati on of
cerebral edema or hematoma. Anti hypertensi ve

drugs should be administered after respi ratory depression and pai n are el iminated as causes. The
hypertensi ve response usual ly subsides wi thi n 12 hours. When i ndi cated, preoperati ve
anti hypertensi ve drugs are rei nstituted and maintai ned.
After cli ppi ng of the aneurysm, cerebral vasospasm continues to pose a threat to neurol ogic
integrity. Postoperative hypotension must be avoi ded, and the pati ent' s i ntravascul ar volume must
be accurately assessed with either a central venous pressure or pul monary artery catheter. As
previ ously discussed, a hi gher than normal intravascul ar flui d volume should be maintai ned.
Arteriovenous Malformations
An arteri ovenous mal formati on (AVM) of the brai n consists of a tangl e of congeni tal l y mal formed
bl ood vessel s that forms an abnormal communicati on between the arteri al and venous systems.
The arteri al afferents fl ow directl y i nto venous efferents without the usual resistance of an
i nterveni ng capi l l ary bed; thus, oxygenated blood i s shunted di rectly i nto the venous system,
leavi ng surroundi ng brai n tissue transi ently or permanentl y ischemic. These l esions predominate
i n mal es over femal es (2:1), wi th the onset of compl aints between the ages of 10 and 40. The
chief cl i ni cal features are parenchymal hemorrhage or SAH, focal epi l epsy, and progressi ve focal
neurol ogic sensory-motor defici ts occurring i n a chi l d or young adul t. A vein of Gal en AVM in
infants may present with hydrocephal us and/or high-output cardi ac fai l ure. The natural hi story of
AVMs is not completely understood.
177
The ri sk of hemorrhage i s approxi matel y 1 to 4% per year.
The rate of rebl eedi ng i s 6% i n the fi rst year after a hemorrhage and about 2% per year
thereafter.
176
Mortal ity from ini ti al hemorrhage i s hi gh, wi th reports between 10 and 30%.
Recurrence of hemorrhage with a fatal outcome i s a constant danger. There are several opti ons for
the management of AVMs, i ncl udi ng surgi cal exci sion, embol i zati on, stereotacti c radi osurgery
(proton beams, gamma rays, or l i near accel erator), a combi nation of the above, and l eavi ng AVMs
P.781
al one. Arteriovenous malformati ons of sui table si ze and locati on can be managed successfull y with
surgi cal exci si on. Surgical mortal i ty ranges from 0.6 to 14% and correlates with si ze, l ocation,
and pattern of i nvol vement of the AVM.
177
Earl y postoperati ve morbi di ty ranges from 17 to 23%;
however, outcome studi es report improvement in morbidi ty over ti me.
177
To avoi d i ntraoperati ve
or postoperati ve massi ve brain swel li ng or hemorrhage of large AVMs, operati ons may be staged
or fol l ow preoperative emboli zation.
In addi ti on to provi di ng anesthesi a for crani otomy and resecti on of the AVM, anesthesia may be
requi red for radi ologi c embol i zati on of the AVM. Cl osed embol izati on of cerebral AVMs i s
uncomfortable and invasi ve. Thi s procedure may be performed under l ocal anesthesia with
sedati on or under general anesthesi a. It has been performed successful l y with vari ous
combi nations of sedative drugs (fentanyl, midazol am, or propofol ) that al low neurol ogic
examinati ons during the procedure and permi t i mmedi ate di agnoses of compl i cations.
138, 177

Chi l dren, uncooperati ve pati ents, and those wi th intracrani al hypertensi on or ai rway problems
usuall y requi re general anesthesi a. General anesthesi a does not all ow di rect neurologic

assessment. Potential compl i cations of emboli zation procedures are embol ic or ischemic stroke and
hemorrhage from the AVM, ei ther acute or del ayed.
178
New onset or preexi sti ng sei zures may
occur during the embol izati on procedure, requiri ng treatment wi th benzodi azepines or
barbiturates.
The anestheti c management of patients with AVMs is si mil ar to the management of pati ents
for aneurysm surgery. Depending on the presentati on, the anestheti c approach i s modi fi ed.
For example, a large bleed may present wi th symptoms rel ati ng to mass effects and requi re
maneuvers to reduce ICP. Hi gh flow through a large i ntact AVM may cause a steal with resul ting
cerebral ischemi a and requi re di fferent techni ques to improve CPP. With more extensi ve l esi ons,
hypothermi a and hi gh-dose barbi turates have been recommended for brai n protecti on. Induced
hypotensi on may al so be requi red to reduce l esion si ze and blood fl ow.
Hyperemic compl icati ons, defi ned as peri operati ve edema or hemorrhage, may occur after removal
of the AVM. Al though the mechani sm i s uncl ear, one theory proposes that breakthrough cerebral
edema and hemorrhage resul t when bl ood fl ow from the surgi cal l y obli terated AVM is di verted to
the surroundi ng brai n. The small er vessel s in the brai n surroundi ng the AVM are not accustomed
to the higher pressure-flow state, and autoregulation is exceeded, resul ting i n severe brai n
swel l ing, edema, and hemorrhage. The cl i ni cal syndrome of cerebral hyperperfusion wi th normal
CPP has been call ed normal perfusi on pressure breakthrough.
177
Other studi es report informati on
that i s not consi stent with this theory.
177, 179
Immedi ate treatment shoul d i ncl ude the si multaneous
appl i cati on of hi gh-dose barbi turates, osmoti c diureti cs, hyperventil ati on, and maintenance of a
low-normal MAP. When marked brai n swell i ng occurs i ntraoperati vel y, the pati ent shoul d remai n
i ntubated, hyperventi l ated, and sedated postoperati vel y. Hypertensi on duri ng emergence and
postoperativel y must be controll ed, preferabl y wi th -bl ockers, to prevent bleedi ng i nto the bed of
the AVM.
HEAD INJURY
Head i njury i s a leadi ng cause of permanent di sabi l i ty and death, occurri ng most frequentl y i n
adolescents, young adults, and people ol der than 75 years of age. In al l age groups, mal es are
affected two ti mes more often than femal es and are more li kel y to sustai n severe head i njury. The
leading causes of traumatic brai n injuri es (TBI) are motor vehi cl e crashes, vi olence, and fall s.
More than 50% of pati ents wi th severe head i njury have mul ti pl e i njuri es resul ting i n si gni fi cant
bl ood loss, systemi c hypotensi on, and hypoxi a.
180

Classification of severe head injury i s based on the Glasgow Coma Scal e (Tabl e 27-20), whi ch
defines neurol ogic i mpai rment in terms of eye openi ng, speech, and motor functi on. The total
score that can be obtained is 15, and severe head i njury i s determi ned by a score of 8 or l ess
persisting for 6 hours or more. The Gl asgow Coma and Gl asgow Outcome Scal es permit
P.782
compari son between seri es of traumaticall y head-injured pati ents based on ini ti al cl i ni cal
presentation and eventual outcome. The prognosi s after head injury depends on the type of l esi on
sustained, the age of the pati ent, and the severi ty of the injury as defined by the Gl asgow Coma
Scal e. In general , mortali ty i s cl osel y rel ated to the initi al score on the coma scal e. For any given
lesion and score, however, the el derl y have a poorer outcome than do younger pati ents.
TABLE 27-20 Modified Glasgow coma Scale
EYE OPENING
Spontaneousl y 4
To verbal command 3
To pai n 2
None 1
BEST VERBAL RESPONSE
Oriented, conversing 5
Disori ented, conversi ng 4
Inappropri ate words 3
Incomprehensi ble sounds 2
No verbal response 1
BEST MOTOR RESPONSE
Obeys verbal commands 6
Local i zes to pai n 5
Fl exi on/withdrawal 4
Abnormal fl exi on (decorti cate) 3
Extension (decerebrate) 2
Foll owi ng head trauma, the pri mary injury resul ts from the biomechani cal effect of forces appl i ed
to the skull and brain at the ti me of the insul t and i s mani fested withi n mi ll i seconds. Currentl y,
there i s no treatment for the pri mary i njury. Secondary i njury occurs mi nutes to hours after the
impact and represents compl icati ng processes initi ated by the pri mary i njury, such as ischemia,
brain swel li ng and edema, i ntracrani al hemorrhage, intracrani al hypertensi on, and herniation.
Factors that aggravate the i niti al injury incl ude hypoxi a, hypercarbi a, hypotensi on, anemia, and
hyperglycemia. These contributi ng factors to secondary i njury are preventable. Seizures, infecti on,
and sepsi s that may occur hours to days after i njury wi l l further aggravate brai n damage and must
al so be prevented or treated promptl y.
Secondary insul ts compl icate the course of more than 50% of head-injured pati ents.
180, 181
An
outcome study usi ng data from the Traumati c Coma Data Bank reveal ed that hypotension
occurri ng after head injury i s profoundly detrimental , with more than 70% of pati ents experi enci ng
si gni fi cant morbi di ty and mortal ity (Tabl e 27-21).
181
Furthermore, the combinati on of hypoxia and
hypotensi on i s significantly more detrimental than that of hypotensi on al one (>90% of pati ents
with severe outcome or death). These fi ndi ngs confi rm the importance of avoi ding hypovol emi c
shock i n head-injured pati ents. The management goal i n head-injured pati ents is to ini ti ate ti mel y
and appropri ate therapy to prevent secondary brai n i njury. When the i ni tial i njury is not fatal ,
subsequent neurologi c damage and systemi c compl i cations shoul d be preventable in most patients.
No response (fl acci d) 1
Mi l d head i njury = 1315; moderate = 912; severe = 8.
(Adapted from Teasdal e G, Jennett B: Assessment of coma and i mpaired consci ousness:
A practi cal scal e. Lancet 2:81, 1974; and Jennett B: Assessment of the severity of head
injury. J Neurol Neurosurg Psychiatry 39:647, 1976.)
TABLE 27-21 Impact of Hypoxia and Hypotension
a
on Outcome after Severe Head
Injury (GCS 8)
SECONDARY
INSULTS
OUTCOME PERCENTAGE
NUMBER OF
PATIENTS
GOOD OR
MODERATE
SEVERE OR
VEGETATIVE
DEAD
Total cases 699 43 21 37
Nei ther 456 51 22 27
Hypoxi a 78 45 22 33
Hypotensi on 113 26 14 60
Pri mary i njury or bi omechanical trauma to brain parenchyma i ncl udes concussi on, contusi on,
lacerati on, and hematoma. Not al l severel y head-injured pati ents requi re surgery. Generali zed
brain i njury wi th edema or contusi on i s a common fi ndi ng i n pati ents, whether or not a surgi cal l y
correctable mass l esi on is present. Di ffuse cerebral swel l ing occurs because of sudden
intracerebral congestion and hyperemi a. Twenty-four hours or more after the i ni ti al insul t,
cerebral edema develops in the extracel lular spaces of the white matter. Nonoperative treatment
of di ffuse cerebral swel l i ng i ncludes hyperventil ati on, diuresi s with mannitol and furosemi de, and
barbiturates i n conjuncti on with ICP moni toring.

Depressed skull fractures and acute epidural , subdural, and intracerebral hematomas usual l y
requi re crani otomy. Chronic subdural hematomas are often evacuated through burr hol es.
Depressed skull fractures under lacerati ons shoul d be el evated and debri ded wi thi n 24 hours to
minimize the risk of infection. Bony fragments and penetrati ng objects shoul d not be manipul ated
in the emergency room, because they may be tamponading a l acerated vessel or dural si nus.
Traumatic epi dural hematoma i s an i nfrequent compl i cation of head injury, usual ly the result of a
motor vehi cl e acci dent. The ini ti al i njury tears mi ddl e meni ngeal vessel s or dural sinuses and
causes unconsciousness. When a spasm and cl ot occur in the vessel(s), the bl eedi ng stops and the
patient recovers, experienci ng a luci d i nterval . Over the next several hours, the vessel bleeds and
the pati ent rapi dl y deteriorates (especi all y wi th arteri al bl eedi ng). In rapi dl y deteri orati ng
condi ti ons, treatment shoul d not be del ayed pendi ng radi ol ogi c evaluati on. Emergency evacuati on
is necessary. Venous epi dural hematomas devel op more sl owly, and there may be ti me for
di agnosti c testing. The cl i ni cal presentati on of acute subdural hematomas ranges from mi ni mal
defici ts to unconsci ousness and si gns of a mass l esi on (hemiparesi s, unil ateral decerebrati on, and
pupi ll ary enl argement). A l uci d i nterval may occur. The most common cause of subdural hematoma
is trauma, but i t may occur spontaneousl y and is associated wi th coagul opathi es, aneurysms, and
neopl asms. It i s consi dered acute i f the pati ent becomes symptomati c wi thi n 72 hours, subacute
between 3 and 15 days, and chronic after 2 weeks. Subacute and chroni c subdural hematoma are
usuall y observed in pati ents over age 50 years. There may be no hi story of head trauma. The
cl i ni cal presentati on i n these patients may vary from focal signs of brai n dysfunction to a
depressed l evel of consci ousness or development of an organi c brain syndrome. Intracrani al
hypertensi on i s usual ly associ ated wi th acute subdural hematoma. Intensive medi cal therapy to
correct el evated ICP and control brai n edema and swel l i ng may be requi red before, duri ng, and
after hematoma evacuation. With intracerebral hematomas, the cl i ni cal pi cture may vary from
mi ni mal neurologi c defici ts to deep coma. Large, sol itary intracerebral hematomas shoul d be
evacuated. Lesi ons causi ng del ayed neurol ogic deteri orati on from fresh hemorrhage are al so
evacuated but carry a poor prognosi s. Dependi ng on the degree of cerebral injury, pati ents with
intracerebral hematomas may require i ntensive medi cal therapy to control intracranial
hypertensi on and cerebral edema. Coup and contrecoup i njuries usual l y cause cerebral contusi on
and intracerebral hemorrhage. In general , contused brai n ti ssue i s not removed; occasi onal l y,
Both 52 6 19 75
Hypoxi a = PaO
2
< 60 mmHg; hypotension = SBP < 90 mmHg; GCS = Gl asgow Coma
Scal e.
a
At ti me of hospi tal arri val .
Data adapted from the Traumati c Coma Data Bank
181
P.783
however, contused ti ssue over the frontal or temporal poles may be removed to control edema
formation and prevent herni ati on.
Emer gency Ther apy
Emergency therapy shoul d begin at the site of the acci dent, i n the ambul ance, and most certai nl y,
in the emergency room. The first step is to secure an open airway and ensure adequate ventil ati on
to prevent secondary injury from hypoxi a and hypercarbi a. Before securing the airway i n a head-
injured pati ent, a qui ck assessment of the patient' s neurol ogi c status and concomi tant i njuries
shoul d be made.
The i nci dence of cervi cal spine i njuri es in survi vi ng head-injury vi cti ms i s 1 to 3% i n adul ts and
0.5% in chi ldren.
182, 183
Vi cti ms of head-first fal l s or high-speed motor vehicl e acci dents have a
10% or greater chance of cervical spi ne fractures. X-ray eval uati on with a cross-table lateral vi ew
can mi ss 20% of cervical spi ne fractures.
183
To increase the rel iabil i ty of radi ographi c evaluati on,
anteroposteri or and odontoid views, in additi on to a l ateral vi ew, have been recommended.
Reportedly, thi s combi nati on mi sses onl y 7% of fractures.
182
When a cervi cal spi ne fracture has
not been excluded by x-ray eval uati on, cervical al i gnment wi th i n-li ne stabil i zati on i s
recommended duri ng emergent i ntubati on.
184, 185
(In-li ne stabi l izati on requires an assi stant to
stabi l ize the pati ent' s head by posi ti oni ng his or her hands al ong the side of the head wi th
fingerti ps on the mastoi d hol di ng the occi put down on a backboard.)
When facial fractures and soft ti ssue edema prevent direct vi sual i zati on of the larynx, a fi beropti c
intubati on or i ntubation wi th an il l uminated stylet or intubati ng l aryngeal mask ai rway may be
attempted. In the presence of severe faci al and/or l aryngeal i njuries, a cri cothyrotomy may be
requi red. Nasal i ntubations are avoided i n the presence of a suspected basal skul l fracture, severe
faci al fractures, and bl eedi ng di athesi s.
For pati ents without faci al i njuri es, the si mpl est and most expediti ous approach to i ntubati on i s
preoxygenation fol l owed by rapi d-sequence i nduction wi th cri coi d pressure and mai ntenance of i n-
li ne stabi l izati on. Al l head-injured pati ents are assumed to have a ful l stomach. Awake, oral
intubati on without anesthetic agents may be possi bl e i n the severely i njured pati ent, but thi s i s
di fficul t i n the awake or uncooperati ve, combati ve patient. Dependi ng on the pati ent' s
cardi ovascul ar status, virtuall y any of the i ntravenous i nduction agents, except ketamine, can be
used. The choi ce of muscl e rel axants i s

controversi al. Succi nyl chol i ne can i ncrease ICP. In the setti ng of acute ai rway compromise, ful l
stomach, and need to perform subsequent neurol ogic exami nations, the benefi ts of rapid onset
and eli mi nation of succi nylchol ine may outwei gh the risk of transi entl y i ncreasi ng ICP.
Foll owi ng control of the airway i n the head-injured pati ent, attention should focus on resuscitati on
of the cardiovascular system. Transient hypotension after head i njury i s not uncommon, but
sustained hypotension usual ly resul ts from hemorrhage secondary to other systemi c i njuri es.
These injuri es must be sought and aggressi vel y treated.
When mul tipl e trauma compl i cates head i njury, there i s no i deal crystal l oi d resusci tati on flui d. A
major concern during resuscitati on i s the development of cerebral edema. Ani mal i nvestigations
reveal that total serum osmol al i ty i s a key factor in brai n edema formation.
186, 187
When serum
osmol al i ty i s reduced, cerebral edema devel ops i n normal and abnormal brai n. This occurs because
the blood-brain barrier i s rel ati vel y i mpermeable to sodi um. Soluti ons contai ni ng sodium i n
concentrations l ower than that i n serum cause water movement i nto the brai n, increasi ng brain
water. Thus, hypoosmol ar sol utions (0.45% NaCl and l actated Ringer' s sol uti on) are more l i kel y
than isoosmol ar fl ui ds (0.9% sal ine) to i ncrease brai n water content. Large-vol ume fl ui d
resusci tati on wi th i soosmol ar crystal loids reduces col loi d oncotic pressure and i ncreases peripheral
ti ssue edema. However, i n ani mal investi gati ons, the brai n behaves differentl y than other ti ssues,
and profound lowering of col l oi d oncoti c pressure wi th mai ntenance of serum osmol ali ty does not
resul t in edema i n normal brai n
186
and i n some head-injury model s.
187, 188
These resul ts can be
expl ai ned by the uni que structure of the bl ood-brai n barri er and the fact that col loid oncotic
pressure gradi ents generate weak forces in compari son wi th osmol ar gradi ents.
186
Some doubt has
P.784
been cast on the appl icabi l i ty of these laboratory fi ndi ngs to cl i ni cal practice. The cryogeni c-injury
model used in these experi ments may not be equi val ent to head injury i n pati ents. In head-injured
pati ents, brai n capi l lary permeabi l i ty may be rendered si mi l ar to that of peri pheral tissues when
the bl ood-brai n barri er i s damaged. In addi ti on, the time course of these experi ments di d not
al low observation of edema developi ng 24 to 48 hours after i ni ti al resuscitati on, whi ch occurs i n
head-injured pati ents. An investi gati on usi ng the percussive head-injury model in rats has shown
that reducti on i n col loid oncotic pressure can aggravate cerebral edema under certain
condi ti ons.
189
Therefore, i t seems reasonable to avoi d a profound reducti on i n col loi d oncotic
pressure i n cl i ni cal practice. Isoosmol ar coll oid solutions, such as 5% al bumin or 6% hetastarch,
can be administered to maintai n oncoti c pressure and intravascul ar vol ume. Fresh whol e blood,
when avai l abl e, i s the i deal col l oi d resuscitati on fl uid for hypovol emi c pati ents wi th ongoing bl ood
loss.
Hypertoni c sal ine sol uti ons (3%, 7.5%) can be very useful for volume resusci tation in head-
i njured pati ents because they lower ICP, i ncrease blood pressure, and may i mprove regi onal
CBF.
190
Hypertoni c sal i ne produces an osmoti c di ureti c effect on the brain that i s si mil ar to that of
other hyperosmol ar soluti ons (e.g., mannitol). Hypertoni c sal i ne therapy may be more effecti ve
than other diureti cs i n certai n cl ini cal condi tions, for exampl e, i n patients with refractory
intracranial hypertension
141
or i n those who require brain debul ki ng and mai ntenance of
intravascul ar vol ume.
140
With long-term use, there i s concern over the physi ol ogic i mpl i cations of
el evated serum sodi um, such as a depressed level of consciousness and/or seizures. More studies
are required to determine dose-response curves and the safety and effi cacy of these sol uti ons.
During fl ui d resusci tation of the head-injured pati ent, the goal s are to maintai n serum osmolal ity,
avoi d profound reducti on i n coll oid oncoti c pressure, and restore ci rcul ati ng bl ood vol ume.
Immedi ate therapy is di rected at preventi ng hypotension and mai ntai ni ng CPP above 60 mmHg.
191

When i ndi cated, an ICP moni tor i s inserted to gui de fl ui d resusci tati on and prevent severe
el evati ons i n ICP. Isoosmol ar crystal l oi d sol uti ons, col loi d sol uti ons, or both are admi ni stered
acutely to restore ci rculating bl ood vol ume. Glucose-contai ning sol uti ons should not be
administered because of a si gni fi cant association between plasma gl ucose l evel s and worse
neurol ogic outcome in head-injured pati ents. Substanti al bl ood loss requires transfusi on wi th
crossmatched or fresh whol e bl ood. A mi ni mum hematocrit between 30 and 33% is recommended
to maximize oxygen transport.
Hypertensi on, tachycardia, and increased cardi ac output often develop i n pati ents with isolated
head trauma, especi all y young adults.
144
ECG abnormali ties and fatal arrhythmi as have been
reported. The hyperdynami c circul atory responses and ECG changes may resul t from a surge i n
epi nephri ne that accompani es head i njury.
144
Ei ther labetal ol or esmol ol can be used to control
hypertensi on and tachycardi a in thi s si tuati on.
In some pati ents, severe i ntracrani al hypertension preci pitates reflex arteri al hypertensi on
and bradycardi a (Cushi ng' s tri ad). A reducti on i n systemi c bl ood pressure i n these patients
can further aggravate cerebral i schemi a by reduci ng CPP. Systemi c bl ood pressure must be
lowered cauti ousl y when i ntracrani al hypertensi on i s severe. In such cases, a reducti on of ICP may
interrupt this refl ex response.
After stabi li zation of head-injured pati ents, including control of ai rway and systemi c blood
pressure, therapeutic i nterventions to control intracrani al hypertensi on are i nstituted. The head i s
el evated 15 and maintai ned i n a neutral posi tion wi thout rotation or fl exi on. Mannitol , 0.25 to 1
g/kg, is given to lower ICP acutely, or a combination of furosemide and mannitol may be
administered. Hyperventi l ati on and barbi turate therapy may be consi dered when other measures
have fai l ed.
191, 192
Appropri ate moni tori ng must be i nsti tuted and hypotensi on avoi ded.

Mechani cal hyperventil ati on to a PaCO
2
25 to 30 mmHg was routi nel y empl oyed i n head-injured
pati ents based on an assumpti on that hyperventi l ation, by reduci ng CBF, wi l l reduce ICP, thereby
preservi ng CPP and CBF. Cli nical i nvesti gati ons suggest that head-injured pati ents are i schemic
within the fi rst 24 hours of i njury.
143, 194
In these pati ents hyperventi lation may further decrease
CBF and aggravate cerebral i schemi a.
Recentl y publ i shed gui del i nes for the management of severe traumatic brai n injury no l onger
recommend hyperventilation to a PaCO
2
of 25 to 30 mmHg as a fi rst-ti er therapy.
192, 193
In fact,
the 2000 gui del i nes recommend avoidi ng the use of prophyl actic hyperventi l ation (PaCO
2

35
mmHg) therapy duri ng the fi rst 24 hours after severe TBI.
193
When hyperventi lation is ini ti ated for
control of i ntracrani al hypertensi on, the PaCO
2
shoul d be mai ntai ned in the range of 30 to 35
mmHg i n order to accompl i sh ICP control whi l e mi nimizing the associ ated ri sk of i schemi a.
Hyperventil ati on to PaCO
2
values less than 30 mmHg should be consi dered onl y when second-ti er
therapy of refractory i ntracrani al hypertensi on i s required. Continuous measurement of jugul ar
bul b oxygen saturation or CBF moni tori ng i s recommended during hyperventi l ati on to gui de
therapy.
192
In emergency si tuati ons, we shoul d continue to hyperventi l ate pati ents in whom the
cl i ni cal control of i ntracranial hypertension i s the pri mary concern. However, when the cl i ni cal
si tuati on no longer requi res i t or there is evi dence of cerebral i schemi a, normocapni c venti lation
should be insti tuted.
Anest het i c Management
The pati ent i s evaluated by CT scan and taken di rectl y to the operati ng room. There is usuall y
mi ni mal ti me avai labl e for resusci tati on and preanestheti c assessment. Informati on that should be
obtai ned preoperati vel y i s descri bed i n Tabl e 27-22.

The anestheti c management i s a conti nuati on of the i ni tial resuscitati on, i ncl udi ng ai rway
management, fl ui d and el ectrol yte bal ance, and ICP control . The routine moni tors for major
neurosurgi cal procedures are appl i ed.
Major goals of anesthetic management are to optimi ze cerebral perfusi on and oxygenati on, to
avoi d secondary damage, and to provide adequate surgi cal condi ti ons. Cerebral perfusi on pressure
(CPP = MAP - ICP) shoul d be maintai ned between 60 and 110 mmHg. If ICP increases to a greater
extent than MAP, CPP i s reduced, and the brai n becomes i schemi c. Uncontrol led i ncreases in ICP
can resul t in herni ati on and death. The choice of anestheti c agents depends on the condi ti on of
the pati ent. In the hemodynamicall y stabl e pati ent with severe i ntracrani al hypertensi on, narcoti cs
in conjuncti on wi th a thi opental infusi on (2 to 3 mg/kg/h) and nondepol ari zi ng muscle relaxant
can be admini stered with oxygen and ai r. In patients wi th l ess severe i ntracrani al hypertension,
anesthesia can be mai ntai ned wi th vari ous combi nati ons of barbi turates, benzodiazepi nes,
narcoti cs, and sub-MAC concentrati on of a potent inhal ati on agent. Anestheti c management is
di rected at avoi dance of secondary brai n i njury. Intraoperati ve hypotensi on secondary to blood
loss or precipi tated by anestheti c drugs must be avoi ded by appropri ate vol ume expansi on.
Mai ntenance of venti lation (PaCO
2
of 35 mmHg) and oxygenati on (PaO
2

60 mmHg) is extremely
important.
P.785
TABLE 27-22 Pre-anesthetic Assessment of the Head-Injured Patient
Airway (cervi cal spi ne)
Breathi ng: venti l ati on and oxygenati on
Ci rcul atory status
Associ ated injuri es
Neurologi c status (Gl asgow Coma Scal e)
Preexi sti ng chroni c i ll ness
Circumstances of the injury: Time of injury
Duration of unconsciousness
Associ ated alcohol or drug use
Intraoperati ve brai n swel l i ng or herniation from the operative site may complicate hematoma
decompression. Such causes as i mproper patient posi ti oni ng, contral ateral i ntracerebral
hematoma, venous drai nage obstructi on from packi ng, and acute hydrocephal us from
intraventri cul ar hemorrhage must be eli mi nated. In thi s setti ng, the adequacy of hyperventil ati on
must also be veri fi ed. A large al veolar-arterial CO
2
gradi ent may exi st, so that end-ti dal CO
2
may
not refl ect arteri al CO
2
. The respi ratory system and equi pment shoul d be reviewed to ensure
normal peak inspiratory and expi ratory pressures. Hemopneumothorax, hi gh i ntra-abdomi nal
pressures, a ki nked endotracheal or expi ratory tube, or a stuck expi ratory val ve can produce
marked peak inspi ratory or expiratory pressures as wel l as hypoxemi a and hypercarbi a. Fl ui d and
el ectrol yte balance must be reeval uated in pati ents wi th cerebral swel li ng. Manni tol l oses its effect
after 1 to 3 hours, and i t may be necessary to repeat the manni tol bolus to i ncrease osmol arity.
Vol ume overl oad and hyponatremi a may al so cause cerebral swel l i ng and must be corrected. If
cerebral swel l ing persi sts, the anesthetic shoul d be converted to opi oi d and thi opental infusi ons
with oxygen and ai r. Thi opental may be gi ven i n a seri es of bol uses over 5 to 10 mi nutes to a total
dose of 5 to 25 mg/kg, fol l owed by an i nfusi on of 4 to 10 mg/kg/h. To avoi d barbi turate-i nduced
myocardi al depressi on and hypotension, it may be necessary to i ncrease prel oad and add a
vasopressor such as dopami ne. Mal i gnant brai n swel l ing may require removal of brai n ti ssue and a
temporary scal p closure wi th a l oose dural patch to minimi ze ICP after cl osure.
Emergence from anesthesi a usual ly involves transporti ng an intubated, ventil ated, and
anesthetized pati ent to the intensi ve care uni t. Even in an uncompl icated craniotomy for
evacuation of hematoma, a peri od of postoperati ve venti l ation is recommended because brai n
swel l ing i s maxi mal 12 to 72 hours after i njury. Hypertensi on and coughing or bucki ng on the
endotracheal tube shoul d be avoi ded because i t can l ead to si gni fi cant i ntracrani al bleedi ng.
Labetal ol or esmol ol can be used to treat hypertension, and suppl emental barbi turates are given
to sedate the pati ent.
Syst emi c Sequel ae
The systemic effects of head i njury are di verse and can compl i cate management.
195
These i nclude
cardi opul monary probl ems (ai rway obstruction, hypoxemia, shock, adul t respi ratory di stress
syndrome, neurogeni c pul monary edema, ECG changes), hematologi c problems (di sseminated
intravascul ar coagul ati on), endocri nol ogi c problems (pi tui tary dysfuncti on i.e., diabetes
i nsi pi dus, SIADH), metabol i c problems (nonketotic hyperosmol ar hypergl ycemi c coma), and
gastrointesti nal probl ems (stress ulcers, hemorrhage). Condi tions not di scussed el sewhere i n thi s
chapter are revi ewed.
Aspi rati on, pneumoni a, flui d overl oad, and trauma-rel ated adul t respi ratory di stress syndrome are
common causes of pulmonary dysfunction in head-injured pati ents. A ful mi nant pul monary edema
may also occur. Neurogenic pul monary edema i s characteri zed by marked pul monary vascul ar
congesti on, intra-al veolar hemorrhage, and a protei n-ri ch edema fl uid. Speci fi c features of thi s
syndrome are i ts rapi d onset, its rel ati onshi p to hypothal ami c l esi ons, and the abil i ty to prevent or
attenuate it by -bl ockers and CNS depressants. Neurogeni c pul monary edema i s thought to resul t
from massi ve sympathetic discharge from i njured brai n secondary to i ntracrani al hypertensi on.
Traditi onal therapy for pul monary edema of cardi ac origi n is i neffecti ve, and the outcome i s
frequently fatal. Therapy consists of i mmedi ate pharmacol ogi c or surgi cal reli ef of i ntracrani al
hypertensi on, supporti ve respi ratory care, and careful fluid management.
In head-injured pati ents, several cl otting abnormal i ti es may be present. Di sseminated
intravascul ar coagul ati on has been reported after mil d and severe brai n trauma and anoxi c brai n
damage, and i t presumabl y devel ops after rel ease of brai n ti ssue thrombopl astin i nto the systemic
ci rculati on. Treatment of the underl yi ng disease process usuall y resul ts i n spontaneous recovery of
the coagul ati on defects. Occasi onall y, admi ni stration of cryopreci pitate, fresh frozen pl asma,
pl atel et concentrates, and bl ood may be requi red.
Anteri or pi tui tary i nsuffici ency after head injury i s a rare occurrence. However, patients exhi biti ng
post-traumati c di abetes insi pidus may devel op a del ayed i mpai rment of anteri or pitui tary
hormones, requi ri ng repl acement therapy. Posterior pitui tary dysfuncti on occurs more frequentl y
after head trauma. Diabetes i nsi pidus may occur after crani ofacial trauma and basal skul l fracture.
Its cl i ni cal presentati on i ncl udes polyuria, polydi psi a, hypernatremi a, high-serum osmol al i ty, and
di l ute uri ne. Frequentl y, post-traumati c di abetes i nsi pi dus i s transi ent, and treatment i s based on
water repl acement. If the pati ent cannot mai ntai n fl ui d balance, exogenous vasopressi n may be
administered. The SIADH secreti on i s associ ated with hyponatremi a, serum and extracell ul ar flui d
hypoosmol al i ty, renal excreti on of sodium, uri ne osmol al i ty greater than serum osmol al i ty, and
normal renal and adrenal functi on. The patient devel ops symptoms and si gns of water i ntoxi cati on
(anorexi a, nausea, vomi ti ng, i rritabi l i ty, personali ty changes, and neurol ogic abnormal i ti es).
SIADH secreti on usual l y begi ns 3 to 15 days after

trauma, l asti ng no more than 10 to 15 days wi th appropri ate therapy. Treatment i ncl udes water
restriction wi th or without hypertonic sal i ne.
Many factors i n neurosurgi cal pati ents predi spose to nonketoti c hyperosmol ar hypergl ycemi c
coma, such as steroi ds, prol onged manni tol therapy, hyperosmol ar tube feedi ngs, phenytoi n, and
l i mi ted water repl acement.
195
Di agnosti c cri teri a for nonketotic hyperosmolar hypergl ycemi c coma
are hypergl ycemi a, gl ucosuria, absence of ketosis, pl asma osmol al i ty >330 mOsm/kg,
dehydrati on, and CNS dysfuncti on. Hypovol emi a and hypertonici ty are the i mmediate threats to
l i fe. Serum sodi um may be hi gh, normal , or l ow, dependi ng on the state of hydrati on. Serum
potassium i s l ow. Seri al l aboratory tests are essenti al . Once sodi um defi cits are replaced and
bl ood pressure and uri ne output are stabl e, water defi cits are replaced wi th 0.45% sal ine.
Hypergl ycemi a usual ly responds to rel ati vely small doses of insul in. Intermittent furosemide
therapy may be given for cerebral edema prophylaxi s in the el derl y, the adul t-onset di abetic, or
the pati ent wi th compromi sed renal functi on.
SUMMARY
Guidel i nes for the management of severe traumatic brain i njury were publ i shed by The Brai n
Trauma Foundation in 1996.
192
Revisi ons to the gui del i nes were publ i shed i n 2000 in a document
that di scusses vari ous management protocol s and treatments i n l i ght of supporti ng evi dence.
193

Management updates are bei ng publ i shed on the Web as new information is made avai labl e and
the gui deli nes are revi sed.
191
Publ i cati on of these recommendations, gui del i nes, and/or standards
by The Brai n Trauma Foundati on reflects on ongoing effort to improve outcome in thi s hi gh-ri sk
popul ati on through evi dence-based management and standardi zed care.
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> Tabl e of Contents > Secti on V - Management of Anesthesi a > Chapter 28 - Respi ratory Functi on i n Anesthesi a
Chapter 28
Respiratory Function in Anesthesia
M. Christine Stock
KEY POINTS

P.791
In a person with normal lungs, both breathi ng and coughi ng can be performed
excl usi vel y by the di aphragm.
In the adul t, the tip of an orotracheal tube moves an average of 3.8 cm with
flexion and extension of the neck, but can travel as much as 6.4 cm. In i nfants
and chi l dren, di spl acement of even 1 cm can move the tube above the vocal
cords or bel ow the carina.
The fol lowi ng anatomy shoul d be consi dered when contempl ati ng the use of a
doubl e-lumen tube. The adult right main-stem bronchus i s ~2.5 cm l ong before
it branches into l obar bronchi . In 10% of adul ts, the ri ght upper l obe bronchus
departs from the ri ght main-stem bronchus less than 2.5 cm above the cari na.
In 2 to 3% of adults, the right upper l obe bronchus opens i nto the trachea,
above the cari na.
When l ung compl iance i s smal l , l arger changes in pleural pressure are needed to
create the same Vt. Pati ents wi th l ow lung compl i ance breathe wi th small er Vt
and more rapi dl y, maki ng spontaneous respi ratory rate the most sensi tive
cl i ni cal i ndex of lung compl i ance.
Caroti d and aorti c bodi es are sti mul ated by PaO
2
values less than 60 to 65 mm
Hg. Thus, pati ents who depend on hypoxic ventilatory drive do not have PaO
2

val ues >65 mm Hg. The peri pheral receptors' response wi ll not rel i abl y i ncrease
ventil atory rate or minute venti l ati on to heral d the onset of hypoxemi a duri ng
general anesthesi a or recovery.
There are three eti ol ogi es of hyperventi l ati on: arteri al hypoxemi a, metabol ic
acidemia, and central eti ol ogi es (e.g., intracrani al hypertensi on, hepatic
ci rrhosis, anxiety, pharmacologi c agents).
Increases in dead space venti l ati on pri maril y affect CO
2
eli mi nation (with
mi ni mal infl uence on arteri al oxygenati on), and physi ol ogi c shunt i ncrease
pri mari l y affects arteri al oxygenati on (with mi ni mal i nfl uence on CO
2

Anesthesi ol ogists directl y manipul ate pul monary function. Thus, a sound and thorough worki ng
knowl edge of appl i ed pul monary physiology is essenti al to the safe conduct of anesthesia. This
chapter discusses pulmonary anatomy, the control of ventil ati on, oxygen and carbon di oxi de
transport, venti lationperfusi on relationshi ps, l ung volumes and pul monary functi on testing,
abnormal physi ol ogy and anesthesia, the effect of smoki ng on pul monary functi on, and assessing
ri sk for PPCs.
FUNCTIONAL ANATOMY OF THE LUNGS
el i mi nation).
During spontaneous venti l ati on, the rati o of al veolar venti lation to dead space
ventil ati on i s 2:1. The al veol ar-to-dead space venti lation rati o duri ng positi ve-
pressure ventil ati on i s 1:1. Thus, mi nute ventil ati on duri ng mechani cal
venti l atory support must be greater than that duri ng spontaneous venti lation to
achi eve the same PaCO
2
.
PaCO
2

PETCO
2
unless the pati ent i nspires or recei ves exogenous CO
2
. The
di fference between PaCO
2
and PETCO
2
is due to dead space ventil ati on. The
most common reason for an acute i ncrease in dead space venti l ation is
decreased cardiac output.
The best eval uation of the effi ciency with whi ch the lungs oxygenate the arterial
bl ood is the calcul ati on of shunt fracti on. It i s the onl y i ndex of oxygenati on
that takes i nto account the contri buti on of mi xed venous bl ood to arterial
oxygenati on.
When functi onal resi dual capaci ty (FRC) is reduced, lung compl i ance fal l s and
resul ts i n tachypnea, and venous admi xture increases, creating arteri al
hypoxemi a.
There i s no compel li ng evidence that defi nes rul es or parameters for orderi ng
preoperati ve pulmonary functi on tests. Rather, they should be obtained to
ascertai n the presence of the reversibl e pul monary dysfunction (bronchospasm)
or to defi ne the severi ty of advanced pul monary di sease.
Smoki ng pati ents shoul d be advi sed to stop smoking at least 2 months pri or to
an elective operati on to decrease the risk of postoperative pul monary
compl i cati ons (PPCs).
The operati ve si te i s one of the most i mportant determi nants of the risk of PPC.
The hi ghest risk for PPC is associ ated wi th nonlaparoscopi c upper abdomi nal
operati ons, fol l owed by l ower abdomi nal and i ntrathoraci c operati ons.
The singl e most i mportant aspect of postoperati ve pul monary care and
preventi on of PPC i s getti ng the pati ent out of bed, preferably walking.
Thi s secti on emphasi zes functional l ung anatomy, wi th structure described as i t appl i es to the
mechani cal and physiol ogi c functi on of the lungs.
Thor ax
The thoracic cage is shaped l ike a truncated cone, wi th small superi or and large inferi or openi ngs
and diaphragms attached at the base. The sternal angle i s l ocated i n the hori zontal plane that
passes through the vertebral col umn at the T4 or T5 l evel . Thi s pl ane separates the superi or from
the inferior medi asti num. The predominant venti latory changes i n thoraci c diameter occur in the
anteroposteri or di recti on i n the upper thoraci c regi on and in the l ateral or transverse di recti on i n
the lower portion of the thorax.
Muscl es of Vent i l at i on
The venti l atory muscles are endurance muscl es. Poor nutri ti on, chroni c obstructive pul monary
di sease (COPD) wi th gas trappi ng, and i ncreased ai rway resistance predi spose to the
development of ventil atory fai lure due to venti latory muscle fati gue. The venti latory muscl es
incl ude the diaphragm, i ntercostal muscl es, abdomi nal muscl es, cervi cal strap muscles,
sternocl ei domastoid muscles, and the l arge back and i ntervertebral muscles of the shoul der gi rdle.
The primary ventil atory muscl e i s the diaphragm, with mi nor contributi ons from the i ntercostal
muscles. Normal l y, at rest, inspirati on requires work and expi rati on i s passi ve. As venti l atory
effort i ncreases, abdomi nal muscl es assist wi th ri b depressi on and i ncrease i ntra-abdomi nal
pressure to faci l itate forced exhal ation causi ng the stitch athl etes experi ence when they acti vely
exhale. Wi th a further i ncrease i n effort, the cervi cal strap muscl es help elevate the sternum and
upper porti ons of the chest. Fi nal l y, the l arge back and paravertebral muscles of the shoulder
gi rdle become important duri ng maximum ventilatory effort. In a person wi th normal l ungs, both
breathi ng and coughi ng can be performed excl usi vel y by the di aphragm.
Ventil atory muscl es must create suffi ci ent force to l ift the ri bs to create subatmospheri c pressure
in the i ntrapl eural space. Breathing i s an endurance phenomenon, thus involving fatigue-resistant
fibers, characteri zed by a sl ow-twi tch response to el ectrical sti mulati on. They comprise
approxi mately 50% of the di aphragmatic fi bers and, because of thei r hi gh oxi dati ve capaci ty,
functi on mostl y as endurance uni ts.
1
Fast-twi tch muscl e fi bers, whi ch are susceptibl e to fati gue,
have rapi d responses to electri cal sti mul ation, i mpart strength, and al l ow the muscl e to produce
greater force over a short peri od of ti me. Thus, the di aphragm i s composed of fast-twi tch fi bers
that are useful duri ng bri ef peri ods of maxi mal venti latory effort (coughi ng, sneezi ng) and sl ow-
twi tch fi bers provi de endurance (breathi ng wi thout rest).
2
The muscles of the abdomi nal wal l, the
most powerful muscl es of expi rati on, are important for expul sive efforts such as coughi ng.
3

To perform work, a muscl e must be fi rml y anchored at both i ts ori gin and i nserti on. The
di aphragm i s unique because i ts i nserti on i s mobi lean untethered central tendon that ori gi nates
from fi bers di rectl y attached to the vertebral bodies and the costal porti ons of the l ower ri bs and
sternum. Di aphragmati c contraction resul ts in descent of the diaphragmati c dome and expansion
of the thoraci c base. These changes resul t in decreased i ntrathoracic and i ntrapl eural pressure,
wi th a correspondi ng i ncrease in i ntra-abdomi nal pressure.
The cervi cal strap muscl es are acti ve even during breathi ng at rest. They are the most important
inspi ratory accessory muscl es, and become the pri mary i nspi ratory muscl es when di aphragmatic
functi on i s impai red, as i n pati ents wi th cervi cal spi nal cord transection.
Lung St r uct ur es
Wi th an intact respiratory system, the expandable lung ti ssue compl etel y fi ll s the pl eural cavi ty.
The vi sceral and parietal pleurae are constantl y in contact wi th each other, creati ng a potenti al
intrapl eural space in whi ch pressure decreases when the di aphragm descends and the ri b cage
expands. At passive end i nspi ration, the resul tant subatmospheri c i ntrapl eural pressure is a
refl ecti on of the opposi ng and equal forces between the tendency of the l ung to coll apse and the
chest wal l muscul ature to remai n expanded. These equal and opposi ng forces at end i nspirati on
resul t in the functional resi dual capaci ty (FRC), the volume of gas i n the lungs at passive end
expirati on. The intrapleural space normal l y has a sl ightl y subambient pressure (-2 to -3 mm Hg)
at FRC. Wi th i nspi rati on, the intrapl eural pressure becomes more negati ve as the chest wal l
expands. Major di vi si ons of the right and l eft lung are li sted in Tabl e 28-1. Worki ng knowl edge of
the bronchopul monary segments is i mportant for local i zi ng l ung pathol ogy, i nterpreti ng lung
radi ographs, i denti fyi ng l ung regi ons duri ng bronchoscopy, and operati ng on the lung. Each
bronchopul monary segment i s separated from i ts adjacent segments by wel l -defi ned connecti ve
ti ssue planes. Therefore, pul monary pathol ogy i ni ti all y tends to remain segmental .
TABLE 28-1 Major Divisions of the Lung
LUNG SIDE/LOBE BRONCHOPULMONARY SEGMENT
RIGHT
Upper Api cal
Anterior
Posterior
Mi ddl e Medi al
Lateral
Lower Superi or
Medi al basal
Lateral basal
Anteri or basal
Posterior basal
LEFT
Upper Apical posterior
Anterior
Li ngul a Superi or
The l ung parenchyma can be subdivi ded i nto three ai rway categories based on functi onal l ung
anatomy (Tabl e 28-2). The conducti ve ai rways provide basic gas transport but no gas exchange.
The next group, whi ch has smal ler di ameters, i s transi tional airways. Transi ti onal ai rways are
conduits for gas movement, and addi ti onal l y perform l i mi ted gas di ffusi on and

exchange. Finall y, the smal l est respi ratory ai rways' pri mary functi on i s gas exchange.
Conventi onal l y, l arge ai rways with diameters of >2 mm create 90% of total ai rway resistance. The
number of al veoli i ncreases progressi vel y with age, starting at approximately 24 mi l li on at bi rth
and reachi ng the final adult count of 300 mi l li on by the age of 8 to 9 years. The al veol i are
associated wi th about 250 mil l ion precapi l lari es and 280 bi l li on capi l l ary segments, resulti ng in a
surface area of ~70 m
2
for gas exchange.

Conductive Airways
In the adul t, the trachea is a fi bromuscul ar tube ~10 to 12 cm l ong with an outside diameter
of ~20 mm. Structural support is provi ded by 20 U-shaped hyali ne carti lages, wi th the open
part of the U faci ng posteri orl y. The cri coi d membrane tethers the trachea to the cri coid carti l age
at the l evel of the si xth cervical vertebral body. The trachea enters the superi or medi asti num and
bi furcates at the sternal angle (the lower border of the fourth thoraci c vertebral body). Normal l y,
Inferi or
Lower Superi or
Posterior basal
Anteromedi al basal
Lateral basal
P.792
TABLE 28-2 Functional Airway Divisions
TYPE FUNCTION STRUCTURE
Conductive Bulk gas movement Trachea to termi nal bronchiol es
Transiti onal Bulk gas movement Respi ratory bronchiol es
Li mi ted gas exchange Al veol ar ducts
Respi ratory Gas exchange Al veol i
Al veol ar sacs
half of the trachea is intrathoraci c and hal f i s extrathoraci c. Both ends of the trachea are attached
to mobi le structures. Thus, the adul t cari na can move superi orl y as much as 5 cm from i ts normal
resti ng posi ti on. Ai rway moti on becomes i mportant in the intubated patient. In the adul t, the tip
of an orotracheal tube moves an average of 3.8 cm with fl exion and extension of the neck but can
travel as far as 6.4 cm.
4
In i nfants and chil dren, tracheal tube movement wi th respect to the
trachea i s even more cri tical: di splacement of even 1 cm can move the tube above the cords or
bel ow the cari na.
The next ai rway generation is composed of the right and l eft mai n-stem bronchi . The diameter of
the ri ght bronchus i s general l y greater than that of the left. In the adul t, the ri ght bronchus
leaves the trachea at ~25 from the verti cal tracheal axi s, whereas the angle of the l eft bronchus
is ~45. Thus, i nadvertent endobronchi al i ntubati on or aspi rati on of forei gn material i s more l i kel y
to occur i n the ri ght l ung than the left. Furthermore, the ri ght upper l obe bronchus di ves al most
di rectl y posteri or at ~90 from the ri ght mai n bronchus. Foreign bodi es and fl ui d aspi rated by a
supine subject usuall y fall into the ri ght upper l obe. In chi l dren younger than 3 years of age, the
angl es created by the right and l eft mai n-stem bronchi are approxi mately equal, wi th takeoff
angles of about 55.
The adul t ri ght mai n bronchus is ~2.5 cm l ong before i t ini ti al l y branches i nto l obar bronchi.
However, in 10% of adul ts, the ri ght upper l obe bronchus departs from the ri ght mai n-stem
bronchus less than 2.5 cm from the cari na. Furthermore, i n ~2 to 3% of adul ts, the ri ght upper
l obe bronchus opens i nto the trachea, above the carina. Pati ents wi th these anomal i es require
special consi deration when pl aci ng doubl e-lumen tracheal tubes, especi al l y i f one contempl ates
i nserti ng a ri ght-si ded endobronchi al tube. After the ri ght upper and mi ddl e l obe bronchi di vi de
from the ri ght mai n bronchus, the main channel becomes the right lower l obe bronchus.
The left main bronchus is ~5 cm long before i ts i ni tial branchi ng poi nt to the l eft upper l obe and
the li ngual. Then, it continues on as the l eft lower l obe bronchus.
The bronchiol es, typi cal l y 1 mm in di ameter, are devoi d of carti l agi nous support and have the
hi ghest proporti on of smooth muscl e i n the wall . Of the three to four bronchiolar generati ons, the
final generati on i s the termi nal bronchiol e, whi ch is the l ast ai rway component that does not
parti cipate in gas exchange.
Transitional Airways
The respi ratory bronchi ol e, which foll ows the terminal bronchi ol e, is the fi rst si te in the
tracheobronchi al tree where gas exchange occurs. In adults, two or three generati ons of
respiratory bronchi oles l ead to alveol ar ducts, of whi ch there are four to fi ve generati ons, each
with multi ple openi ngs into al veol ar sacs. The fi nal di vi si ons of alveol ar ducts termi nate in
al veolar sacs that open i nto alveol ar clusters.
Respiratory Airways and the AlveolarCapillary Membrane
The pul monary capi l l ary beds are the densest capi l lary networks in the body. This extensi ve
vascul ar branchi ng system starts wi th pul monary arteri ol es in the region of the respi ratory
bronchi ol es. Each al veol us i s cl osel y associated wi th ~1,000 short capil l ary segments.
The alveol arcapil l ary interface i s compli cated but wel l desi gned to facil i tate gas exchange.
Viewed with electron microscopy, the alveol ar wal l consi sts of a thi n capil l ary epi thel ial cel l , a
basement membrane, a pulmonary capi l l ary endothel i al cel l , and a surfactant li ning l ayer. The
flattened, squamous type I al veolar cel l s cover ~80% of the al veolar surface. Type I cel ls contain
flattened nucl ei and extremely thi n cytoplasmic extensi ons that provi de the surface for gas
exchange. Type I cel l s are

hi ghl y di fferenti ated and metabol i cal ly li mited, which makes them hi ghl y suscepti bl e to i njury.
When type I cel ls are damaged severely (duri ng acute l ung i njury or adul t respi ratory di stress
syndrome), type II cel l s repl i cate and modi fy to form new type I cel l s.
5

P.793
Type II al veol ar cel l s are interspersed among type I cell s, pri maril y at alveol arseptal junctions.
These pol ygonal cel l s have vast metabol ic and enzymati c activity, and manufacture surfactant. The
enzymati c activity requi red to produce surfactant i s onl y 50% of the total enzymati c activity
present in type II al veol ar cel l s.
6
The remaini ng enzymati c acti vi ty modulates l ocal electrolyte
bal ance, as wel l as endotheli al and l ymphati c cel l functi ons. Both type I and type II alveol ar cell s
have tight intracel lul ar juncti ons, thus provi ding a rel ati vel y i mpermeabl e barri er to fluids.
Type III alveol ar cell s, alveol ar macrophages, are an important element of l ung defense. Thei r
mi gratory and phagocytic acti vi ti es resul t i n the ingesti on of forei gn material s wi thin alveol ar
spaces.
7
Al though functional pul monary macrophages reduce the i ncidence of lung i nfecti on,
8
they
are al so an i ntegral part of the l ung i nfl ammatory response. Therefore, whether thei r presence i s
good (to reduce the change of i nfection) or bad (because they contribute to the i nflammatory
response) i s hi ghl y controversi al.
9

Fi nal ly, numerous fi nger-li ke projections of the capi l l ary endothel i al cel ls greatl y i ncrease thei r
surface area. They al so provi de intimate contact between the capi l lary endothel ial cel l and the
enti re ci rculating bl ood vol ume. Thus, the al veol ar-capil l ary membrane has two pri mary functi ons:
transport of respiratory gases (oxygen and carbon di oxi de), and the production of a wide vari ety
of local and humoral substances.
P ul monar y Vascul ar Syst ems
Two major circul atory systems suppl y bl ood to the l ungs: the pul monary and bronchi al vascul ar
networks. The pulmonary vascular system deli vers mi xed-venous bl ood from the ri ght ventricl e to
the pul monary capi l lary bed vi a the pul monary arteri es. After gas exchange occurs i n the
pul monary capi l l ary bed, oxygen-ri ch and carbon di oxi de-poor bl ood i s returned to the l eft atrium
via the pul monary vei ns. The pul monary vei ns run i ndependentl y al ong the intralobar connective
ti ssue planes. The pul monary capi l lary system adequatel y provi des for the metaboli c and oxygen
needs of the alveol ar parenchyma. However, the bronchial arteri al system must provi de oxygen to
the conducti ve ai rways and pul monary vessel s. Anatomi c connections between the bronchial and
pul monary venous ci rcul ati ons create an absolute shunt of ~2 to 5% of the total cardi ac output,
and represents normal shunt.
LUNG MECHANICS
Lung movement i s enti rel y passi ve and responds to forces external to the l ungs. Duri ng
spontaneous venti lation, the external forces are produced by ventil atory muscl es. The l ungs'
response i s governed by the impedance of the chest wal l and by the airways. Thi s i mpedance, or
hi ndrance, fal l s mainl y i nto two categori es: (1) el asti c recoil of the lung and gasli qui d i nterface,
and (2) resi stance to gas fl ow.
El ast i c Wor k
The l ungs' natural tendency i s to col l apse; thus, expi rati on at rest is normal ly passive because gas
flows out of the l ungs when they elasti cal l y recoil . The thoracic cage exerts an outward-di rected
force, and the lungs exert an i nward-di rected force. Together these forces result i n a
subatmospheri c i ntrapl eural pressure. Because the outward force of the thoraci c cage exceeds the
inward force of the lung, the overall tendency of the l ung i s to remai n i nfl ated when i t resi des
within the thoracic cage. At FRC, the outward and i nward forces on the l ung are equal . Thus, at
passi ve end-exhalation, the respi ratory muscl es are rel axed and the lung returns to i ts resti ng
vol ume wi thin the rel axed thorax: FRC. Gravi tational forces create a more subatmospheric
pressure i n nondependent areas of the l ung than in dependent areas. In the upri ght adul t, the
di fference i n intrapleural pressure from the top to the bottom of the l ung i s ~7 cm H
2
O.
Surface tensi on at an ai rflui d i nterface produces forces that tend to further reduce the area of
interface. The gas pressure withi n a bubbl e i s al ways hi gher than the surrounding gas pressure
because of the bubble' s surface tensi on. Thus, the bubbl e remai ns i nflated. The al veol i resembl e
bubbl es i n thi s respect, al though al veol ar gas communi cates with the atmosphere vi a the airways,
unl i ke a bubbl e. The Laplace equati on descri bes thi s phenomenon: P = 2T/R, where P i s the
pressure withi n the bubbl e (dyn cm
-2
), T is the surface tension of the liquid (dyn cm
-1
), and R
i s the radi us of the bubbl e (cm).
During i nspirati on, the surface tensi on of the li quid i n the l ung increases to 40 mN/m, a val ue
cl ose to that of pl asma. During expi ration, thi s surface tension fall s to 19 mN/m, a value l ower
than that of most other flui ds. The al veol i experience hysteresi s, that i s, di fferent pressure
vol ume rel ati onshi ps duri ng i nspirati on and expi rati on. In contrast to a bubbl e, the pressure
within an al veol us decreases as the radi us of curvature decreases. Thus, gas tends to flow from
larger to smal l er al veol i , thereby mai ntai ni ng stabil i ty and preventi ng l ung col l apse.
The alveol ar transmural pressure gradi ent, or transpulmonary pressure, is the difference between
intrapl eural and al veol ar pressure and i s directl y proporti onal to l ung volume. Intrapl eural
pressure can be safel y measured with a percutaneousl y inserted catheter;
10
however, cli ni ci ans
rarel y perform thi s technique. Esophageal pressure can be used as a refl ecti on of i ntrapl eural
pressure, but the esophageal bal l oon must resi de in the midesophagus to avoi d inaccurate
measurement.
11
Commercial ly avai l abl e esophageal pressure monitors i ncrease the ease and
accuracy of measuri ng esophageal pressure as a refl ecti on of i ntrapl eural pressure.
12
These
moni tors are useful for esti mating the el asti c work performed by the pati ent duri ng spontaneous
ventil ati on, mechani cal venti lation, or a combinati on of spontaneous and mechani cal venti lation.
By esti mati ng intrapleural pressure on a real -ti me basis, i t i s possi bl e to quanti tate the pati ent's
work of breathing as one intervenes. For example, low level s of i nspi ratory pressure support can
compensate for the work of breathi ng i mposed by the endotracheal tube.
13

Physi ol ogi c work of breathi ng i ncl udes el astic work (i nspiratory work required to overcome the
el asti c recoi l of the pulmonary system) and resi sti ve work (work to overcome resi stance to gas
flow in the airway). For a pati ent i n whom breathi ng apparatus i s empl oyed, the concept of total
work of breathi ng encompasses physi ol ogi c work pl us equi pment-i mposed venti l atory work: the
work performed by the pati ent to overcome the resi stance i mposed by the breathi ng apparatus.
Exampl es of imposed work i ncl ude the resistance i mposed by tracheal tubes and demand val ves.
If the l ungs are sl owl y i nflated and defl ated, the pressurevol ume curve duri ng i nflation di ffers
from that obtai ned duri ng deflation. The two curves form a hysteresi s l oop that becomes
progressi vel y broader as the ti dal volume i s i ncreased (Fi g. 28-1). A greater pressure than
anti ci pated i s requi red duri ng infl ati on, and recoi l pressure is l ess than expected duri ng defl ati on.
Thus, the lung accepts deformation poorl y and, once deformed, assumes i ts origi nal shape sl owl y.
Thi s el asti c hysteresis i s important for the mai ntenance of normal l ung compl i ance

but i s not cl ini call y si gnifi cant. Thus, in the foll owi ng di scussi on, i t i s i gnored.
P.794
FIGURE 28-1. Dynamic pressurevol ume l oop of resti ng ti dal vol ume. Qui et, normal
The sum of the pressurevol ume rel ati onshi ps of the thorax and l ung results i n a si gmoidal
curve (Fi g. 28-2). The vertical li ne drawn at end expi rati on coi nci des wi th FRC. Normal l y,
humans breathe on the steepest part of the si gmoidal curve, where compl iance i s hi ghest. The
compl i ance of the curve is represented by the sl ope of the curve (V/P). In restri cti ve diseases,
the curve shi fts to the right, the slope i s depressed, or both. These changes resul t i n smal ler FRCs
and lower l ung compl i ance. When lung compl i ance is smal l, larger changes i n intrapleural pressure
are needed to create the same tidal vol ume; that i s, the thorax has to suck harder to get the
same vol ume of gas i nto the l ungs. The body, bei ng a smart organism, prefers to move less gas
with each breath rather than sucki ng harder to achi eve the same ti dal vol ume. Thus, pati ents with
low l ung compli ance typi cal ly breathe wi th smal ler tidal volumes at more rapi d rates, maki ng
spontaneous venti latory rate one of the most sensi tive i ndi ces of l ung compli ance.
Conti nuous posi ti ve ai rway pressure (CPAP) wi ll shi ft the vertical li ne to the ri ght, thus al lowi ng
the pati ent to breathe on a steeper and more favorable porti on of the vol umepressure curve,
resul ti ng in a slower venti latory rate wi th a l arger ti dal volume.
At the other end of the spectrum, patients with diseases that increase l ung compl iance experience
larger than normal FRC (gas trappi ng), and their pressurevol ume curves shi ft to the l eft and
steepen. These patients expend l ess elasti c work to i nspi re, but elasti c recoi l i s reduced
breathing i s characterized by hysteresi s of the pressurevol ume l oop. The lung is more
resistant to deformati on than expected and returns to i ts ori gi nal configuration less easi ly
than expected. The slope of the l i ne connecting the zenith and nadi r l ung vol umes is l ung
compl i ance, ~500 mL/3 cm H
2
O = 167 mL/cm H
2
O.
FIGURE 28-2. Pul monary pressurevol ume rel ati onshi ps at di fferent val ues of total l ung
capaci ty (TLC), ignori ng hysteresi s. The soli d l i ne depicts the normal pulmonary pressure
vol ume rel ati onshi ps. Humans normal l y breathe on the l inear, steep part of this si gmoidal
curve, where the slope, whi ch i s equal to compl i ance, i s greatest. The vertical li ne at zero
defines functi onal resi dual capaci ty (FRC), regardl ess of the posi ti on of the curve on the
graph. Mi l d restri cti ve l ung di sease, i ndi cated by the dashed li ne, shi fts the curve to the ri ght
with little change in slope. However, with restri cti ve di sease, the patient breathes on a lower
FRC, at a poi nt on the curve where the sl ope i s l ess. Severe restri cti ve pulmonary disease
profoundl y depresses the FRC and diminishes the sl ope of the entire curve (dashed-dotted
li ne). Obstructive disease (dotted l i ne) el evates both FRC and compl i ance.
si gni fi cantl y. Chroni c obstructive lung disease and acute asthma are the most common exampl es
of diseases wi th high l ung compl i ance. If l ung compl i ance and FRC are suffici ently hi gh that el asti c
recoi l is mi ni mal, the pati ent must use venti latory muscl es to acti vel y expire. The difficulty these
patients experi ence in emptyi ng the l ungs i s compounded by the i ncreased ai rway resi stance.
Both compl i ance and i nspiratory elasti c work can be measured for a si ngle breath by measuri ng
ai rway (Paw), i ntrapl eural (Ppl ) pressures, and tidal vol ume. If esophageal pressure i s measured
careful ly, the esophageal pressure values can be substi tuted for Ppl val ues. Lung compl iance, C
L
,
the sl ope of the vol umepressure curve, is gi ven by the equati on

where P
L
is transpulmonary pressure, PL
i
and PL
e
are transpul monary pressure at end-inspi ratory
and end-expi ratory, Vt i s ti dal vol ume, Paw
e
and Paw
i
are expi ratory and i nspi ratory ai rway
pressures, and Ppl
e
and Ppl
i
are expi ratory and inspi ratory intrapl eural pressures.
El asti c work (W
el
) i s performed duri ng inspi rati on onl y because expi ration is passi ve duri ng normal
breathing. The area within the tri angl e i n Fi gure 28-2 descri bes the work requi red to inspire. The
equati on that yi el ds el astic work (and the area of the triangl e) is

= (Vt)[(Paw
i
- Ppl
i
) - (Paw
e
- Ppl e)]
Resi st ance t o Gas Fl ow
Both lami nar and turbul ent flows exi st withi n the respi ratory tract, usual l y i n mi xed patterns. The
physi cs of each, however, i s signi fi cantl y different and worth consi derati on.
Laminar Flow
Below criti cal fl ows, gas proceeds through a strai ght tube as a seri es of concentri c cyl inders that
sl i de over one another. Ful ly devel oped flow has a parabol i c profi l e wi th a vel oci ty of zero at the
cyl i nder wal l and a maxi mum vel oci ty at the center of the advanci ng cone. Peri pheral cyl inders
tend to be stati onary, and the central cyli nder moves fastest. Thi s type of streamli ned flow is
usuall y inaudibl e. The advancing conical front means that some fresh gas reaches the end of the
tube before the tube has been completely filled wi th fresh gas. A cl i ni cal i mpl icati on of l ami nar
flow in the airways i s that si gni fi cant al veol ar ventil ati on can occur even when the ti dal vol ume
(Vt) is l ess than

anatomic dead space. This phenomenon, noted by Rohrer i n 1915,
14
i s i mportant i n hi gh-frequency
ventil ati on.
Laminar gas fl ows i n a strai ght, unbranched tube encounter meets resi stance that can be
calculated by the fol l owi ng equati on:

where P
B
and P
A
are barometri c and alveol ar pressures. The i nverse rel ati onship between
resistance and the fourth power of the radi us expl ains the cri ti cal i mportance of narrowed ai r
passages. Vi scosi ty is the only physi cal gas property that i s rel evant under condi ti ons of l aminar
flow. Heli um has a l ow densi ty, but i ts viscosi ty i s cl ose to that of ai r. Therefore, hel i um wi l l not
i mprove gas fl ow i f the fl ow i s l aminar. Usual l y, flow is turbulent when there i s cri ti cal ai rway
narrowi ng or abnormal l y high ai rway resi stance, maki ng low-densi ty heli um useful therapy (see
next section).
Turbulent Flow
P.795
Hi gh fl ow rates, parti cul arl y through branched or i rregul arl y shaped tubes, disrupt the orderl y fl ow
of lami nar gas. Turbul ent fl ow is usuall y audible and is al most i nvariabl y present when hi gh
resistance to gas flow i s probl emati c. Turbul ent fl ow usual l y presents wi th a square front so fresh
gas wi ll not reach the end of the tube unti l the amount of gas entering the tube i s al most equal to
the volume of the tube. Thus, turbulent fl ow effecti vel y purges the contents of a tube. Four
condi ti ons that wi ll change lami nar fl ow to turbulent fl ow are hi gh gas flows, sharp angles withi n
the tube, branchi ng i n the tube, and a change in the tube' s di ameter.
Resi stance during l aminar flow i s i nversel y proporti onal to gas fl ow rate. Conversel y, during
turbulent flow, resistance increases i n proporti on to the flow rate. A detai led descri pti on of these
phenomena i s beyond the scope of thi s chapter, but the reader i s referred to descri ptions by
Nunn.
15

Increased Airway Resistance
Bronchiolar smooth muscle hyperreacti vi ty (true bronchospasm), mucosal edema, mucous
pl ugging, epi theli al desquamation, tumors, and forei gn bodi es al l i ncrease ai rway resi stance. The
normal response to i ncreased inspiratory resistance is i ncreased i nspiratory muscl e effort, with
little change in FRC.
16
Accessory muscl es act according to the degree of resi stance. The consci ous
subject can detect smal l increases i n i nspi ratory resi stance.
17

Emphysematous pati ents retain remarkabl e abi l ity to preserve an adequate alveol ar venti l ati on,
even with gross ai rway obstruction. In pati ents wi th preoperati ve FEV
1
values <1 L, PaCO
2
is
normal i n most patients. Furthermore, asthmati c pati ents compensate well for i ncreased ai rway
resistance and al so keep the mean PaCO
2
in the l ower end of normal range.
18
Thus, an i ncreased
PaCO
2
in the setti ng of increased ai rway resistance deserves serious attention and may si gnal that
the pati ent's compensatory mechani sms are nearl y exhausted.
Mi l d expi ratory resi stance does not resul t in acti vati on of the expi ratory muscl es in consci ous or
anesthetized subjects. The i ni ti al work to overcome expi ratory resi stance i s performed by
augmenti ng i nspi ratory force unti l a suffi cientl y hi gh l ung vol ume i s achi eved so elasti c recoi l
overcomes expi ratory resi stance.
19
The i mmediate effects of excessi ve expi ratory resi stance are to
use accessory muscl es to force gas from the l ungs. Thi s response is useful during acute increases
in expi ratory resi stance. However, pati ents who chroni cal ly use accessory muscl es to expi re are at
ri sk for venti latory muscl e fatigue i f they experi ence an acute worseni ng of venti latory work, most
commonly preci pitated by pneumoni a or heart fail ure.
Physiologic Changes in Respiratory Function Associated with
Aging
Physi ol ogi c aging of the l ung i s associ ated wi th di l ati on of the al veoli , enl argement of the
ai rspaces, decrease in exchange surface area, and l oss of supporti ng ti ssue. Changes i n the agi ng
lung and chest wal l resul t i n decreased l ung recoil , and increased residual vol ume and FRC.
Compl i ance of the chest wal l di mi ni shes, thereby increasi ng the work of breathi ng compared wi th
younger subjects. Respiratory muscl e strength decreases with agi ng and i s strongly correl ated
with nutri ti onal status and cardi ac index. Expi ratory fl ow rates decrease wi th a fl owvol ume curve
suggestive of small ai rway resistance. Despi te these changes, the respi ratory system i s abl e to
maintai n adequate gas exchange at rest and duri ng exerti on throughout l i fe, with only modest
decrements in PaO
2
and no change in PaCO
2
. The respi ratory centers lose sensi tivity to hypoxemi a
and hypercapni a; thus, the el derly exhi bi t a bl unted venti l atory response when chal l enged by
heart fail ure, ai rway obstructi on, or pneumoni a.
CONTROL OF VENTILATION
Mechani sms that control venti l ati on are extremely complex, requiri ng i ntegration wi th many parts
of the central and peri pheral nervous systems (Fi g. 28-3). LeGal lois, who l ocali zed the respi ratory
centers i n the brai nstem i n 1812, demonstrated that breathing does not depend on an intact
cerebrum. Rather, breathi ng depends on a smal l regi on of the medull a near the ori gin of the vagus
nerves.
21
Countl ess studi es in the past two centuries have greatly increased our knowl edge and
understandi ng of the anatomi c components of venti latory control. However, experi mental work
performed in ani mal s is diffi cult to appl y to humans because of i nterspeci es vari ati on.
Gener at i on of Vent i l at or y P at t er n
Refer to Tabl e 28-3 for defi niti ons of terms used i n thi s secti on. A respiratory center is a speci fi c
area i n the brai n that i ntegrates any neural traffi c resul ting i n spontaneous venti l ation. Withi n the
ponti ne and medul l ary reticul ar formati ons, there are several di screte respiratory centers that
functi on as the control system (see Fi g. 28-3).
FIGURE 28-3. Cl assic central nervous system (CNS) respi ratory centers. Diagram il l ustrates
major respi ratory centers, neurofeedback ci rcuits, primary neurohumoral sensory inputs, and
mechani cal outputs.
TABLE 28-3 Definition of Respiratory Pattern Terminology
WORD DEFINITION
Eupnea Good breathing: conti nuous i nspi ratory and expi ratory movement
without i nterrupti on
Apnea No breathi ng: cessation of venti latory effort at passive end-
Initi al descri pti ons of brai nstem respi ratory functions are based on classi c ablati on and electri cal
stimul ati on studi es. Another method for local i zi ng respi ratory centers entai ls recording acti on
potential s from different areas of the brainstem wi th mi croelectrodes. Thi s method is based on the
assumpti on that l ocal brai n acti vi ty that occurs in phase wi th respi ratory activity is evi dence that
the area under study has respiratory neurons.
22
These techni ques are i mperfect for preci sel y
local izing di screte respi ratory centers.
Medul l ar y Cent er s
The medull a oblongata contai ns the most basi c venti l atory control centers in the brai n. Specific
medul l ary areas are acti ve primari ly duri ng inspirati on or duri ng expi rati on, with many neural
inspi ratory or expi ratory interconnecti ons. The inspi ratory centers that resi de i n the dorsal
respiratory group (DRG) are l ocated i n the dorsal medul lary reti cul ar formati on. The DRG is the
source of el ementary venti l atory rhythmi city
23, 24
and serves as the pacemaker for the
respiratory system.
25
Whereas resting l ung volume occurs at end expi rati on, the electri cal activity
of the venti latory centers i s at rest at end inspirati on. The rhythmi c acti vi ty of the DRG persi sts
even when al l incoming

peri pheral and i nterconnecti ng nerves are secti oned or bl ocked completel y. Isol ati ng the DRG in
this manner resul ts in ataxi c, gaspi ng venti l ati on wi th frequent maxi mum i nspi ratory efforts:
apneusti c breathi ng.
The ventral respi ratory group (VRG), whi ch i s l ocated i n the ventral medul lary reti cular formati on,
serves as the expiratory coordi nati ng center. The inspi ratory and expi ratory neurons functi on by a
system of reci procal i nnervati on, or negati ve feedback.
22
When the DRG creates an i mpul se to
inspi re, inspirati on occurs and the DRG impul se is quenched by a reci procating VRG i mpul se. Thi s
VRG transmissi on prohi bi ts further use of the inspiratory muscl es, thus all owing passi ve expi rati on
to occur.
P ont i ne Cent er s
The pontine centers process i nformati on that ori ginates i n the medul l a. The apneusti c center i s
located in the mi ddl e or lower pons. With activati on, thi s center sends i mpul ses to i nspi ratory DRG
neurons and i s desi gned to sustai n i nspi ration. El ectri cal stimul ati on results i n i nspi ratory
spasm.
26
The middl e and l ower pons contain speci fi c areas for phase-spanning neurons.
27
These
neurons assist wi th the transi tion between i nspirati on and expirati on, and do not exert di rect
control over ventil atory muscl es.
The pneumotaxi c respi ratory center i s i n the rostral pons. A si mpl e transecti on through the
expi rati on (l ung vol ume = FRC)
Apneusi s Cessation of ventilatory effort wi th l ungs fi l led at TLC
Apneustic
venti l ati on
Apneusi s wi th peri odic expi ratory spasms
Biot Ventil atory gasps i nterposed between peri ods of venti lation apnea;
al so agonal venti lation
FRC, fucnti onal resi dual capacity; TLC, total l ung capacity.
P.796
brainstem that i sol ates thi s porti on of the pons from the upper brai nstem reduces ventil atory rate
and increases tidal vol ume. If both vagus nerves are addi ti onal l y transected, apneusis resul ts.
28

Thus, the pri mary functi on of the pneumotaxi c center i s to l i mi t the depth of i nspirati on. When
maxi mal l y acti vated, the pneumotaxi c center secondari l y i ncreases venti latory frequency. The
pneumotaxic center performs no pacemaki ng function and has no i ntrinsi c rhythmici ty.
Hi gher Respi r at or y Cent er s
Many hi gher brai n structures cl early affect ventil atory control processes. In the midbrai n,
stimul ati on of the reticul ar acti vating system increases the rate and ampli tude of venti l ati on.
29

The cerebral cortex also affects breathi ng pattern, al though

precise neural pathways are not known. Occasi onal l y, the ventil atory control process becomes
subservi ent to other regulatory centers. For example, the respiratory system plays an important
role in the control of body temperature because i t suppli es a large surface area for heat exchange.
Thi s is especi all y i mportant i n animal s i n whi ch panti ng i s a pri mary means of di ssi pati ng heat.
Then, venti latory pattern i s infl uenced by neural i nput from descending pathways from the
anteri or and posteri or hypothalamus to the pneumotaxic center of the upper pons.
Vasomotor control and certai n respi ratory responses are closel y li nked. Stimul ati on of the carotid
si nus not only decreases vasomotor tone, but al so inhi bits venti l ati on. Al ternati vel y, sti mulati on of
the caroti d body chemoreceptors (see Chemical Control of Venti l ati on section) resul ts i n an
increase i n both ventil atory acti vi ty and vasomotor tone.
Ref l ex Cont r ol of Vent i l at i on
Refl exes that directl y i nfluence venti l atory pattern usuall y do so to prevent airway obstruction.
Deglutition, or swal l owing, i nvol ves the gl ossopharyngeal and vagus nerves. Sti mul ati on of the
anteri or and posteri or pharyngeal pi l l ars of the posteri or pharynx i nduces swal l owing. Duri ng
swal lowi ng, inspirati on ceases momentari ly, i s usual ly foll owed by a si ngl e l arge breath, and
bri efl y i ncreases ventil ati on.
Vomi ting si gnifi cantly modifies normal venti latory acti vi ty.
30
Swal l owi ng, sal i vati on,
gastrointesti nal refl exes, rhythmi c spasmodi c ventil atory movements, and si gnifi cant
di aphragmati c and abdomi nal muscul ar acti vi ty must be coordi nated over a very bri ef i nterval .
Because of the obvi ous risk of aspi rati ng gastri c contents, i t is advantageous to inhi bi t inspi ration
duri ng vomi ti ng. Input i nto the respi ratory centers occurs from both crani al and spi nal cord
nerves.
Coughi ng resul ts from sti mul ati on of the tracheal subepi theli um, especi all y al ong the posterior
tracheal wall and carina.
31
Coughi ng al so requi res coordi nati on of both ai rway and ventil atory
muscle acti vi ty. An effective cough requi res deep inspirati on and then forced exhal ati on agai nst a
momentari ly closed glotti s to increase i ntrathoracic pressure, thus al l owing an expul si ve
expiratory maneuver.
Propri oception in the pulmonary system, the qual itati ve knowl edge of the gas vol ume wi thi n the
lungs, probably arises from smooth muscle spindl e receptors. These propri oceptors, which are
located wi thin the smooth muscl e of all ai rways, are sensi tive to pressure changes. Ai rway stretch
refl exes can be demonstrated duri ng distention of isolated ai rways so ai rway pressure, rather than
vol ume di stenti on, appears to be the pri mary sti mul ati on.
32
Cl ini cal condi tions i n whi ch pul monary
ai rway stretch receptors are stimul ated i ncl ude pul monary edema and atel ectasi s.
Gol gi tendon organs (tendon spindles), which occur in seri es arrangements wi thin venti l atory
muscles, faci li tate propri oception. The i ntercostal muscl es are ri ch i n tendon spindles, whereas the
di aphragm has a l imited number. Thus, the pulmonary stretch refl ex primari ly involves the
intercostal muscl es but not the di aphragm. When the lungs are ful l and the chest wall i s stretched,
these receptors send signals to the brai nstem that i nhi bit further i nspi rati on.
In 1868, Heri ng and Breuer reported that l ightl y anesthetized, spontaneously breathi ng ani mal s
P.797
woul d cease or decrease ventil atory effort during sustai ned l ung di stenti on.
33
Thi s response was
bl ocked by bi l ateral vagotomy. The HeringBreuer refl ex is promi nent in l ower-order mammals and
is suffici ently acti ve i n l ower mammals that even 5 cm H
2
O CPAP wi l l i nduce apnea. In humans,
however, the reflex is onl y weakl y present, as evi denced by the fact that humans wi l l conti nue to
breathe spontaneously wi th CPAP in excess of 40 cm H
2
O.
Chemi cal Cont r ol of Vent i l at i on
Peripheral Chemoreceptors
In a si mpl i sti c vi ew of chemi cal venti l atory control , the peri pheral chemoreceptors pri maril y
respond to l ack of oxygen, and the central nervous system (CNS) receptors pri maril y respond to
changes i n PCO
2
, pH, and aci d-base di sturbances.
The peri pheral chemoreceptors are composed of the caroti d and aorti c bodi es. The carotid
bodi es, l ocated at the bifurcati on of the common caroti d artery, have predomi nantl y
ventil atory effects. The aortic bodi es, which are scattered about the aortic arch and i ts branches,
have predomi nantl y ci rcul atory effects. The neural output from the carotid body reaches the
central respi ratory centers via the afferent gl ossopharyngeal nerves. Output from the aorti c bodies
travel s to the medul l ary centers vi a the vagus nerve. Both carotid and aorti c bodi es are sti mul ated
by decreased PaO
2
, but not by decreased SaO
2
or CaO
2
. When PaO
2
fall s to l ess than 100 mm Hg,
neural acti vi ty from these receptors begi ns to increase. However, it i s not unti l the PaO
2
reaches
60 to 65 mm Hg that neural acti vi ty i ncreases suffici ently to substanti al l y augment mi nute
ventil ati on. Thus, patients who depend on hypoxi c venti l atory dri ve have PaO
2
values in the mid-
60s. Once these pati ents' PaO
2
values exceed 60 to 65 mm Hg, ventilatory drive di mi ni shes and
PaO
2
fall s unti l venti l ati on i s again sti mul ated by arteri al hypoxemi a. When we wi thdraw
mechani cal venti l ation from the pati ent who depends on hypoxic ventil atory dri ve, the PaO
2
must
fal l to l ess than 65 mm Hg so the pati ent wi l l regai n hypoxic ventil atory dri ve.
The caroti d bodi es are al so sensi ti ve to decreased pH
a
, but thi s response is minor. Si mi l arl y,
changes i n PaCO
2
do not sti mulate these receptors suffici ently to al ter mi nute venti lation.
Increases in blood temperature, hypoperfusion of the caroti d bodi es themselves, and some
chemi cal s wil l sti mul ate these receptors. Sympatheti c gangl ion sti mulation by ni cotine or
acetylchol ine wi l l sti mul ate the carotid and aorti c bodi es; thi s effect i s bl ocked by hexamethoni um.
Bl ockade of the cytochrome el ectron transport system by cyani de wi ll prevent oxi dati ve
metaboli sm and thus sti mul ate these receptors.
Ventil atory effects resul ti ng from sti mul ati on of these receptors cause i ncreased venti l atory rate
and ti dal vol ume. Hemodynami c changes resul ting from sti mulation of these receptors i ncl ude
bradycardia, hypertensi on, i ncreases in bronchiol ar tone, and i ncreases in adrenal secreti on. The

Clinical Anesthesia

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Clinical Anesthesia

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Editors: Barash, Paul G.; Cullen, Bruce F.; Stoelting, Robert K.

Title: Cl i ni cal Anest hesi a, 5t h Edi t i on

35 mmHg), descri bes an i ncrease in minute

45 mmHg), occurs because of a decrease i n mi nute al veolar venti lation (

desi gnates normal: (a)

20 mEq/L and enhanced water

2.0 mEq/L, paral ysi s, or electrocardiographi c [ECG]

40% sequence identi ty and are denoted by an Arabi c numeral

Thi opental 36 <30 510 + 0+

= response aboli shed.

100 mmHg, PaCO

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